Three unrelated children from ethnically diverse backgrounds who were treated for acute leukaemia became profoundly and irreversibly deaf during treatment. Aminoglycoside levels were within the therapeutic range. Genetic testing showed all three to have a maternally inherited mutation of mitochondrial DNA, m.1555A>G, known to cause sensitivity to the ototoxic effects of aminoglycosides. One child has received a cochlear implant, and another will be implanted shortly. Children diagnosed with acute leukaemia should be tested for this mutation at diagnosis, and alternative antibiotics chosen for the treatment of sepsis. Consideration should be given to elective testing of other groups of patients likely to receive aminoglycosides.

This chapter contains sections titled: Introduction Acute myeloid leukemia Acute promyelocytic leukemia (APL) [16–19] Myelodysplastic syndromes Down's syndrome and myeloid malignancy Strategy for follow - up and important late effects Summary and future directions for management References

Introduction Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of immune dysregulation that may be inherited or acquired. Causative genetic mutations are seen in around 50% of cases of primary HLH. Secondary HLH may be triggered by infections (most commonly viral), or by other conditions including malignancies and rheumatological disorders. Diagnostic criteria include prolonged high fever, hepatosplenomegaly, cytopenias and characteristic biochemical markers including elevated triglycerides, ferritin and low fibrinogen. Haematopoieitic cell transplantation (HCT) is the only curative treatment for primary HLH. The authors present their experience of HCT for HLH in a single centre over a 14 year period. Materials and Methods A retrospective case-note review was performed for all patients who fulfilled the diagnostic criteria for HLH, between 1994 and 2008. Data were collected for patients who had undergone HCT, or had died prior to HCT. Results 67 patients fulfilled criteria for HLH. Sixteen of 67 (24%) died prior to HCT. Fifty patients proceeded to HCT, of whom 35 (70%) remain alive and in remission. The mean time from diagnosis to HCT was 7 months. The median age at diagnosis was 0.35 years (range 0.1–9.8), 32/50 were male. Twelve received haploidentical grafts, 14 matched family donor, 11 matched unrelated donor, 11 mis-matched unrelated donor and 2 mis-matched family donor grafts. Twenty-three had myeloablative, 25 reduced intensity and 2 minimal intensity conditioning. After 1999 all patients having HCT for HLH underwent reduced intensity HCT. 15/50 (30%) patients died post-HCT. Causes of death were: pneumonitis (3), veno-occlusive disease (2), infections (3), cardiac failure (1), bleeding (1), seizure (1), EBV-related lymphoproliferative disease (1), drug toxicity (1), secondary AML and disease recurrence (1). Overall 9/21 (43%) patients are surviving from the cohort diagnosed prior to 2000, and 31/46 (67%) post 2000. Conclusion Outcome for HLH has improved with time reflecting earlier diagnosis and disease control, and the use of reduced intensity HCT with HLA matched donors. However, significant mortality from disease and from HCT related complications still remains and further progress is required.

Reduced intensity conditioning (RIC) enables SCT in children with pre-existing organ toxicity. However, there are concerns about mixed chimerism(MC) in the long term that is sometimes not sufficient for cure. In a cohort of 148 patients undergoing RIC SCT (Fludarabine 150 mg/m2, Melphalan 140 mg/m2, Campath 1H 0.6-1 mg/kg) we compared chimerism between those who received BM (n=109) Vs PBSC (n=41). Median age at transplant was 3.6 years and median follow-up was 4.7 years.The majority were transplanted for primary immunodeficiency disorders (n=120) and donors were MUD (n=67), mMUD (n=45), MSD (n=17), MFD (n=14) and mMFD (n=8). Survival was equivalent, 70% for BM and 75% for PBSC. Incidence of aGVHD≥ grade 2 was higher with PBSC (40% vs 20% for BM) but the incidence of chronic GVHD was low (10%). Chimerism studies were done using STR at 1, 3, 6, 9 and 12 months post transplant and 3 monthly thereafter. All but one child engrafted but 4 children had early autologous reconstitution. At 1 year post SCT 65%, 9%, 9% and 7% had complete donor chimerism (CC), high MC (50-95% donor chimerism), low MC (10-49% donor chimerism) and very low MC (<10% donor chimerism) respectively and these were stable at last follow-up. All children with CC and high MC are cured of their disease. 26 children (17%) had low or very low MC. The incidence of low and very low MC was significantly higher with BM (24/109,22%) than with PBSC (2/41,5%).Children with low and very low level MC had a poorer prognosis: 5/26 needed a second transplant, 3/26 died, 2 had DLI, 1 CD34 top-up, 1 has ongoing poor immune reconstitution. In conclusion, use of PBSC leads to good long term chimerism with acceptable GVHD and we advocate that PBSC should be the stem cell source of choice in RIC SCT in children.

