Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome

BACKGROUND AND OBJECTIVESAllogeneic stem cell transplantation (SCT) offers the best chance of cure and long-term survival for children with myelodysplastic syndromes (MDS).DESIGN AND SETTINGRetrospective analysis of pediatric patients with primary MDS treated with allogeneic SCT at a single institution treated between January 1993 and December 2008.PATIENTS AND METHODSOf 16 consecutive children who received allogeneic SCT for treatment of MDS in our center, 14 patients met the criteria of MDS according WHO I and II criteria. The median age was 4.8years (range, 1-14 years) and 64% were male. The median time from diagnosis to transplant was 6 months. MDS stage was refractory cytopenia (RC) in 9, refractory anemia with excess blasts (RAEB) in 5. Monosomy 7 was present in 35% of the patients. The majority of patients (11/14) were conditioned with a busulfan-based myeloablative (MA) regimen with addition of low-dose of etoposide (30mg/kg). All but one received a bone marrow graft.RESULTSNine patients achieved complete remission (CR), and seven remain alive. At a median follow-up of 3 years (range, 2-14 years) the OS and EFS was 57% (95%CI, 0.28-0.78). Cumulative EFS at 1 0 years was 43% (95% CI: 0.14-0.70). Relapse-related mortality was 21.4%; nonrelapse mortality (NRM) was 28.57%. All the survivors had etoposide in their conditioning regimen. Patients younger than 1 0 years had better survival (P=.001).CONCLUSIONChildren with MDS achieve encouraging OS and EFS following allogeneic SCT. A busulfan-based regimen with a lower dose of etoposide is an effective and less toxic regimen. The outcomes are best in younger patients

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Does high dose cytosine arabinoside improves disease free survival for down syndrome acute myelocytic leukemia patients?

Acute myelocytic leukemia (AML) in Down Syndrome (DS) children is characterized by a young age of onset (\u3c 2 years), a low white blood cell count and high frequency of Megakaryocytic leukemia. DS children with AML have higher disease free survival (DFS) rates as compared to non DS AML patients. Previous studies have suggested that intensification chemotherapy may not be necessary for the treatment of DS children with AML. The objective of this study was to clarify the effectiveness and toxicities of using high dose Cytosine Arabinoside (HD AraC) intensification in the treatment of DS AML. Clinical data for children (\u3c14 years) with DS AML, diagnosed between September 2000 to May 2005, were retrieved from the hospital data base. Patients were divided into two groups; Group A patients received chemotherapy containing HD AraC, while Group B patients did not. A total of 15 patients were included, eight in Group A and seven in group B. The median age at diagnosis was 22 months (A=23 months, B=22 months). The two groups were matched regarding their clinical and laboratory parameters. There was no significant difference in DFS between groups A and B, 75% and 85% respectively (P = 0.82) at a mean observation period of 42.9 months for group A and 23.12 months for group B. The median time to relapse was 6 months for group A and 8 months for group B. The overall treatment related toxicity was higher in Group A patients but achieved only borderline significance (P = 0.06). However, when toxicity was assessed separately for induction and post induction phases of chemotherapy there were significantly more infectious events (17 v. 2; p=0.0006) in the post induction phase which includes HD AraC intensification in Group A. Even when only serious infections (bacteremia, fungal infection, sepsis) were included in the evaluation this difference persisted (7 v. 1; p=0.0339), with less toxicity for Group B patients. No such difference was noted between the two groups during induction chemotherapy. In conclusion the use of HD AraC in post-induction intensification phases for DS AML children does not improve DFS and is associated with more treatment related toxicity

Analysis of the CBFB, CBFA2 and AF-9 genes in familial acute myelogenous leukemia

The cloning of chromosomal translocation breakpoints from sporadic leukemias has identified genes that are implicated in the pathogenesis of acute myelogenous leukemia (AML). Although common, such chromosomal translocations are not necessary for the development of leukemias, suggesting that other underlying genetic factors are involved in the early stages of leukemia development. Familial AML is extremely rare, and families with the disease provide a unique resource for the study of the genes involved in the initial stages of cancer development. We investigate a single family in which several members have developed AML. Three members (a mother and two offspring) are affected with AML M4eo, and a third offspring is affected with AML M2. The average age of onset in the children (7 years) is significantly lower than that for the mother (30 years). Transmission of the disease seems to be in an autosomal-dominant manner. The small size of the pedigree reduces the power of genome-wide linkage analysis and therefore we used a candidate gene approach. Initially three genes were selected for analysis based on their reported involvement in familial and sporadic AML: CBFA2, CBFB and AF9. We performed genotyping at these loci to identify shared haplotypes between affected individuals. We will also report the results of direct mutation analysis of the candidate genes

