Autoimmune hemolytic anemia and immune thrombocytopenia following hematopoietic stem cell transplant: A critical review of the literature

Autoimmune cytopenias (AIC) post‐hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post‐HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft‐versus‐host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post‐HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post‐HSCT patients.     

Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post‐hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation

AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell‐derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First‐line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response.     

BK nephropathy in pediatric hematopoietic stem cell transplant recipients

Abstract:  BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after HCT, most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to antiviral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression because of GVHD. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, antiviral therapy did not seem beneficial as documented by continued renal dysfunction and elevated serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction.     

Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients

This guideline provides clinicians with evidence‐based recommendations on the use of antifungal prophylaxis in children with cancer and undergoing hematopoietic stem cell transplantation (HSCT). Recommendations are divided into: (1) allogeneic HSCT (2) autologous HSCT (3) acute myeloid leukemia or myelodysplastic syndrome and (4) patients with malignancy and neutropenia for >7 days. A systematic review was conducted and evidence summaries compiled. The quality of evidence and strength of each recommendation was determined using GRADE. Implementation of these recommendations will require adaptation to local context. The contribution of this guideline in the prevention of invasive fungal infections requires prospective evaluation. Pediatr Blood Cancer 2014;61:393–400. © 2013 Wiley Periodicals, Inc.     

Transient renal enlargement in pediatric hematopoietic cell transplant recipients

Age‐dependent renal length tables are routinely used when interpreting pediatric ultrasound. Standard renal length tables may not be accurate for HCT patients due to treatment effects on kidney size. The purpose of this study was to determine whether renal size changes from expected lengths based on age after HCT in the absence of other markers of renal disease. Four hundred and fifty renal measurements were made on 101 patients who underwent HCT between 2006 and 2010. Renal length was measured at 1–90 days pre‐HCT and at 0–30, 31–90, 91–180, and 181+ days post‐HCT. Values were compared with normal renal length tables. Average post‐HCT renal lengths were greater than established normative renal length data within every age group. Age‐adjusted average renal lengths measured at 0–30 and 31–90 days post‐transplantation were significantly larger than pre‐HCT renal lengths, with relative increases of 6.9% (4.5, 9.4; p < 0.001) and 3.9% (1.4, 6.4; p = 0.003), respectively. Average renal length did not differ significantly after 90 days post‐transplantation. HCT patients may have larger kidneys in the absence of renal disease. Awareness of the potential phenomenon of transient renal enlargement following HCT can prevent misdiagnosis and eliminate unnecessary diagnostic evaluations, interventions, anxiety, resource allocation, and financial costs.     

Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support

Norovirus infection is a major cause of nonbacterial gastroenteritis. In immunocompetent individuals the illness caused by norovirus is mostly self limiting. Excretion of norovirus has been reported to be prolonged in the immunocompromised including adult HSCT recipients. We report a case series of 13 children who received HSCT and required prolonged parenteral and enteral nutrition due to severe gut dysfunction accompanying protracted norovirus excretion that was monitored by RT-PCR. The median duration of viral excretion was 150 days (range 60-380) and the eventual clearance of norovirus from feces was closely associated with donor T cell recovery in the peripheral blood. There was no disease manifestation beyond the gut but the severity and length of norovirus associated illness suggests that HSCT should be delayed where possible in patients excreting the virus prior to conditioning therapy.     

Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: non-infectious and long-term complications

Pulmonary complications are among the most frequently encountered sequelae of pediatric hematopoietic stem cell transplantation (HSCT). Non-infectious complications are becoming increasingly more common in this unique population. This review addresses the diagnosis and management of non-infectious manifestations of lung disease in pediatric HSCT patients and briefly discusses the long-term pulmonary function of childhood HSCT survivors.     

Successful use of reduced‐intensity conditioning and matched‐unrelated hematopoietic stem cell transplant in a child with Diamond‐Blackfan anemia and cirrhosis

For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14‐yr‐old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%.     

Matched related donor hematopoietic stem cell transplantation results in a long‐term follow‐up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective

HSCT has substantially improved pediatric acquired SAA patients' outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow‐up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3–4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2–4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of <10 months between diagnosis and HSCT is associated with improved survival (hazard ratio, 95% CI = 1.204, 1.010–1.434, p = 0.038). SC source did not significantly affect EFS, incidence of acute GVHD (grades 3–4), or extensive chronic GVHD (p = 0.938, 0.121, and 0.487, respectively). Based on our findings, pediatric acquired SAA patients are benefitted most if MRD‐HSCT is carried out early in disease process and SC source does not affect outcome of MRD‐HSCT in these patients.     

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

Pillai A, Hartford C, Wang C, Pei D, Yang J, Srinivasan A, Triplett B, Dallas M, Leung W. Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.
Pediatr Transplantation 2011: 15: 628–634. © 2011 John Wiley & Sons A/S. Abstract: To assess whether a tolerance‐induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA‐matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT (n = 5). Immunoprophylaxis was CSA and short‐course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow‐up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I–II: 1 (11%), Grade III–IV: 0%; MUD, Grade I–II: 1 (20%), Grade III–IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive‐compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.     