Allogeneic stem cell transplant is curative for haemophagocytic lymphohistiocytosis (HLH) and refractory Langerhans cell histiocytosis (LCH). However, patients frequently have significant pre-transplant morbidity and there is high TRM. Because HLH is caused by immune dysregulation, we surmised that a reduced-intensity conditioned (RIC) regimen might be sufficient for cure, while decreasing the TRM. In 2006, we reported the outcome of 12 patients treated with RIC SCT from a matched family/unrelated or haploidentical donor. Here we discuss the update of these patients, including a total of 25 patients treated with RIC SCT for HLH and three for LCH. Twenty-one of the twenty-five patients with HLH (84%) are alive and well with remission at a median of 36 months from SCT. Mortality included pneumonitis (n=3) and hepatic rupture (n=1). All three patients treated with RIC SCT for LCH remain alive and in remission at a median of 5.1 years from SCT. Seven of twenty-four survivors (one with LCH) have mixed chimerism but remain disease-free. These data are supported by other groups including 100% survival in seven patients with HLH and 78% survival of nine patients with LCH. In summary, RIC compares favourably with conventional SCT with long-term disease control in surviving patients with both HLH and LCL, despite a significant incidence of mixed chimerism.

Correction to: Bone Marrow Transplantation (2008) 42, 253–257; doi:10.1038/bmt.2008.160 The author name S Bonanomi was published incorrectly in the above referenced paper. The correct author list is shown above.

Objectives: The role of allogeneic stem cell transplantation (SCT) in paediatric acute myeloid leukaemia (AML) remains controversial. SCT has generally been advocated for poor risk disease in first complete remission (CR), the majority of patients following relapse, and as a last resort in refractory disease. Methods: Twelve consecutive patients (median age 2.2 years) underwent SCT for high risk AML between 2000 and 2006. Patient and graft characteristics are shown in the table. Conditioning regimen consisted of busulphan (Bu) 16 mg/Kg, cyclophosphamide (Cy) 120 mg/Kg, melphalan (Mel) 140 mg/m2; alemtuzumab 1 mg/Kg was added in the unrelated donor setting. Immunotheraputic strategies were employed to maximise a graft-versus-leukaemia (GVL) response escalating through a reduced dose of alemtuzumab, early taper of cyclosporine A (CSA), donor lymphocyte infusion (DLI) and treatment with alpha-interferon (α-IFN). Results: All patients engrafted. Three out 5 patients undergoing matched unrelated donor SCT, who were not in remission, received a 50% reduced dose of alemtuzumab. In 8 children CSA was stopped early < 2 months (n = 4) and < 3 months (n = 4). Six of 12 patients developed acute graft versus host disease (aGVHD), 3 grade 2, 3 grade 1. Five patients have developed limited chronic GVHD (cGVHD). In one patient who developed recipient T-cell chimerism 2 months after SCT despite reduced dose alemtuzumab and early taper of CSA, a DLI of 106/Kg was administered followed by α-IFN. He developed grade 1 aGVHD and the donor T cell chimerism increased to 80% but he never achieved full donor haemopoiesis and relapsed 17 months after SCT. In another patient, who developed no GVHD despite cessation of CSA at day 32, α-IFN was administered: he developed grade 1 aGVHD evolving to limited cGVHD and remains in remission at 9 months. Ten of 12 (83%) patients are alive in CR at a median of 33 months (range 9–80) from SCT. There was no transplant related mortality, but two patients relapsed 3 and 17 months after SCT and subsequently died. Conclusion: This early promising data suggests that the combination of Bu Cy Mel should be studied further as a conditioning regimen in children with high risk AML. Given the substantial risk of relapse, and in the absence of GVHD, this approach should be used as a platform for escalating immunotherapeutic strategies with the endpoint of sustaining 100% donor chimerism or achieving non severe GVHD to maximize the potential for a GVL effect.Tabled 1PatientAge at SCTFAB typeAntecedentCytogeneticsDisease phaseDonor typeGVHD prophylaxis12.0M63q del, trisomy 21CR1MMUDalemtuzumab CSA MTX22.2M7complexCR1MUDalemtuzumab CSA MTX31.7M6complexresistant diseaseMUDalemtuzumab CSA MTX42.7M5normalpartial remission after relapseMMUDalemtuzumab CSA MTX51.6M5t(1;7)(q23;p22) t(7;9;11)CR2MMUDalemtuzumab CSA MTX62.1M0t(7;12)CR2MMUDalemtuzumab CSA MTX73.6M7normalpartial remission after relapseMSDCSA81.4M0normalpartial remission after relapseMUDalemtuzumab CSA MTX95.7secondary AMLmonosomy 7 trisomy 8CR1MMUDalemtuzumab CSA MTX102.4M7MDSmonosomy 7transformed to AMLMSDCSA MTX115.4M2MDSmonosomy 7transformed to AMLMUDalemtuzumab CSA MTX122.2M5JMMLdel 9qtransformed to AMLMUDalemtuzumab CSA MTX Open table in a new tab