PB005 Treatment of DS-AML without HDARAC does not impact on disease outcome

Purpose: Disease related outcome for DS children with AML is higher than non-DS patients, but with more toxicity. Optimally intensive therapy for DS-AML needs to be determined.Method: We retrospectively reviewed the outcome of DS-AML at our institution between 2000 and 2009 treated on two different protocols; Group A utilized HDARAC post-induction and Group B was treated without HDARAC.Results: Twenty patients were treated; 10 patients in each group. There were 15 boys, and the median age was 27.7 months (mean 43.2+6.9; 8\u3c2 yrs, 9 2–4 years and3\u3e4 years). The clinical characteristics of patients in the two groups were similar (median age 29.5 v. 24.2 mo; mean WBC 27.5 v. 13.8 X 109/L; Hg 74.4 v. 80.1 g/L; plt54 v. 18 X109/L, p\u3e0.5 for all). Seven patients had M7 and 8 M2 subtype. Two had CSF positivity. Eight patients had congenital cardiac abnormalities and one dysplastic kidney. One patient in each Arm failed to achieve CR following 2 induction cycles, but both achieved CR following HDARAC. Six have relapsed (Group A¼3, GroupB¼3) at a median of 4.2 months from CR. 5-year OS is 80.4% and RFS is 67.7%. There was no difference in OS or RFS between the two groups (OS 78.8% v. 80%, p=0.7; RFS 70% v. 62.2%, p=0.9). No difference was found for induction-phase toxicity, however there was significantly more infectious toxicity with Group A postinduction (9 v. 3 patients, p=0.02). Specifically, 13 v. 1 episode of F/N (p=0.001), 4v. 0 invasive fungal infections (p=0.082), 3 v. 1 non-BS bacterial infections(p=0.12) and 4 v. 2 BS bacterial infections (p=0.6). Three patients in Group B developed subclinical reduction in cardiac function.Conclusion: Treatment of DS-AML is feasible without HD-ARAC for most DS-AML patients. HDARAC is associated with increase infectious toxicity without improving disease free survival

Wilms tumor: Successes and challenges in management outside of cooperative clinical trials

Objective/background: Management of Wilms tumor (WT) in children depends on a multidisciplinary approach to treatment, and outcomes have significantly improved as reported by cooperative group clinical trials. Here, we review the clinical outcomes of patients with WT and identify challenges and barriers encountered in multidisciplinary management outside of cooperative clinical trials. Methods: We retrospectively reviewed the clinical records of 35 children with WT treated between April 2002 and June 2013 at the Children’s Cancer Institute in Lebanon. Results: Upfront resection was performed in 23 cases. Biopsies were performed for Stage V tumors (n = 4), those with unresectable tumors or inferior vena caval thrombus (n = 5), and patients who had partial surgery performed elsewhere prior to presentation (n = 2). One patient died due to toxicity prior to surgery. The tumor was Stage I in eight patients, Stage II in five patients, Stages III and IV in nine patients each, and bilateral (Stage V) in four patients. Adherence to The National Wilms Tumor Study-5 recommendations was adequate. At the time of analysis, 30 patients were free of disease and four patients had relapse—all having metastatic disease initially. Conclusion: The National Wilms Tumor Study-5 therapy resulted in favorable outcomes in children with nonmetastatic Wilms tumor in the setting of a multidisciplinary approach to therapy and resolution of financial barriers to medical care. Upstaging due to prior intervention and lung radiation therapy to all those with computed tomography-detected lung nodules may both have resulted in overtreatment of a subset of patients. Finally, the relatively high incidence of bilateral tumors suggests the need for further genetic and molecular studies in this patient population. Keywords: Pediatric cancer, Wilms tumor, Nephroblastom

Improved outcome for children with acute lymphoblastic leukemia after risk-adjusted intensive therapy: A single-institution experience

