Hemophagocytosis after bone marrow transplantation for JAK3‐deficient severe combined immunodeficiency

Hashii Y, Yoshida H, Kuroda S, Kusuki S, Sato E, Tokimasa S, Ohta H, Matsubara Y, Kinoshita S, Nakagawa N, Imai K, Nonoyama S, Oshima K, Ohara O, Ozono K. Hemophagocytosis after bone marrow transplantation for JAK3‐deficient severe combined immunodeficiency.
Pediatr Transplantation 2010: 14:E105–E109. © 2009 John Wiley & Sons A/S. Abstract: HSCT is the optimal treatment for patients with SCID. In particular, HSCT from a HLA‐identical donor gives rise to successful engraftment with long survival. We report a six‐month‐old girl with JAK3‐deficient SCID who developed hemophagocytosis after BMT without conditioning from her HLA‐identical father. She had suffered from pneumonia and hepatitis before BMT. Prophylaxis for GVHD was short‐term methotrexate and tacrolimus. On day 18 after BMT, the patient developed hemophagocytosis in bone marrow when donor lymphocytes were increasing in peripheral blood. Analysis of chimerism confirmed host origin of macrophages and donor origin of lymphocytes. Thus, host macrophage activation was presumably induced in response to donor lymphocytes through immunoreaction to infections and/or alloantigens. HSCT for SCID necessitates caution with respect to hemophagocytosis.     

Treatment of adrenoleukodystrophy with bone marrow transplantation

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even in a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

Malignant hepatic tumor occurring 10 yrs after a histocompatible sibling donor bone marrow transplantation for severe aplastic anemia

A 13-yr-old boy developed post-transplant liver tumor. At three yrs of age, this patient underwent a histocompatible sibling donor BMT for severe aplastic anemia, after a conditioning with antithymocyte globulin and cyclophosphamide. He became a HBV carrier after BMT. Stable mixed chimerism and mild thrombocytopenia, but no active hepatitis continued. At age 13, abdominal pain was a sign of massive tumor. Extremely high levels of alpha-fetoprotein indicated the clinical diagnosis of hepatoblastoma that might be the first report as post-BMT malignancy. The necropsy specimens revealed that the tumor was recipient cell-origin and showed the histopathological features of both hepatoblastoma and hepatocellular carcinoma. Prolonged mixed chimerism and hepatitis virus infection might induce a rare oncogenesis after non-irradiated conditioning.     

Successful unrelated cord blood transplantation for chronic granulomatous disease: a case report and review of the literature

Abstract:  CGD is a rare inherited immunodeficiency disorder that is caused by disability of oxidative killing. We presented a two-yr-old boy with CGD who was suffering from multiple systemic abscesses. He received the first BMT from his HLA-haploidentical mother after conditioning with Flu, melphalan, and ATG. Although the maximum of 42% donor chimerism was achieved, it disappeared 73 days after the BMT. Then, we performed 5/6-matched unrelated cord blood re-transplantation after conditioning with Flu, Bu, and TBI (2 Gy). Engraftment and complete donor chimerism were achieved on days 18 and 19, respectively. The patient is now free from infection and maintains complete donor chimerism without GVHD 36 months after the cord blood re-transplantation. We postulate that the unrelated CBT has a potential to be an alternative strategy and might be beneficial for patients with CGD who do not have an HLA-identical donor.     

Successful allogeneic hemopoietic stem cell transplantation in a case of Wiskott–Aldrich syndrome and non‐Hodgkin lymphoma

WAS is a severe X‐linked recessive disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. A six‐yr‐old boy with WAS diagnosed as B‐cell NHL (Stage III) localized in the liver who underwent successful HSCT from HLA‐one antigen mismatch sibling donor has been presented here. His conditioning regimen included ATG, busulfan, and fludarabine. He received 2.3 × 10⁶/kg CD 34(+) stem cells and 11 × 10⁸/kg nucleated cells at day 0. Neutrophil engraftment was achieved at day +14 and platelet engraftment at day +20. He has been in CR for more than two yr after transplantation. Thus, HSCT is an effective treatment for children with WAS even after development of lymphoma.     

