Micah Skeens

Congenital amegakaryocytic thrombocytopenia: The diagnostic importance of combining pathology with molecular genetics

Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare bone marrow failure syndrome that presents with isolated thrombocytopenia within the first year of life. Classic diagnostic bone marrow findings reveal absent or significantly decreased megakaryocytes with otherwise normal marrow cellularity. We present a newborn with thrombocytopenia whose initial bone marrow aspirate showed an appropriate number of megakaryocytes. CAMT was subsequently diagnosed after molecular testing demonstrated a mutation in the thrombopoietin receptor. The presence of a normal number of megakaryocytes on an initial bone marrow aspirate should not exclude CAMT from the differential diagnosis of thrombocytopenia within the first year of life. Pediatr Blood Cancer 2008;50:1263–1265.

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. a joint pediatric blood and marrow transplant consortium and children's oncology group study (ASCT0521)

Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.

Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation.

Anti‐seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non‐induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT. Pediatr Blood Cancer 2012;59:762–764.

Metabolic syndrome and endocrine dysfunctions after HSCT in children

MS and endocrine dysfunction(s) are common well‐recognized complications after HSCT. We retrospectively analyzed our data on 160 patients with a median age at transplant of five yr (0.3–23), who had been followed for a median of seven yr (range 3–18) at Nationwide Childrens Hospital after transplant. Dyslipidemia and MS were seen in 13% and 7.5% patients, respectively, and 58% of these patients were <20 yr of age. Twelve patients met the criteria for diagnosis of MS, but four of these did not meet the International Diabetic Federation or WHO criteria. Variation in the diagnostic criteria for MS leading to underdiagnosis is discussed. Female gonadal failure (27%) and hypothyroidism (21%) were the most common endocrine dysfunctions, followed by short stature and GH deficiency (17%) each. TBI and younger age at HSCT were associated with the highest burden of long‐term effects, and female sex was more significantly associated with MS‐related dysfunction (p < 0.05). Uniform diagnostic criteria for MS and close follow‐up after transplant are important for the early diagnosis and management of these late effects, thereby improving the overall quality of life of these patients.

High Variability in the Reported Management of Hepatic Veno-Occlusive Disease in Children after Hematopoietic Stem Cell Transplantation

Veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Patients with VOD are often critically ill and require close collaboration between transplant physicians and intensivists. We surveyed members of a consortium of pediatric intensive care unit (PICU) and transplant physicians to assess variability in the self-reported approach to the diagnosis and management of VOD. An internet-based self-administered survey was sent to pediatric HSCT and PICU providers from September 2014 to February 2015. The survey contained questions relating to the diagnosis and treatment of VOD. The response rate was 41% of 382 providers surveyed. We found significant variability in the diagnostic and management approaches to VOD in children. Even though ultrasound is not part of the diagnostic criteria, providers reported using reversal of portal venous flow seen on abdominal ultrasound in addition to Seattle criteria (70%) or Baltimore criteria to make the diagnosis of VOD. Almost 40% of respondents did not diagnose VOD in anicteric patients (bilirubin < 2 mg/dL). Most providers (75%) initiated treatment with defibrotide at the time of diagnosis, but 14%, 7%, and 6% of the providers waited for reversal of portal venous flow, renal dysfunction, or pulmonary dysfunction, respectively, to develop before initiating therapy. Only 50% of the providers restricted fluids to 75% of the daily maintenance, whereas 21% did not restrict fluids at all. Albumin with diuretics was used by 95% of respondents. Platelets counts were maintained at 20,000 to 50,000/mm(3) and 10,000 to 20,000/mm(3) by 64% and 20% of the respondents, respectively. Paracentesis was generally initiated in the setting of oliguria or hypoxia, and nearly 50% of the providers used continuous drainage to gravity, whereas the remainder used an intermittent drainage approach. Nearly 73% of the transplant providers used VOD prophylaxis, whereas the remainder did not use any medications for VOD prophylaxis. There was also considerable variation in the management strategies among the transplant and critical care providers. We conclude that there is considerable self-reported variability in the diagnosis and management of VOD in children. The practice variations reported in this study should encourage the development of standard practice guidelines, which will be helpful in improving the outcome of this potentially fatal complication.

Educating Families of Children Newly Diagnosed With Cancer Insights of a Delphi Panel of Expert Clinicians From the Children’s Oncology Group

Parents/caregivers require specialized education in order to care for their child with a newly diagnosed cancer. Currently, no evidence-based guidelines exist to identify content essential for inclusion in patient/family education prior to a child’s initial discharge home; this study used Delphi methodology to obtain multidisciplinary consensus regarding essential content amongst pediatric oncology experts from the Children’s Oncology Group. Three questionnaire rounds were employed to identify essential content, evaluate the importance of the educational topics identified, and gain expert consensus regarding the final ranking of topics identified and whether or not each topic was considered mandatory for inclusion in education for newly diagnosed patients. Disease-specific topics were also identified for patients with leukemia, solid tumors, and central nervous system tumors. The results of this study provide, for the first time, multidisciplinary expert consensus regarding key content essential for inclusion in discharge education for newly diagnosed pediatric oncology patients.

Disseminated Rhizomucor pusillus causing early multiorgan failure during hematopoietic stem cell transplantation for severe aplastic anemia.

Matched sibling donor hematopoietic stem cell transplantation is the standard of care for severe aplastic anemia, with an overall survival of 80% to 90%. Only 60% to 70% of patients respond to treatment with immunosuppressive therapy. The main life threatening complications are infections, graft failure, and graft versus host disease. A 10-year-old patient with severe aplastic anemia underwent matched sibling donor hematopoietic stem cell transplantation, but developed sudden onset of fatal multiorgan failure on day +12. The cause of death was found only after autopsy.

