Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation

Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopietic stem cell transplantation.
Pediatr Transplantation 2012: 16: E39–E42. © 2010 John Wiley & Sons A/S. Abstract: TA‐TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA‐TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA‐TMA after allogeneic HSCT.     

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.     

Successful treatment with eculizumab for posterior reversible encephalopathy syndrome due to underlying transplant‐associated thrombotic microangiopathy in patients transplanted for sickle cell disease

Preexisting endothelial dysfunction and vascular injury sustained during allogeneic hematopoietic cell transplantation (HCT) increases risk for endothelial injury‐related complications such as posterior reversible encephalopathy syndrome (PRES) and transplant‐associated thrombotic microangiopathy (TA‐TMA) in patients with sickle cell disease (SCD). We report two patients with SCD who developed PRES following allogeneic HCT. In both patients, PRES‐related symptoms resolved only after a diagnosis of TA‐TMA was established and eculizumab therapy was initiated. Renal manifestations at diagnosis included non‐nephrotic range proteinuria and hypertension. This report highlights the importance of screening PRES‐affected SCD HCT recipients for TA‐TMA as usual treatment strategies may be inadequate.     

Hematopoietic stem cell transplantation‐associated thrombotic microangiopathy accompanied by renal arteriolar C4d deposition

HSCT‐associated thrombotic microangiopathy (TA‐TMA) is a severe complication with a poor prognosis. Recently, it has been reported that complement system dysregulation, such as CFH autoantibodies and deletions CFH‐related genes 3 and 1, induced TA‐TMA. In addition, C4d‐positive renal arterioles are both a good marker of complement system activation and a useful diagnostic tool for TA‐TMA. Because dysregulation of the complement system is associated with TA‐TMA, the complement system might be a therapeutic target, such as eculizumab, a terminal complement inhibitor. Herein, we describe an eight‐yr‐old boy who developed TA‐TMA accompanied by severe renal dysfunction. His renal specimen showed diffuse C4d deposition in the renal arterioles, which is consistent with TA‐TMA. Although the patient gradually improved without eculizumab, renal arteriolar C4d staining in sample with TA‐TMA shows the complement system activation and may guide the target therapy using the eculizumab.     

Eculizumab and thrombotic microangiopathy after hematopoietic stem cell transplantation: A report on its efficacy and safety in two pediatric patients

Background

Thrombotic microangiopathy (TMA) is a severe complication after hematopoietic stem cell transplantation (HSCT), with the reported mortality rate in such cases usually reaching 90%.

Third-party mesenchymal stromal cell infusion is associated with a decrease in thrombotic microangiopathy symptoms observed post-hematopoietic stem cell transplantation

TA-TMA is a pathology that occurs after allogenic HSC transplantation with an incidence of 4-13%, and represents one of the most severe vascular damage related with this therapy. We report here the case of a nine-yr-old girl suffering from a severe refractory aplastic anemia who received an unrelated, 9/10 HLA-matched HSC. Soon after transplantation, the patient developed a graft-versus-host disease (GvHD), a TA-TMA, and renal insufficiency. These pathologies remained refractory to the various treatments undertaken and required several hospitalizations in the intensive care unit. On day 106 post-HSC transfusion, after several episodes of intensive care, the patient was infused with mismatched, third-party MSCs. Schizocyte levels rapidly decreased after MSC infusion, and two wk later, most biological parameters returned to normal. Erythrocyte and thrombocyte transfusions were discontinued, and the patient remained stable for 10 wk. Thereafter, TA-TMA symptoms, viral reactivation, pleural and cardiac effusions reappeared and lead to the death of the patient. Our observations suggest that allogenic MSC infusion may decrease the symptoms of TA-TMA, but further investigation is required to determine how and when MSC should be infused to develop a long-lasting protective effect.     