Successful allogeneic unrelated bone marrow transplantation using reduced-intensity conditioning for the treatment of X-linked adrenoleukodystrophy in a one-yr-old boy

Abstract:  The childhood cerebral form of X-linked ALD is a demyelinating disorder of the central nervous system, which rapidly leads to total disability and death. Allogeneic stem cell transplantation benefits patients who show early evidence of the demyelination. We report here a one-yr-old boy with ALD who received HLA-matched unrelated BMT in an early stage of the disease after careful planning and observation since his birth. BMT was performed when MRI began to show slight signal intensity changes in the white matter of the brain. Pretransplant conditioning consisted of fludarabine, l -PAM and TBI (2 Gy). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. The patient showed an uneventful BMT course with fast and stable engraftment. Following BMT, the plasma levels of VLCFA decreased gradually and MRI changes improved. The patient did not have any evidence of further neurological deterioration 22 months following the transplant. Although this is still a short follow-up, it has been shown that BMT should be considered when a child has a biochemical diagnosis and MRI findings of ALD without any neurological signs. RIST should be considered as a pretransplant conditioning for ALD.     

Continued complete remission without systemic therapy for isolated testicular relapse after bone marrow transplantation in a boy with acute lymphoblastic leukemia

Abstract:  ITR after BMT in cases of acute lymphoblastic leukemia is relatively rare. Treatment for ITR after BMT generally consists of a combination of local irradiation, orchiectomy, and systemic chemotherapy. However, the effectiveness of these modalities has not been established. Both irradiation and systemic chemotherapy including a second transplantation would result in additional toxicity. In this report we describe a boy with ITR 91 months after BMT who has remained in complete remission more than two yr after a unilateral orchiectomy. We did not treat this patient with systemic chemotherapy, as his ITR developed very late. Our experience suggests that orchiectomy alone is a reasonable option for very late ITR after BMT.     

BK virus-associated fatal renal failure following late-onset hemorrhagic cystitis in an unrelated bone marrow transplantation

The human polyomavirus BK (BKV)-associated hemorrhagic cystitis (HC) has been a frequent and seldom life-threatening complication after bone marrow transplantation (BMT). The authors report a male with myelodysplastic syndrome, who developed BKV-associated late-onset HC 12 days after HLA-matched unrelated BMT. His urine contained epithelial cells with intranuclear inclusion bodies suggestive of BKV infection and was positive for BKV in polymerase chain reaction. He did not respond to any treatment for HC. In addition, he developed BKV-associated acute renal failure on day 26, followed by hepatic veno-occlusive disease on day 42. This is the first case in which BKV may be associated with fatal progressive renal failure.     

BK VIRUS-ASSOCIATED FATAL RENAL FAILURE FOLLOWING LATE-ONSET HEMORRHAGIC CYSTITIS IN AN UNRELATED BONE MARROW TRANSPLANTATION

The human polyomavirus BK (BKV)-associated hemorrhagic cystitis (HC) has been a frequent and seldom life-threatening complication after bone marrow transplantation (BMT). The authors report a male with myelodysplastic syndrome, who developed BKV-associated late-onset HC 12 days after HLA-matched unrelated BMT. His urine contained epithelial cells with intranuclear inclusion bodies suggestive of BKV infection and was positive for BKV in polymerase chain reaction. He did not respond to any treatment for HC. In addition, he developed BKV-associated acute renal failure on day 26, followed by hepatic veno-occlusive disease on day 42. This is the first case in which BKV may be associated with fatal progressive renal failure.     

An Unusual Case of Calcineurine Inhibitor Pain Syndrome

Cyclosporine induced pain syndrome (CIPS) is a newly diagnosed complication of calcineurine inhibitors, mainly observed in solid organ and hematopoetic transplantations. The present case is a male child with steroid resistant nephrotic syndrome on low therapeutic level cyclosporine treatment. He presented with intractable and debilitating leg pain, with no reported history of previous injury or trauma. The pain was reluctant to antimicrobial and sedative treatment. MRI revealed bone marrow and soft tissue edema in the mid shaft of patient’s right leg. Inspite of unusual manifestations, CIPS was suggested and cyclosporine discontinued. However, the pain did not improve and was resistant to calcium blocker. Subsequently, core decompression was performed as an unusual treatment of CIPS, revealing normal bone morphology. The pain improved rapidly and the patient was discharged a few days later.     

Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology

Transfusion-dependent Diamond-Blackfan anemia (DBA) patients opt for allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Clinical outcomes of 19 transplanted Japanese patients were analyzed. Prior to HSCT, 10 patients (53%) suffered hemosiderosis with organ dysfunction, and all eight with short stature (42%) had adverse effects of prednisolone. Median age at the time of HSCT was 56 months. Transplantation sources were 13 bone marrow [six human leukocyte antigen (HLA)-matched siblings, and six HLA-matched and one HLA-mismatched unrelated donors], five cord blood (two HLA-matched siblings and three HLA-mismatched unrelated donors), and one peripheral blood from haploidentical mother. All 13 patients with bone marrow transplantation (BMT) and two with sibling cord blood transplantation (CBT) had successful engraftment. Of three patients who underwent unrelated CBT, one died after engraftment, and the other two had graft failure but succeeded in a second BMT from an HLA-disparate father and unrelated donor, respectively. One died shortly after haploidentical PBSCT. The five-yr failure-free survival rate after BMT was higher than CBT (100%: 40%, p=0.002). Platelet recovery was slower in seven unrelated BMT than in six sibling BMT (p=0.030). No other factors were associated with engraftment and survival. These results suggest that allogeneic BMT, but not unrelated CBT, is an effective HSCT for refractory DBA.     

Post-traumatic duodenopancreatectomy in a child.

We describe a 5-year-old boy who complained of severe abdominal pain after a car accident. He was sitting on the lap of the driver and his abdomen was pressed closely between the pregnant driver and the steering wheel. At operation, associated injuries to the duodenum and pancreas were detected which could not be repaired. The transected pancreas and extensive duodenal injury underwent a Whipple-type reconstruction. On postoperative day six, the patient was re-operated due to extensive liver necrosis which was detected on abdominal computerized tomography and a partial liver resection was performed. He was discharged on day 16 after the second operation and has done well so far.     

Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: A retrospective study of the risk factors

Abstract:  CMV infection is one of the major causes of morbidity and mortality after HSCT. The aim of this single center retrospective study was to analyze risk factors for CMV infection in pediatric patients who underwent HSCT. We retrospectively reviewed the medical records of 117 pediatric patients who underwent allogeneic HSCT at Asan Medical Center between December 2000 and January 2007. After HSCT, CMV antigenemia was detected by identifying CMV pp65 early antigen in white blood cells. The incidence of CMV antigenemia was 24% (28/117) at a median of 38 days (range: 19–123 days) after HSCT. In multivariate analysis, CMV antigenemia occurred significantly more often in CMV seropositive recipients, patients who received grafts from alternative donors, T-cell depleted grafts, patients on ATG-containing conditioning regimens, or patients who received steroid for acute GVHD (p < 0.05). CMV antigenemia tend to develop earlier in patients who received ATG-containing conditioning regimens (p = 0.09). A second episode of CMV antigenemia was observed in three out of 28 patients (11%). The incidence of CMV disease was 5.9% (7/117) at a median of 97 days (range: 34–120 days). Manifestation of CMV disease included retinitis in two, pneumonitis in two, hepatitis in one, hepatitis with colitis in one, and gastritis in one. Six of the 12 patients (50%) with HG antigenemia (CMV pp65 antigen positivity ≥40 cells) developed clinical CMV disease, a rate that was significantly higher than seen in patients with LG antigenemia (6.25%; p < 0.01). We recommend that patients with these risk factors should carefully undergo regular evaluations for CMV infection. We also suggest that earlier and more aggressive preemptive treatment and serial follow-up of CMV disease is necessary in patients with HG-antigenemia.     

