Rolla Abu-Arja

Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

X‐linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B‐cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patients leukemia. Pediatr Blood Cancer 2015;62:1674–1676.

Anicteric veno-occlusive disease after hematopoietic stem cell transplantation in children.

Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome is a potentially fatal complication following hematopoietic stem cell transplantation (HSCT) and occurs in ~ 30% of the children undergoing HSCT. Two diagnostic criteria have been used for the diagnosis of VOD, the Baltimore criteria by Jones et al. comprising hyperbilirubinemia of42mg/dL and any two of the following: weight gain of 45% from baseline, hepatomegaly or ascites. The diagnosis of VOD based on the Seattle criteria by McDonald et al. can be made if any two of the following are present by day +20 after HSCT: hyperbilirubinemia (42mg/dL), ascites or weight gain of 42% from baseline, or hepatomegaly. Prompt diagnosis and early intervention is crucial as patients with severe VOD may develop multi-organ failure, requiring intensive care and carry a high mortality of up to 84%. Yet there is no consensus on grading severity of VOD. Although liver biopsy is helpful for confirming the diagnosis, in the setting of coagulopathy and thrombocytopenia, it is usually avoided. Ultrasonography has been used in the diagnosis of VOD; in the study by Lassau et al. on multivariate analysis, two ultrasound criteria (splenomegaly and ascites) and one doppler criterion (flow recorded in paraumbilical vein) were correlated with the severity of VOD (P = 0.0001). Demonstration of reversal of portal venous blood flow by ultrasonography can be helpful, but is often a late finding indicating advanced disease. The Baltimore criteria are more often used in adults and appear to be more stringent than the Seattle criteria; as patients without hyperbilirubinemia are excluded. In contrast, the Seattle criteria may lead to over diagnosis, as some patients may meet the diagnostic criteria earlier in the course of the disease. Higher serum bilirubin levels have been associated with increased severity of VOD and worse outcomes. Bearman et al. used total serum bilirubin level and percentage weight gain to create risk curves that would predict the likelihood of developing severe VOD. Total serum bilirubin is often used as a marker for response to treatment with defibrotide, as discussed in studies by Ho et al. and Richardson et al. However some patients with VOD may not have hyperbilirubinemia but still have all the other features consistent with VOD. In a recent study by Myers et al., five patients had a bilirubin of ⩽ 2mg/dL at the time of diagnosis of VOD and reversal of portal venous flow (PVF) by ultrasonography; two of these continued to have a bilirubin of o2mg/dL. There have been few studies focusing specifically on anicteric VOD. The primary aim of this study is to assess the clinical course and outcomes of patients with anicteric VOD after HSCT in children. A retrospective review of the medical charts of all patients diagnosed with VOD while undergoing HSCT from 1992 through June 2014 at Nationwide Children’s Hospital, Columbus, OH, USA was performed. Both Seattle and Baltimore criteria were retrospectively applied to each patient diagnosed and treated as VOD. Patients who were diagnosed with VOD but maintained a total serum bilirubin level ⩽ 2mg/dL during the entire course of treatment for VOD were defined as having ‘Anicteric VOD’. The level of supportive care during treatment for VOD was defined as follows: ‘Level 1’—general floor level management (that is, diuretics, pain control, fluid restriction, transfusion and so on), ‘Level 2’: paediatric intensive care unit level support for ⩽ 2 body systems (that is, mechanical ventilation for respiratory failure, vasopressors for heart failure and so on) and ‘Level 3’: paediatric intensive care unit level support ⩾ 3 body systems (that is, mechanical ventilation+vasopressors+dialysis and so on). Standard descriptive statistical methods were used for analysis. Statistical analysis was done using SAS 9.3 statistical software (SAS Institute, Cary, NC, USA). Categorical variables were compared between VOD groups using a Fisher’s exact test. Continuous variables were compared using a nonparametric twosided Wilcoxon rank-sum test. P-values o0.05 were considered significant. Acquisition of patient data was approved by the Institutional Review Board at Nationwide Children’s Hospital. Thirty patients were diagnosed with VOD during the study period and patient demographics and characteristics are presented in Tables 1 and 2. One patient with undocumented bilirubin level was excluded from the study. The remaining 29 patients were included in the final analysis. Nine of 29 (31%) had anicteric VOD and 20/29 (69%) had VOD with icterus. The majority (n= 26) of the patients received myeloablative conditioning for malignant (n= 24) or non-malignant (n= 5) diseases. There was no difference in the characteristics of patients with anicteric VOD versus icteric VOD with regard to percentage weight gain, hepatomegaly, abdominal pain, demonstration of PVF reversal, duration of treatment or outcome. Ascites was seen in 5 of the 9 (55.6%) and 19 of 20 (95%) cases with anicteric and icteric VOD, respectively. The median level of supportive care was level 2 for the icteric VOD group as compared with level 1 for the anicteric group (P= 0.007). While analysing ultrasonography results for the two groups, of the nine patients with anicteric VOD, data were missing in four (all recovered from VOD), one showed reversal of PVF and recovered, four patients had no reversal of PVF (two recovered and two died). In the icteric VOD group, 12 showed reversal of PVF (five recovered and seven died), five had no reversal of PVF (one recovered and four died) and three had missing data (two recovered and one died). Overall, six patients with no reversal of PVF died from VOD (two with anicteric VOD and four with icteric VOD). Seven cases were diagnosed with VOD by the Seattle criteria at a median of day +15 after transplant. However, curative treatment with defibrotide was delayed by 1–11 days for lack of hyperbilirubinemia; and two of these never developed hyperbilirubinemia. Curative anticoagulation therapy was given in 1/9 (11%) cases with anicteric VOD versus 9/20 (45%) of the icteric VOD. Fourteen (14) of the 29 patients died (48%) from complications of VOD, 2 with anicteric and 12 with icteric VOD died. Although there have been numerous studies characterizing VOD and its treatments, few studies have specifically focused on anicteric VOD. There seems to be a poor understanding and awareness of anicteric VOD as a diagnosis relative to icteric VOD. As patients with anicteric VOD do not meet the Baltimore criteria, the diagnosis of VOD and its treatment may be delayed if only the Baltimore criteria are followed. It is well known that delay in the initiation of supportive care and curative treatment may result in Bone Marrow Transplantation (2016) 51, 135–137

