Neighborhood poverty and pediatric allogeneic hematopoietic cell transplantation outcomes: a CIBMTR analysis.

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

Acute Pancreatitis Is Associated with Increased Risk of In-Hospital Mortality and Health Care Utilization Among Pediatric Patients with Hematopoietic Stem Cell Transplantation.

OBJECTIVE: To analyze the impact of acute pancreatitis on mortality and hospital outcomes among the pediatric population following hematopoietic stem cell transplantation (HSCT). STUDY DESIGN: We analyzed nationally representative, nonoverlapping years of the National Inpatient Sample and Kids Inpatient Database between 2003 and 2016, including all pediatric patients who had HSCT. Patients were divided into those with and without a diagnosis of acute pancreatitis and compared for demographics, clinical characteristics, comorbid conditions related to both HSCT and acute pancreatitis, and outcome measures such as in-hospital mortality and health care resource use (length of hospital stay and total hospitalization charges). RESULTS: We analyzed a total of 128 772 hospitalizations of children and adolescents with HSCT. The overall incidence rate of acute pancreatitis was approximately 1%, with an overall increasing trend between 2003 and 2016, P < .001. The overall mortality rate was significantly greater among patients with acute pancreatitis (14.9% vs 3.6%, P < .001). Multivariate regression analysis showed that acute pancreatitis was independently associated with 3.4 times (95% CI 2.86-4.02, P < .001) increased risk of in-hospital mortality. Patients with acute pancreatitis who underwent HSCT had a greater incidence of end-organ damage and thrombotic events. Pediatric acute pancreatitis was associated with 24.3 additional days of hospitalization (95% CI 22.9-25.7, P < .001) and incurred additional $213 496 in hospitalization charges (95% CI 193 768-233 063, P < .001). CONCLUSIONS: Pediatric recipients of HSCT who develop acute pancreatitis have adverse outcomes with increased in-hospital mortality, end-organ damage, prolonged hospital stay, and greater hospitalization charges.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.

A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders.

BACKGROUND: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 106 /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.

The Impact of Donor Type on Outcomes and Cost of Allogeneic Hematopoietic Cell Transplantation for Pediatric Leukemia: A Merged Center for International Blood and Marrow Transplant Research and Pediatric Health Information System Analysis.

Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P = .09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR], .73; 95% confidence interval [CI], .62 to .86; P < .001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P < .001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR, .67; 95% CI, .56 to .81; P < .001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P = .0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT.

Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days -21 to -19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with "early" alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.

Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS). METHODS: Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression. RESULTS: We identified 507 patients (66% CYBB mutants) diagnosed in 1953-2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1 years after diagnosis (0-45.8 years). OS was negatively associated with CYBB mutation (HR = 6.25; p = 0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR = 1.26; p = 0.65). Transplant at ≤ 14 years old was associated with improved TRS (93% v. 82% at T + 60 months) (HR = - 4.51; p = 0.035). Patients transplanted before 15 years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p = 0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p = 0.0010). Compared to non-HSCT patients ≥ 15 years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p = 0.0039) and lower frequency of disability (11% v. 52%; p = 0.014). CONCLUSION: Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15 years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2.

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.

Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Society for Blood and Marrow Transplantation.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia: A CIBMTR Analysis.

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P < .001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile versus 88% for all other quartiles). Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation.

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease.

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.

Post-hematopoietic stem cell transplant hemophagocytic lymphohistiocytosis or an impostor: Case report and review of literature.

HLH occurring after HSCT is a relatively rare disease. Many conditions may mimic or trigger HLH in post-HSCT period (eg, cytokine release syndrome, engraftment syndrome, graft rejection/failure, acute graft-vs-host disease, infections systemic inflammatory response syndrome/sepsis, and thrombotic microangiopathy). Moreover, this period is usually marked by febrile illness, cytopenia, and a "cytokine storm" leading to elevation of inflammatory biomarkers like ferritin and sCD25. These parameters overlap with the diagnostic criteria for HLH. Such confounding factors make the management of post-HSCT HLH quite challenging. We illustrate this critical issue with case report of a patient who was diagnosed with HLH after allogeneic HSCT for tAML. He received MP and CsA for HLH but VP-16 was not administered due to fear of severe myelosuppression. Fortunately, he responded well to treatment and remains in remission to date. We recommend caution while using HLH-94/HLH-2004 guidelines for the diagnosis and management of post-HSCT HLH. In this article, we pinpoint these issues with a brief review of all the pediatric cases and clinical studies of post-HSCT HLH along with a critical evaluation of its various diagnostic criteria. Finally, based on the limitations of current diagnostic criteria, we suggest a need for formulating disease-specific diagnostic criteria for post-HSCT HLH.