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.     

Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts

Olkinuora HA, Taskinen MH, Saarinen‐Pihkala UM, Vettenranta KK. Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts.
Pediatr Transplantation 2010:14:242–248. © 2009 John Wiley & Sons A/S. Abstract: Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment‐related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999‐9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P<0,001) and secondary graft failure were significantly (P=0,001) associated with early (during the first 100 days post HSCT), multiple (≥ 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.     

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.     

Solid organ transplants following hematopoietic stem cell transplant in children

Bunin N, Guzikowski V, Rand ER, Goldfarb S, Baluarte J, Meyers K, Olthoff KM. Solid organ transplants following hematopoietic stem cell transplant in children.
Pediatr Transplantation 2010: 14:1030–1035. © 2010 John Wiley & Sons A/S. Abstract: SOT may be indicated for a select group of pediatric patients who experience permanent organ failure following HSCT. However, there is limited information available about outcomes. We identified eight children at our center who received an SOT following an HSCT. Patients were six months to 18 yr at HSCT. Diseases for which children underwent HSCT included thalassemia, Wiskott–Aldrich syndrome, Shwachman–Diamond/bone marrow failure, sickle cell disease (SCD), erythropoietic porphyria (EP), ALL, chronic granulomatous disease, and neuroblastoma. Time from HSCT to SOT was 13 days to seven yr (median, 27 months. Lung SOT was performed for two patients with BO, kidney transplants for three patients, and liver transplants for three patients (VOD, chronic GVHD). Seven patients are alive with functioning allografts 6–180 months from SOT. Advances in organ procurement, operative technique, immunosuppressant therapy, and infection control may allow SOT for a select group of patients post‐HSCT. However, scarcity of donor organs available in a timely fashion continues to be a limiting factor. Children who have undergone HSCT and develop single organ failure should be considered for an SOT if there is a high likelihood of cure of the primary disease.     

Hematopoietic stem cell transplantation without in vivo T‐cell depletion for pediatric aplastic anemia: A single‐center experience

For young patients, HLA‐MRD HSCT is the first‐line treatment of SAA. However, due to China's birth control policy, few patients could find suitable sibling donors and HLA‐MUD. More and more transplantation centers have used Haplo‐D as the donor source for young adult and pediatric patients. However, studies with larger amount of pediatric patients are rare. We retrospectively analyzed the data of children with AA who were treated with allogeneic HSCT and compared the therapeutic efficacy of Haplo‐HSCT and MRD/MUD group. A total of 62 patients were enrolled. Implantation was successfully performed in 58 patients. There was no significant difference in the time for reconstruction of hematopoietic function between patients in the two groups. Thirty‐two had grade I‐IV aGVHD with incidence of 51.61%. The incidence of aGVHD was 79.41% for patients in the Haplo‐HSCT, significantly higher than that of 17.86% for patients in the MRD/MUD group (P < .01). However, the incidence of cGVHD was not significantly different between patients in the two groups (26.47% vs 10.71%, P = .09), the incidence of CMV infection was 28.57% and 52.94% for patients in the MRD/MUD and Haplo group, respectively, showing no significant difference (P = .053). The incidence of EBV infection was 47.06% for patients in the Haplo group and 28.57% for patients in the MRD/MUD group, showing no significant difference (P = .11). However, the 3‐ and 5‐year cumulative OS and FFS rates showed statistically significant difference in the two groups, P = .012 and .045, respectively. Compared to Haplo‐HSCT, MRD/MUD is more economic. In this study, we achieved good Haplo transplantation results. The incidences of cGVHD and CMV/EBV were not significantly different between Haplo group and MRD/MUD group. Although OS and FFS of the Haplo group were not as good as those of the MRD/MUD group, it is still acceptable as an alternative treatment under emergency.     

Outcomes of pediatric identical living‐donor liver and hematopoietic stem cell transplantation

Chronic IS is associated with significant morbidity in transplant recipients. Moreover, IS does not prevent chronic graft failure frequently. Allograft immune tolerance in LT can be induced by complete donor chimerism through allogenic HSCT combined with identical LDLT. This approach may exempt patients from chronic lifelong IS. However, it is unclear whether its benefits justify its risks. Here, we present three cases from our institution and analyze seven additional reports of children treated with HSCT/LDLT, all receiving HSCT due to hemato‐oncological indications. In eight of 10 cases, donor macrochimerism resulted in allograft tolerance. Nine patients survived. One patient died due to fulminant ADV infection. Further complications were GvHD (n = 3) and bone marrow failure (n = 2). In conclusion, donor‐specific allograft tolerance can be achieved by identical‐donor HSCT/LDLT. However, at present, this approach should generally be limited to selected indications due to a potentially unfavorable risk–benefit ratio. Novel toxicity‐reduced conditioning protocols for HSCT/LDLT in the absence of malignant or non‐hepatic disease may prove to be a sufficiently safe approach for inducing graft tolerance in children receiving a LDLT in the future. This concept may reduce the burden of lifelong IS.