Pretransplant paranasal sinus disease is associated with a high incidence of transplant‐related mortality in hematopoietic stem cell transplantation for children and adolescents

To determine whether pretransplant PSD affects the clinical outcomes in HSCT, a retrospective cohort analysis of 73 pediatric and adolescent patients who underwent HSCT was performed. Pretransplant PSD was defined as the presence of a fluid level or mucosal swelling or total opacity on sinus X‐ray or CT examination performed before HSCT. Pretransplant PSD was observed in 21 (29%) patients. The probability of 2‐year OS after HSCT was 42% in patients with pretransplant PSD (PSD group), and 64% in those without (non‐PSD group) (P=.012). The cumulative incidence of 2‐year TRM was 48% in the PSD group, and 17% in the non‐PSD group (P=.005). The cumulative incidences of pulmonary complications and respiratory failure at 2 years after HSCT were significantly higher in the PSD group (41% vs 15%, P=.022; 44% vs 14%, P=.009, respectively). PSD at the time of HSCT should be recognized as an additional potential risk factor for mortality. Further investigation is required to clarify the reasons for the present findings to improve the outcomes of patients with pretransplant PSD.     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

Transplant‐related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant‐related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high‐risk group (P = .006). High‐risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.     

Non‐sibling hematopoietic stem cell transplantation using myeloablative conditioning regimen in children with Maroteaux‐Lamy syndrome: A brief report

Maroteaux‐Lamy syndrome is a rare inherited lysosomal storage disorder with a progressive course. HSCT is a curable option for treatment in these patients. The following report describes our experience in HSCT for three patients with Maroteaux‐Lamy syndrome using non‐sibling donors. All of the patients received the same myeloablative regimen consisting of intravenous busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Patients underwent HSCT from haploidentical other‐related (n=1), full‐matched other‐related (n=1), and one‐locus‐mismatched unrelated donor. Stem cell sources included bone marrow (n=1), peripheral blood (n=1), and cord blood (n=1). Currently, two patients who received transplant from other‐related donors showed full engraftment and regression of the symptoms of the disease, while for the patient with unrelated cord blood donor, graft failure resulted in progression of the disease and death. The result of our study showed beneficial effects of HSCT even from heterozygote donor. Due to rarity of the disease, future multicenter studies are recommended to find the best treatment approaches based on the patients’ status.     

Human herpesvirus‐6 viremia is not associated with poor clinical outcomes in children following allogeneic hematopoietic cell transplantation

HHV‐6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV‐6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV‐6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV‐6, CMV, EBV, and ADV. HHV‐6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3–26.7%) of patients had HHV‐6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15‐day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV‐6 viremia (58%) than in those without HHV‐6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV‐6 viremia in multivariate analysis. Similarly, HHV‐6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV‐6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV‐6 PCR should only be performed on clinical suspicion.     

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n?=?175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n?=?181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p?=?.001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5?days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.     

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.     

Transplantation‐associated thrombotic microangiopathy isolated to a congenital anomaly of the lung

TA‐TMA is a post‐hematopoietic stem cell transplant complication with clinical features of hemolytic anemia and thrombocytopenia. A 26‐month‐old child who had had an allogeneic transplant for treatment of DBA developed severe TA‐TMA with heavy red blood cell and platelet transfusion dependence. Incidentally, he was found to have a lung sequestration. TA‐TMA resolved and transfusion dependence resolved after resection of the sequestration. The finding suggests the malformation vasculature was selectively vulnerable to the trigger of TA‐TMA—raising perhaps a clue to basic pathophysiology of TA‐TMA and/or vascular malformations.     

Meta‐analysis of hematopoietic stem cell transplantation in major histocompatibility complex class II deficiency

Major histocompatibility complex class II deficiency is a rare case of PID. Specific recommendations for hematopoietic stem cell transplant, the only curative treatment option, are still lacking. This meta‐analysis aims to identify the factors associated with better prognosis in these patients. Thirteen articles reporting 63 patients with major histocompatibility complex class II deficiency that underwent hematopoietic stem cell transplant were included. The median age for hematopoietic stem cell transplant was 18 months. The most common source of transplant was bone marrow, with alternative sources as umbilical cord blood emerging during recent years. The highest proportion of engraftment was seen with umbilical cord. Engraftment was higher in patients with matched donors, with better overall survival in patients with reduced‐intensity conditioning. Graft‐vs‐host disease developed in 65% of the patients, with grades I‐II being the most frequently encountered. There was a higher mortality in patients with myeloablative conditioning and no engraftment. There was an inverse correlation between survival and stage of graft‐vs‐host disease. The main cause of mortality was infectious disease, mostly secondary to viral infections. Ideally, matched grafts should be used, and reduced‐intensity conditioning should be considered to reduce early post‐transplant complications. GVHD and viral prophylaxis are fundamental.