Complete Resolution of Lymphoid Interstitial Pneumonia in a Patient With Juvenile Myelomonocytic Leukemia Treated With Allogeneic Bone Marrow Transplant: Killing 2 Birds With 1 Stone.

Lymphoid interstitial pneumonia (LIP) is a rare disease characterized by benign reactive polyclonal proliferation of bronchus-associated lymphoid tissue after exposure to inhaled or circulating antigen(s), leading to a disease symptomatology similar to idiopathic interstitial pneumonia. Its association with diseases that are caused due to immune dysregulation (autoimmune diseases, congenital/acquired immunodeficiency, and allogeneic bone marrow transplant) and response to immunomodulatory/suppressive medications suggests an immunologic pathophysiology. Although LIP has been reported in association with lymphoproliferative diseases like Castleman disease, it has never been described in patients with leukemia. We report the first case of LIP in a patient with juvenile myelomonocytic leukemia (JMML) who was found to have a novel germline mutation of unknown significance in additional sex combs-like-1 (ASXL1) gene and a pathogenic somatic mutation of protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene at diagnosis. The patient underwent a matched unrelated bone marrow transplant for JMML with complete resolution of JMML and LIP with no recurrence to date. We also emphasize the importance of considering LIP in differential diagnosis of pulmonary lesions seen in conjunction with hematologic malignancies and distinguishing it from malignant infiltration of the lung.

Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation.

BACKGROUND: To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation. METHODS: We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT. RESULTS: The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P = 0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre-transplant depression was associated with fewer days-alive-and-out-of-the hospital (means ratio [MR] = 0.97; 95% CI, 0.95-0.99; P = 0.004). There were 512 (13.5%) patients with Pre-transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre-transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98-1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97-0.99; P = 0.002). CONCLUSION: Pre-transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre-transplant depression represent a population that is at risk for post-transplant complications. Cancer 2017;123:1828-1838. © 2017 American Cancer Society.

Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.

Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age <10 years) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range: $344,029-$799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was demonstrated with late transplantation (P=0.775). Among patients with 2-year pre- and post-transplant data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001), length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes need to be studied prospectively in young children without severe disease and an available matched sibling to provide conclusive evidence for the superiority of this approach. Reduced post-transplant healthcare utilization inpatient care indicates that transplantation may provide a sustained decrease in healthcare costs over time.

Outcomes and healthcare utilization in children and young adults with aplastic anemia: A multiinstitutional analysis.

BACKGROUND: Aplastic anemia is a bone marrow failure syndrome with high mortality affecting children and young adults. Although current treatment guidelines recommend hematopoietic stem cell transplant (HCT) for patients with matched sibling donors, outcomes with alternate donor options have been improving. PROCEDURE: We analyzed a validated multiinstitutional pediatric cohort using one of the largest pediatric and young adult database, the Pediatric Health Information System, for patients diagnosed with aplastic anemia (AA) from 2006 to 2015. Outcomes with upfront and salvage transplants were analyzed along with healthcare utilization. RESULTS: Among 2,169 patients in the study period, almost 20% underwent HCT, while others received immunosuppressive therapy. In a multivariate model, there was no significant difference in mortality with upfront or salvage transplants (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.6-2.58, P = 0.567), while every platelet transfusion was associated with higher mortality (OR 1.37, 95% CI 1.12-1.67, P = 0.002). Healthcare utilization was significantly higher in salvage transplants requiring frequent hospitalization and transfusion requirements. Treatment mortality and graft failure rates were significantly reduced in the salvage transplant group in recent years (2011-2015 as compared to 2006-2010). CONCLUSION: As outcomes with HCT continue to improve in severe AA, transplant with good alternate donors should be considered upfront in children and young adults.

Refractory Pure Red Cell Aplasia Manifesting as Deficiency of Adenosine Deaminase 2.

Primary progress has been made in the last 2 years, particularly in finding novel disease-causing genes for a number of autoinflammatory diseases and primary immunodeficiencies. Whole-exome sequencing has dramatically increased the pace at which causative genes are being discovered. CECR1 (Cat eye syndrome chromosome region, candidate 1) gene encodes adenosine deaminase 2 (ADA2) protein. Patients who carry CECR1 mutation(s) suffer from deficiency of ADA2 (DADA2). Here, we describe a patient with pure red cell aplasia discovered to have DADA2. We also review the literature on DADA2. This report will help raise awareness of physicians for this complex disease.