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan‐cyclophosphamide‐melphalan (Bu‐Cy‐Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less‐toxic myeloablative conditioning regimen containing busulfan‐fludarabine (Bu‐Flu) would be associated with equivalent outcomes.

Impact on Care of the Bone Marrow Transplant Patient With the Utilization of Twenty-Four Hour Coverage by Nurse Practitioners: 21

PBMTC Fall Conference September 19–21, 2005 01. Umbilical Cord Blood Transplantation From Related and Unrelated Donors in Children Patients A. Ghavamzadeh, K. Alimoghaddam, A.A. Hedayatiasl, A. Mousavi, M. Iravani, B. Bahar, M. Jahani, M. Faranoush, A.R. Shamshiri. HematologyOncology and Bone Marrow Transplantation Research Center Tehran University of Medical Science. Introduction: Cordblood banks have increased the use of cord blood transplantation (CBT) in patients with hematologic, non-hematologic and malignant disorders. Cord blood transplantation may lower the risk of graftversus –host disease (GVHD). Patients & Methods: Ten patients (Pts) with Thalassemia (7), AML (1), Hurler’s (1), SCID (1) received cord blood transplantation from their HLAidentical siblings and unrelated donors. Age range was 8mo-14 yrs (M/F = 8/2, median age 5.5 years). Eight Pts received cord blood stem cell from siblings and 2 Pts received from unrelated donors. There were no mismatches in (6) and there were mismatches of one HLA antigen in (2) and two HLA antigens in (2) Pts (unrelated donors). Conditioning regimens consisted Cyclophosphamide, Busulfan (+ATG for unrelated donors). GVHD prophylaxis regimen was Cyclosporine A6 Methotrexate(MTX). Results: Five Pts engrafted (one patient received MTX in GVHD prophylaxis and 4 Pts no received MTX). Five Pts had graft failure (all of them received MTX in GVHD prophylaxis). The median volume collected was 69 mL (range 25–110), the median number of WBC was 2.913 10 (range 0.93 10– 10.623 10), MNC was 2.083 10 (0.453 10–5.843 10) and CD34 was 1.763 10 (range 0.093 10–9.53 10). The median number of days required for neutrophil count .0.53 10/L was 21 (range 14–48) and platelet count of .203 10/L was noticed on day 60 (range 26–70). Two patients which transplanted with unrelated CB had aGVHD grade III and one patient which transplanted with related CB had aGVHD grade I and no cGVHD. Conclusion: Cord blood is a feasible alternative source of HSCT for Pts with hematologic disorders. Recipients of cord blood transplant from HLAidentical siblings have a lower incidence of acute and chronic GVHD than recipients of bone marrow transplants from HLA-identical siblings. Use of MTX for GVHD prophylaxis may associate with a greater risk of graft failure. 02. Allogeneic Blood and Marrow Transplantation in Fanconi Anemia With Fludarabine Based Conditioning Regimen A. Ghavamzadeh, M. Iravani, M. Jahani, K. Alimoghadam, A.A. Hedayatiasl, G.R. Bahoush, A. Mousavi, B. Bahar. Hematology-Oncology and Bone Marrow Transplantation Research Center Tehran University of Medical Sciences. Background: Fanconi anemia (FA) is an autosomal recessive disorder, usually characterized by several congenital malformations, progressive bone marrow failure and an increased incidence of malignancies. Cells from FA patients are hypersensitive to DNA crosslinking agents, which are used as a diagnostic tool. Methods: Because 2002, six patients (Pts) with Fanconi Anemia received blood and marrow transplantation from their HLA-identical sibling. Age range was 6–18 yrs (M/F = 4/2, median age 10.5 years). 5 patients received peripheral blood stem cell and 1 patient received bone marrow transplantation. They received Fludarabine 30 mg/m/IV (from day -9 to -5), ATG 10 mg/kg/IV (from day -4 to -1) and Cyclophosphamide 10 mg/kg/IV (from day -4 to -3) in preparative regimen. GVHD prophylaxis regimen was Cyclosporine A+ Methotrexate. Results: Median time of absolute neutrophil count .0.5 3 10/L was +10 (Range 5–13 days) and platelet count of 203 10/L was noticed on day + 12 (Range 5–24 days). Engraftment was demonstrated by STR_PCR analysis. Two patients developed aGVHD (grade I = 1, grade II = 1). At present 5 out of 6 are alive and disease free. One patient died due to rejection and pneumonia. No patient developed cGVHD. Conclusions: Allogeneic blood and marrow transplantation with this regimen is a suitable treatment of Fanconi anemia. More assessment is needed for evaluating of this regimen. 03. Allogeneic Bone Marrow Transplantation Following Conditoning With Busulphan and Melphalan Jairam Sastry, MBBS, MD, MRCP, MRCPCH, Peter J. Shaw, MA, MBBS, MRCP, FRACP. The Children’s Hospital at Westmead Sydney, NSW, Australia. Introduction: The outcome of treatment of AML in children is improving steadily. Allogeneic BMT still provides the best control of AML, but limited by excess mortality, related mainly to the complications of the conditioning regimen, infection and GVHD. We report the outcome and toxicity of a BU/MEL combination conditioning in children undergoing allogeneic BMT for AML. Methods: 7 children who under went allogeneic BMT for AML following conditioning with BU/MEL. Retrospective analysis of case notes and unit databases was done to collect data. Results: Six of the seven patients showed WBC engraftment. The median time of recovery to WBC

Anicteric Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation in Children

1.0 3 10/L and absolute neutrophil count (ANC) to