Successful second hematopoietic cell transplantation in severe congenital neutropenia.

Allogeneic HCT is curative for SCN; however, a standard conditioning regimen or intensity has not been established. We describe a patient with SCN associated with c.1A>G (M1V) mutation in ELANE gene resulting in refractoriness to G-CSF, who received reduced-intensity HCT and developed secondary graft failure requiring a second myeloablative HCT. This case suggests that M1V mutation confers a poor G-CSF response and HCT using the best available donor is beneficial.

TACL'ing supportive care needs in pediatric early phase clinical trials for acute leukemia: A report from the therapeutic advances in childhood leukemia & lymphoma (TACL) consortium supportive care committee.

A Supportive Care Committee was recently developed within the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium. This was substantiated by the significantly high rate of serious adverse events (SAE) (CTCAE Grade ≥3 toxicity) experienced by patients with relapse/refractory acute leukemia enrolled on our phase I trials. Such treatment-related toxicity has resulted in patients being removed from study and thus potentially not receiving clinical benefit from the novel therapy. In addition, increased treatment-related toxicity may compromise new agents from moving forward in their clinical development. To address these challenges, TACL initiated a Supportive Care Committee to help mitigate the treatment-related toxicity risk that exists in heavily pre-treated patients with relapse/refractory leukemia. This manuscript reviews the mission of the TACL Supportive Care Committee presented at the 2016 TACL Investigators' Meeting (Los Angeles, CA) and the future direction in providing enhanced supportive care guidelines for all TACL studies.

Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplant Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents: Part 2-Focus on Ascites, Fluid and Electrolytes, Renal, and Transfusion Issues

Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria.

Bacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis.

Bacterial bloodstream infections (BSI) cause significant transplant-related morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). This manuscript reviews the risk factors for and the bacterial pathogens causing BSIs in allo-HCT recipients in the contemporary transplant period. In addition, it offers insight into emerging resistant pathogens and reviews clinical management considerations to treat and strategies to prevent BSIs in allo-HCT patients.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Impact of early CMV reactivation in cord blood stem cell recipients in the current era.

Several studies have reported an association between CMV reactivation and a decreased incidence of relapse for AML after adult donor allogeneic hematopoietic cell transplantation (HCT). Limited data, however, are available on the impact of CMV reactivation on relapse after cord blood (CB) stem cell transplantation. The unique combination of higher incidence of CMV reactivation in the seropositive recipient and lower incidence of graft versus host disease (GvHD) in CB HCT permits a valuable design to analyze the impact of CMV reactivation. Data from 1684 patients transplanted with CB between 2003 and 2010 for AML and ALL were analyzed. The median time to CMV reactivation was 34 days (range: 2-287). CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) among both AML and ALL CB recipients (reactivation, AML: relative risk (RR) 1.41 (1.07-1.85); ALL: 1.60 (1.14-2.23); Serology, AML: RR 1.39 (1.05-1.85), ALL: RR 1.61 (1.18-2.19)). For patients with ALL, but not those with AML, this yielded inferior overall survival (P<0.005). Risk of relapse was not influenced by CMV reactivation or positive CMV serostatus for either disease.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body's primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT.

Immune restoration following hematopoietic stem cell transplantation: an evolving target.

Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versus-host disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplant-related toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and anti-microbial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplant-related toxicity in the transplant recipient.

Deactivation of the innate cellular immune response following endotoxic and surgical injury.

The innate cellular immune (iCMI) system provides for the rapid production of interferon-gamma (IFN gamma) by NK cells in response to microbial threats. In this review, we examine the cellular and cytokine mechanisms of innate cellular immunity as determined in murine endotoxemia. This will be contrasted to the subsequent suppression of these same responses present in the mouse model of endotoxin tolerance, which is characterized by profound deficiency in both IL-12 and IFN gamma synthesis. Transient IFN gamma deficiency due to altered iCMI function has also been described in trauma or burn patients and is termed "clinical immune paralysis." If the common pathogenesis of these entities can be better understood, immune-based interventions might be identified for restoring iCMI function. In addition to the gain in basic immunologic insight, research on this subject may deliver future forms of prophylaxis against infection that do not rely on antibiotics and that will not promote antimicrobial resistance.

Immune reconstitution in pediatric stem-cell transplantation.

Hematopoietic stem-cell transplantation (HSCT) has successfully been used to cure many pediatric disorders. However, the immunologic alterations associated with transplantation result in profound immunodeficiencies in the transplant recipient, resulting in significant infectious morbidity and mortality. The precarious process of immune reconstitution in the transplant recipient is neither instantaneous nor complete, but influenced by multiple factors such as graft-versus-host disease (GVHD), conditioning regimen, patient age and underlying disease. Studies in pediatric HSCT have revealed unique attributes of immune recovery in pediatric transplant recipients. Future studies addressing these findings are needed to complement novel immunotherapies emerging from the field of transplant immunology.