Allogeneic stem cell transplantation (SCT) is curative for hemophagocytic lymphohistiocytosis (HLH). However, patients frequently have significant morbidity before transplantation and there is high transplant-related mortality (TRM). Because first-degree HLH is caused by immune dysregulation, a reduced-intensity conditioned (RIC) regimen might be sufficient for cure while decreasing the TRM. Twelve patients with HLH underwent RIC SCT from a matched family/unrelated or haploidentical donor. Eleven were conditioned with fludarabine/melphalan with additional busulphan for haploidentical grafts. One received fludarabine and 2-Gy total body irradiation (TBI). All patients showed engraftment at a median of 14 days. Nine of 12 (75%) are alive and in complete remission (CR) a median of 30 months (range, 9-73 months) after SCT. Two patients died from pneumonitis and one from hepatic rupture. Four patients developed acute graft-versus-host disease (GVHD) and 3 have chronic GVHD. Three of 9 survivors have mixed chimerism but remain free of disease. In summary, RIC compares favorably to conventional SCT with long-term disease control in surviving patients despite a significant incidence of mixed chimerism.

Between 1988 and 2002, 868 children (0–15 years) were entered into MRC AML 10 (1988–95, n=341) and AML 12 (1995–2002, n=527) trials. Children were allocated to one of three MRC risk groups: good risk - patients with t(8,21),inv(16),t(15,17) irrespective of bone marrow status after course 1 or the presence of other genetic abnormalities; standard risk - patients with neither favourable nor adverse cytogenetics and not more than 15% blasts in the bone marrow after course 1; poor risk - patients with more than 15% blasts in the bone marrow after course 1 or with adverse abnormalities of -5,-7, del(5q), abn(3q), complex (>/-5 abnormalities) and without favourable genetic abnormalities. Outcome from CR - death in CR (DCR), relapse risk (RR), disease-free survival (DFS) and survival from CR (OSCR) - was analysed by MRC risk group.

Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.