Background and objective: Because of the need for more comprehensive information on the least toxic and most effective forms of therapy for children with acute lymphoblastic leukemia (ALL), we reviewed our experience in the treatment of children with ALL at King Faisal Specialist Hospital and Research Centre (KFSH&RC) and King Fahad National Center for Children\u27s Cancer and Research (KFNCCC&R) over a period of 18 years with a focus on patient characteristics and outcome.Methods: During the period of 1981 to 1998, records of children with ALL were retrospectively reviewed with respect to clinical presentation, laboratory findings, risk factors, stratification, therapy and outcome. The protocols used in treatment included 4 local protocols (KFSH 81, 84, 87 and 90), and subsequently, Children\u27s Cancer Group (CCG) protocols, and these were grouped as Era 1 (1981-1992) and Era 2 (1993-1998).Results: Of 509 children with ALL treated during this period, 316 were treated using local protocols and 193 using CCG protocols. Drugs used in Era 1 included a 4-drug induction using etoposid (VP-16) instead of L-asparaginase. Consolidation was based on high dose methotrexate (MTX) 1 g/m(2) and maintenance was based on oral mercaptopurine (6-MP) and MTX with periodic pulses using intravenous teniposide (VM-26), Ara-C, L-asparaginase, adriamycin, prednisone, VP-16 and cyclophosphamide. International protocols were introduced in Era 2, which was also marked by intensification of early treatment, a wider selection of cytoreductive agents, and the alternating use of non-cross-resistant pairs of drugs during the post-remission period. The end-of-induction remission rate improved from 90% in Era 1 to 95% in Era 2, which was of borderline statistical significance (P=.049). The 5-year event-free survival (EFS) improved from 30.6% in Era 1 to 64.2% in Era 2 (P\u3c.001). Improvement in outcome was achieved without any significant increase in morbidity or mortality, due to improvement in both systemic therapy and supportive care. The most important independent prognostic factors were intensity of therapy, poor risk category assignment and CNS disease at diagnosis.Conclusion: Outcome in children with ALL has improved because of intensification of treatment protocols and better supportive care

Invasive chaetomium infection in two immunocompromised pediatric patients

The majority of fungal infections are caused by species such as Candida and Aspergillus. Other rare and emerging opportunistic fungal infections are on the increase. Risk factors for such infections include receipt of antimicrobial agents, chemotherapy, immunosuppression secondary to hematopoietic stem cell or solid organ transplantation, neutropenia, presence of indwelling intravascular catheter, prior hemodialysis, or previous fungal colonization. We present here the first 2 reports of fatal and invasive Chaetomium infections in pediatric patients. The first case occurred in a child with acute myeloid leukemia (AML) and the other in a child with hemophagocytic syndrome (HSP)

225: The addition of etoposide to Bu16/Cy200 in the conditioning of children with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (SCT) is associated with improved survival

Relapse remains the major concern for children with AML undergoing SCT, and we have previously shown that intensifying the conditioning by adding etoposide at 60 mg/kg and consequently reducing the busulfan (Bu) dose to 12 mg/kg and the cytoxan (Cy) to 90 mg/kg did not result in any significant improvement of the survival; we suggested then that the reduction of Bu/Cy doses necessitated by addition of the high dose of etoposide could have affected the outcome and we hypothesized that adding a lower dose of etoposide and keeping the Bu/Cy at the conventional doses may offer better survival to AML patients undergoing allogeneic SCT. We present here our results using such a protocol. Patients and Methods: From March 2003 until December 2006, 33 patients with AML (24 in CR1, 8 in CR 2) underwent allogeneic SCT and were conditioned with Bu 16 mg/kg po, Cy 200 mg/kg iv plus etoposide 900 mg/m2 iv, median age was 9.6 years. This cohort of patients (group B) was compared with 18 AML patients (17 in CR 1, 1 in CR 2) who underwent SCT from July 93 thru February 96, median age at SCT was 7.25 years, patients were conditioned with only Bu 16 mg/kg po and Cy 200 mg/kg iv (group A). Results: Median days to ANC ≥ 500 × 106/l was 21 days and 15 days in groups A and B respectively, median days to platelet count ≥ 20 × 109/l was 22 days and 26 days in groups A and B respectively (P= NS). The incidence of complications was similar, acute GVHD grade 2 or higher developed in 5% and 9% in groups A and B respectively (P= NS), hemorrhagic cystitis developed in 11% and 15% in groups A and B respectively, no VOD developed in either group. The 4 year overall survival for groups A and B respectively was 50% and 68.2% (P = 0.3) and the 4 year event-free survival for groups A and B respectively was 33% and 68.2% (P = 0.1). Conclusions: The addition of etoposide to Bu16/Cy200 was not associated with increased toxicity, and although it did not reach statistical significance, it does appear to be associated with a better overall and event-free survival. Larger scale studies are advised to further corroborate our findings