Successful rescue of refractory acute antibody-mediated renal allograft rejection with splenectomy--a case report

Highly sensitized patients receive fewer kidney transplants and have a high risk for severe rejection with increased rates of graft loss. We present a highly sensitized child who after desensitization protocol received a kidney transplant and developed refractory acute antibody-mediated rejection. He failed to respond to standard therapy and needed an urgent splenectomy as rescue therapy. Our patient, an 18-yr-old AA male with ESRD due to obstructive uropathy received a second DD transplant. The allograft functioned immediately with SCr 1.4 mg/dL on day #5. On day #8, he was re-admitted with fever, oligoanuria, and renal failure. He was started on methylprednisolone pulse, thymoglobulin, intravenous immunoglobulin, and PP. The transplant kidney biopsy revealed features suggestive of acute AMR. On day #14, the patient remained dialysis dependent with no response to therapy. He underwent an urgent splenectomy and a slow increase in urine output and GFR was noted. The SCr one month post-splenectomy was 1.1 mg/dL. At one yr post-txp, his GFR remained stable with SCr 0.9 mg/dL on tacrolimus, mycophenolate mofetil, and prednisone. Urgent splenectomy successfully reversed refractory acute AMR, in our highly sensitized patient with second renal transplant.     

Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient

Post-transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin-inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus-associated CIPS, and the first report in the pediatric setting.     

The second mini-transplant for unstable mixed chimerism within the first 100 days after hematopoietic stem cell transplant in severe thalassemia

Allogeneic HSCT is the only curative treatment for severe thalassemia disease. MC occurs in one-third of these patients within the first two months after HSCT; this is a major risk factor of graft rejection, especially when RHCs are more than 25%. There is still no consensus for the management of MC, especially in the early phase of HSCT. The DLI has also been described in the treatment of MC following HSCT for hemoglobinopathies, but its success is still not guaranteed. The second HSCT has been an approach used in an attempt to cure patients who reject their graft. Concern about toxicity of conditioning regimen, the second HSCT is usually delayed for at least a year after the first HSCT. We would like to demonstrate the successful use of the second mini-allogeneic HSCT in hemoglobin E/β-thalassemia with evidence of unstable MC in the first 100 days after allogeneic HSCT to prevent further graft loss after allogeneic HSCT.     

Rituximab for post-transplant recurrences of FSGS

Abstract:  A 14-yr-old boy whose primary kidney disease was FSGS developed severe recurrence of proteinuria immediately after a second living-related kidney transplant. Despite pre- and post-operative PP and immunosuppressive treatment consisting of steroids, CycA, daclizumab, and MMF, daily protein excretion and serum creatinine increased. We therefore administered rituximab on the fourth day of transplantation. He received four weekly doses of rituximab (375 mg/m²/dose), which resulted in a rapid clearing of circulating CD19-positive B cells, and remission of proteinuria was achieved six wk after the first rituximab treatment. Graft function was excellent six months after transplantation with proteinuria of 8 mg/m²/h. We conclude that rituximab may be an effective treatment for post-transplant recurrence of FSGS.     

Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy

In an attempt to elucidate prognostic factors, the data on 12 boys who underwent haematopoietic stem cell transplantation (HSCT) for cerebral X-linked adrenoleukodystrophy were evaluated. Two further patients received HSCT but died from transplantation-related complications. The data included neurological examination, neuropsychological testing and magnetic resonance imaging (MRI). Follow-up after HSCT was up to 5.5 years. Six patients showed a moderate to severe clinical deterioration after HSCT including two who died within 6 months. In this group, a MRI severity score of 10 or higher before HSCT was associated with severe impairment and a score of more than 12 was followed by rapid deterioration and death after HSCT. The presence of neurological symptoms before HSCT also affected prognosis. Six patients showed no deterioration in neurological or neuropsychological assessment after HSCT. CONCLUSION: our data confirm that haematopoietic stem cell transplantation can stop the progress of demyelination when performed at a critical early stage of the disease. The prognosis in an individual patient for the clinical course after stem cell transplantation can in general be given based on the status before transplantation, although individual patients may show an unexpected course.     

Aspergillus "fungus ball" of the bladder after hematopoietic transplantation in a pediatric patient: successful treatment with intravesical voriconazole and surgery

Abstract:  Aspergillosis is an important cause of mortality in allogeneic HSCT. A "fungus ball" formation of Aspergillus in the bladder has seldom been reported. We report a child that underwent HSCT and developed possible disseminated aspergillosis with an intravesical "fungus ball," diagnosed by genitourinary MRI and PCR of the mass that was removed from the bladder. It is important to consider this complication in a patient with HC after HSCT. The treatment included a combination of systemic antifungal therapy along with intravesical voriconazole and surgical removal.     

Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant

Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute‐onset worsening neurological deficits on day +226 after the second transplant and a post‐mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.