Monosomy 7 (−7) and deletion 7q [del(7q)] are rare in childhood AML and are considered to be associated with a poor outcome. We retrospectively analyzed data on 267 children with de novo AML or RAEB-T (PB or BM blasts > 20%) with −7 or del(7q) with or without additional cytogenetic aberrations (other). Patients were diagnosed between 1985 and 2003. Karyotypes showed −7 (n=90), −7 other (n=82), del(7q) (n=22), and del(7q) other (n=73). All 24 patients with RAEB-T had −7 +/− other. The median age at diagnosis was 7.6 years (range; 0–18.1) with no difference in age distribution between cytogenetic subgroups. The most common additional cytogenetic aberrations were inv(3)/t(3;3) in 19 patients (−7, n=17; del(7q), n=2) and favorable aberrations [t(8;21), inv(16), and t(15;17)] observed in 25 patients (−7, n=3; del(7q), n=22). The 5-year overall probability of survival for the whole group was 39%, SE=3%, and survival was higher in patients with del(7q) +/− other compared with −7 +/− other (52% vs. 30%). The survival of patients with del(7q) and favorable cytogenetic aberrations (n=22) was higher than that of other patients with del(7q) (75% vs. 46%, p=0.026). There was no significant difference in survival for patients with −7 and −7 other. Complete remission (CR) was obtained in 188 patients (−7 +/− other 62%; del(7q) +/− other 88%), of these, 67 received hematopoietic stem cell transplantation (HSCT) in CR1. There was no significant difference (Mantel-Byar test) in survival for patients who received HSCT in CR1 (49%, SE= 7%) and those who received chemotherapy only (51%, SE=5%, 54% for patients surviving at least the median time to HSCT). In conclusion childhood AML subgroups −7 and del(7q) differ in their associated cytogenetic aberrations and response to therapy.

Primary hemophagocytic lymphohistiocytosis (HLH) is a disease characterized by hypercytokinaemia and T cell dysregulation, due to mutations of the perforin, SAP and other so far uncharacterized genes. Patients may achieve a remission with immunomodulation consisting of epipodophyllin/steroids +/− cyclosporin A, but the only curative option is allogeneic stem cell transplant (SCT). Patients often have significant pre-transplant morbidity with lung, liver and central nervous system disease and are hence at high risk of transplant related morbidity and mortality. Because HLH is caused by immune dysregulation, we hypothesized that a non-myeloablative conditioning regime might be sufficient for cure, by restoring normal immune regulation, while decreasing the transplant related morbidity and mortality. We report the outcome of 11 children with HLH transplanted with a reduced intensity regime (RI) from an unrelated (fully matched, n=4, 1 antigen-mismatched, n=2) or haploidentical (n=5) donor. Of 7 patients assessed, 1 patient had absent SAP expression and 2 had a perforin gene mutation. 8 patients had significant morbidity of at least one other organ (including lung, cardiac, liver and CNS) pre-SCT. All had previously received HLH 94 protocol: 7/11 were in CR at the time of SCT and 4/11 in good PR. The median age at transplant was 16 months (range 3 –151 months). SCT was performed at a median of 7 months from diagnosis (3–14 months). Patients were conditioned with fludarabine 30mg/kg x 5 and melphalan 125 to 140mg/m2. Unrelated donor transplants received serotherapy with Campath 1H 0.2mg/kg x 5 and haplos received busulphan 4mg/kg x 2 and ATG 5mg/kg x 5. One unrelated donor recipient received TBI 2Gy single fraction with fludarabine. Results: All patients engrafted at a median of 13 days post SCT. 8 of 11 (73%) children are alive and in CR a median of 19 months from transplant (range 5 to 61 months). There were 3 transplant related mortalities (2 UD, 1 Haplo) between 3 and 4 months post-SCT from CMV pneumonitis (n=1), multifactorial pneumonitis following previous HLH lung disease (n=1), and hepatic rupture post- transjugular liver biopsy (n=1). 4 patients had CMV reactivation and 2 EBV reactivation. 3 patients developed acute GVHD (2 Grade 2 skin/gut, 1 Grade 1 gut/liver) and 1 had an engraftment syndrome with T-cell sequestration in the lungs. 3/8 evaluable patients have developed limited chronic skin GVHD 6– 15 months post-SCT. 3 patients had early and continuing mixed chimerism with 20%, 84% and 82% donor cells in the peripheral blood at 61, 52 and 24 months respectively from transplant. At a median follow-up of 19 months, no patient has relapsed, including the 3 patients with mixed chimerism. In summary, mixed chimerism appears curative for HLH and our results with SCT using reduced intensity conditioning compare favourably to those seen with conventional BMT, where a 3 year EFS of 62% has been reported in the HLH94 study. We believe this approach may be of major benefit in those patients with severe pre-SCT organ toxicity and merits further study in standard risk patients.