Spinal epidural abscesses in children: a 15-year experience and review of the literature.

We reviewed medical records and laboratory and diagnostic evaluations for 8 pediatric patients with spinal epidural abscesses who were treated during the last 15 years at our institution. Staphylococcus aureus was isolated from 5 of 8 epidural abscesses, including 2 abscesses with methicillin-resistant S. aureus. Unusual isolates were group B Streptococcus in a patient with chronic vesicouretral reflux associated with the posterior urethral valves and Aspergillus flavus in a patient with acute myelogenous leukemia. An analysis incorporating our results and a review of the English-language literature about abscesses in children and adults revealed differences related to age. Abscesses in children were more posterior in epidural location, had greater spinal column extension, and were associated with more favorable clinical outcomes than were abscesses in adults. Magnetic resonance imaging is the diagnostic procedure of choice; however, radionuclide bone scans should be considered for associated distant osteomyelitis in children. Prompt diagnosis and combined medical and surgical treatment remain the cornerstones for the prevention of adverse outcomes.

Improved hematopoiesis using amifostine in secondary myelodysplasia.

An 11-year-old boy with multiply relapsed lymphoblastic disease became transfusion dependent with myelodysplasia and chromosomal abnormalities after 5 years of aggressive therapy. At 5 years of age, he presented with transient idiopathic hypoplastic anemia and neutropenia that spontaneously resolved within a month. Three months later, he experienced lymphoblastic lymphoma in the left parotid region and subsequently experienced disease relapse in his testicles, bone marrow, and central nervous system during a 3-year period. He has received multiagent chemotherapy, autologous peripheral blood stem-cell transplantation, and testicular and whole neuraxis irradiation therapy. After craniospinal irradiation, he did not recover normal bone marrow function. His bone marrow was hypocellular, and he required platelet and erythrocyte transfusions and granulocyte colony-stimulating factor. Marrow cytogenetic studies revealed new multiple translocations. Within a month of the initiation of intravenous amifostine at 200 mg/m2/dose three times a week, his leukocyte count, neutrophil count, and hemoglobin level normalized. His platelet count also improved sufficiently to achieve transfusion independence. He has returned to school and engages in other normal activities for his age. Amifostine may improve hematopoiesis in secondary myelodysplastic syndromes in children.

Infections in children with cancer: a continued need for the comprehensive physical examination.

Few studies have addressed the influence of profound myelosuppressive therapy in contemporary protocols on infectious morbidity in pediatric oncology patients. This study evaluates the types of infections and the methods used to diagnose infection in patients enrolled in current Children's Cancer Group (CCG) protocols. Data were collected on patients enrolled in CCG protocols from January 1, 1992, through December 31, 1995. Of the 155 protocol patients, 102 were completely evaluated and had data collected through August 1, 1996. Patients were divided into two diagnosis groups: leukemia/lymphoma (N = 51) and solid tumor (N = 51). Eighty-five (83%) patients had documented infections and 17 (17%) did not. Overall, 96 (94%) patients had in-dwelling central venous catheters. Twelve categories of infection were identified. Data were analyzed for age, gender, diagnosis, neutropenia, organism, and disease state (primary active, recurrent active, primary remission, and secondary remission). Statistical comparisons were made only on rates, whereas descriptive comparisons were given for numbers of infections and organisms. The infection rates for patients with active disease were 1.01 and 1.15 per 100 patient days (primary versus recurrent) and 0.59 and 0.38 per 100 patient days for patients with disease in remission (primary versus secondary). Diagnosis-group infection rates were 0.66 and 0.68 per 100 patient days for patients with solid tumors and leukemia/lymphoma, respectively. Three hundred thirty infections, including 19 polymicrobial infections, were recorded. The three most common types of infection were otitis media, septicemia, and urinary tract infection. More infections were associated with an age at diagnosis of less than 3 years, a leukemia/lymphoma diagnosis in remission, and an absolute neutrophil count >500 cells/microL. One hundred ninety-four organisms were isolated from 330 infections. Gram-positive organisms (n = 74) such as coagulase-negative Staphylococci (n = 38) predominated over gram-negative organisms (n = 63) for all infectious categories. Specifically, gram-positive organisms (n = 39) were isolated more often from blood cultures than were gram-negative organisms (n = 27). The overall mortality for patients was 36%. Seven of the 37 (19%) patient deaths were attributed to infection. These patients predominantly were girls with neutropenia and leukemia/ lymphoma in active disease who died of gram-negative sepsis. Infections with gram-positive organisms continue to be major causes of morbidity in pediatric oncology patients receiving contemporary CCG protocols. However, infection-related mortality, especially with gram-negative organisms, occurs less frequently than does malignancy-related mortality. Common childhood infections (such as otitis media) seem equally as prevalent as bacteremia in pediatric oncology patients. Thus, a comprehensive physical examination is as imperative as the microbiologic evaluation in diagnosing infection in this patient population.