Recombinant human keratinocyte growth factor: Successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation

Recombinant human keratinocyte growth factor: successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation

Safety Profile of Good Manufacturing Practice Manufactured Interferon γ‐Primed Mesenchymal Stem/Stromal Cells for Clinical Trials

Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice‐compliant two‐step MSC manufacturing protocol to generate MSCs or interferon γ (IFNγ) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFNγ) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFNγ primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post‐mortem examination. We found no evidence of toxicity attributable to the MSC or IFNγ primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFNγ primed MSCs produced by our two‐step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies. Stem Cells Translational Medicine 2017;6:1868–1879

Severe transplant-associated thrombotic microangiopathy in patients with hemoglobinopathies

Incidence and severity of transplant‐associated thrombotic microangiopathy (TA‐TMA) in patients with hemoglobinopathies receiving hematopoietic cell transplant is unknown. We report the outcomes for two patients with TA‐TMA who received eculizumab. A 2.5‐year‐old male with sickle cell disease developed TA‐TMA‐associated pericardial tamponade, severe hypertension, and acute kidney injury 2 months after transplant. A 7‐year‐old female with β‐thalassemia major developed TA‐TMA‐related acute kidney injury, severe hypertension, and seizures at 6 months after transplant. Both patients progressed to chronic kidney disease (CKD). In patients with hemoglobinopathies, preexisting endothelial dysfunction may place them at a greater risk for TA‐TMA and subsequent CKD.

Venous Thromboembolism in Pediatric Hematopoietic Cell Transplant: a Multicenter Cohort Study

Hematopoietic cell transplant (HCT) is associated with a proinflammatory, procoagulant environment that places recipients at increased risk of venous thromboembolism (VTE). Although the incidence of VTE in adult HCT recipients has been extensively studied, similar data for children are lacking. We conducted a multicenter retrospective study to analyze the prevalence of VTE and associated risk factors in a large cohort of patients who underwent HCT at tertiary care US childrens hospitals. The Pediatric Health Information System database, a large administrative database that contains clinical and resource utilization data from 49 freestanding childrens hospitals in the United States, was used to extract data. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients, VTE events, post-HCT complications, and associated risk factors up to 1 year post-transplant. Data on patients who received HCT from January 2010 through September 2014 were collected. A total of 4158 unique patients mean ± standard deviation age at transplant admit, 8.8 ± 6.5 years; range, birth to 33.4 years) were identified. After HCT 290 subjects (6.9%) developed VTE. VTE prevalence was greater in patients aged ≥ 13 versus <13 years (8.54% versus 6.33%; P = .01) and in recipients of allogeneic versus autologous grafts (7.7% versus 5%; P ≤ .01). VTE was associated with prolonged median duration of hospitalization (81 versus 54 days; P ≤.01) and increased 1-year mortality (13.9% versus 5.9%; P ≤ .01). Infections and presence of any graft-versus-host disease (GVHD) were significantly associated with VTE occurrence in recipients of allogenic grafts. Prevalence of VTE in patients who underwent HCT at pediatric tertiary care hospitals is about 7%. Age ≥ 13 years and allogeneic grafts were significant pre-HCT VTE risk factors, with GVHD and infections seen more frequently in patients with VTE.

Hematopoietic stem cell transplantation and acute kidney injury in children: A comprehensive review

AKI in the setting of HSCT is commonly investigated among adult patients. In the same way, malignancies requiring treatment with HSCT are not limited to the adult patient population, AKI following HSCT is frequently encountered within pediatric patient populations. However, inadequate information regarding epidemiology and pathophysiology specific to pediatric patients prevents development of appropriate and successful therapeutic strategies for those afflicted. Addressing AKI in the context of sinusoidal obstruction syndrome, chemotherapy, thrombotic microangiopathy and hypertension post chemotherapy, glomerulonephritis, and graft versus host disease provides greater insight into renal impairment associated with these HSCT‐related ailments. To obtain a better understanding of AKI among pediatric patients receiving HSCT, we investigated the current literature specifically addressing these areas of concern.

Acute myeloid leukemia with RAM immunophenotype: a pediatric case with unusual morphologic features

The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML) that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype.

Hematopoietic cell transplantation for a child with OSTM1 osteopetrosis

HCT prior to onset of neurologic symptoms in children with OSTM1 osteopetrosis does not halt neurologic progression.

Disseminated Bacillus Calmette-Guérin (BCG) infection following allogeneic hematopoietic stem cell transplant in a patient with Bare Lymphocyte Syndrome type II

We describe the first case, to our knowledge, of disseminated Mycobacterium bovis Bacillus Calmette‐Guérin infection in a child with Bare Lymphocyte Syndrome type II after undergoing hematopoietic stem cell transplantation (HSCT). The patient presented 30 days post HSCT with fever and lymphadenitis. Lymph node, blood, and gastric aspirates were positive for M. bovis. The patient received a prolonged treatment course with a combination of isoniazid, levofloxacin, and ethambutol. Her course was further complicated by granulomatous lymphadenitis and otitis media associated with M. bovis that developed during immune suppression taper and immune reconstitution. Ultimately, the patient recovered fully, in association with restoration of immune function, and has completed 12 months of therapy.