Companies often focus efforts to improve business efficiencies on internal systems and significant benefits can be achieved by so doing. However, the magnitude of the realised benefit is restricted if only processes within the organisation are targeted for improvement.This paper describes the implementation of a bespoke web-based supply chain management system / online collaboration system. The main drivers behind the development of the system were late deliveries from the supplier and also sporadic and inaccurate delivery schedule information from the supplier.The implementation approach is discussed along with the problems that were encountered en route and the measures that were undertaken to ensure that implementation was successful. The importance of metrics is stressed as these are essential if any improvements are to be quantified which in turn enables the justification of such projects in financial terms which is compounded by the 'soft' benefits that result from the use of such systems.

MRC AML10 and 12 Trials recruited 5425 patients of whom 4557(84%) entered CR and were treated with chemotherapy only. 741 relapsed and achieved a second CR. These patients were recommended for salvage by stem cell transplantation either sibling or MUD allograft or autograft. In a non-randomised comparison, Mantel-Byar and delayed entry proportional hazards regression were used to investigate outcome and which factors were predictive for survival. Of the 741 patients in CR2 480 received a SCT (116 sib Allo: 192 Autograft and 154 MUD 18 other/unknown) at a median of 107 days from second CR. The overall survival at 5 years was significantly better for those who received SCT (39% vs 22% p=0.00001). Of the 116 patients who received a sibling transplant 54% are alive at 5 years; of the 154 patients who received a MUD graft 40% are alive and of 192 who received an autograft 33% are alive and each transplant type was significantly better than chemotherapy alone (p=0.0001, p=0.002, p=0.002). Much of the benefit derives from reduced relapse risk (5yr RR: allograft 32%; autograft 59%; MUD 38%: no transplant 71% (0.0001). Only in MUD transplant was there a greater mortality (allograft 27%; autograft 27%, MUD 42%, no transplant 25% p=0.003). There was, however, no evidence of heterogeneity in the beneficial effects of transplant when analyses were stratified by age, duration of first remission, time taken to achieve second CR, or cytogenetics. Proportional hazards regression shows that duration of 1st CR, cytogenetics and age are important prognostic factors; adjustment for these factors to some extent changes the results of the analyses. After adjustment, there is still strong evidence of the benefits of allograft (p<0.0001), but the evidence for autograft (p=0.09) and MUD (p=0.02) becomes unclear. As a non-randomised comparison, these results cannot provide absolute evidence of benefit. After adjustment for other prognostic factors, the position for autograft and MUD transplants remains unclear especially as not all selection factors can be accounted for. However, the allograft results appear robust to adjustment and imply significant survival benefit for patients receiving allograft in 2nd CR.

We have reviewed the outcome after relapse in a cohort of 505 children with acute lymphoblastic leukaemia (ALL) seen at a single institution. The majority of relapses (74%) occurred within 3 years from diagnosis, and most involved the bone marrow alone or with overt extramedullary relapse. Early relapse was more common in children with T-ALL and those with unfavourable cytogenetics. Factors influencing second remission included length of first remission and type of relapse. Children who had not received previous cranial irradiation had a superior survival. The German relapse score involving length of first remission, site of relapse and immunophenotype was highly predictive of outcome: event-free survival with 95% confidence intervals at 6 years for patients who received modern treatment [intensive chemotherapy or bone marrow transplantation (BMT)] was 78% (51-92%) for standard risk, 41% (33-49%) for intermediate risk and 19% (10-31%) for highest risk. Retrospective comparison of BMT with chemotherapy showed no difference in the intermediate-risk group but a possible advantage in the highest risk group. Follow-up of 235 patients who relapsed after chemotherapy and received a third course of treatment showed an extremely high early attrition rate, but a small number of patients survived in third remission. We conclude that new approaches are needed to individualize therapy in intermediate-risk patients and to improve the outcome for those in the highest risk group. Only a small number of children can be treated effectively in third remission.