Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced‐intensity conditioning cord blood transplantation

Hatakeyama N, Hori T, Yamamoto M, Inazawa N, Hirako Y, Tsutsumi H, Suzuki N. Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced‐intensity conditioning cord blood transplantation.
Pediatr Transplantation 2010: 14: E4–E10. © 2009 Wiley Periodicals, Inc. Abstract: The prognosis of multisystem LCH in children with risk organ involvement is extremely poor when they fail to respond to conventional chemotherapy. In such patients, allogeneic SCT may produce complete and sustained remission; however, high‐dose myeloablative regimens are frequently associated with treatment‐related morbidity and mortality. More recently, allogeneic SCT following an RIC regimen has been performed as an alternative salvage approach. We describe a nine‐month‐old boy with refractory multisystem LCH with pulmonary aspergillosis who was successfully treated with reduced‐intensity cord blood transplantation.     

Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis

Children with MS‐LCH that fail to respond to conventional chemotherapy have poor outcomes. HSCT represents a potential salvage approach. It has been applied in over 50 cases in recent years. HSCT can achieve greater disease control than chemotherapy, but it carries a high risk of transplant‐related mortality; thus, the haploidentical parental HSCT is used infrequently in pediatric refractory LCH. We report the first successful haploidentical parental HSCT, with no T‐cell depletion, in two girls, aged 26 months and five months, with refractory MS‐LCH. The mothers were donors with 5/6 and 4/6 HLA matches, respectively. The conditioning regimen included busulfan + cyclophosphamide + etoposide + antithymocyte‐globulin ± fludarabine; the GVHD prophylaxis was based on cyclosporine + methotrexate ± mycophenolate‐mofetil ± zenapax. In both cases, the stem cells were sourced from peripheral blood and BM, which included CD34+ cells (13.17 × 10⁶/kg and 40.23 × 10⁶/kg, respectively). These patients survived and showed no signs of disease activity in 54‐ and 44‐month post‐HSCT follow‐ups. Our results indicated that, for patients that fail chemotherapy delivered early in the disease, but do not show organ dysfunction progression, it may be possible to achieve successful haploidentical parental HSCT with a strong myeloablative regimen.     

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four‐yr‐old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non‐malignant lymphoproliferative disorder fueled by excessive IL‐6 production. Treatment with IL‐6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti‐coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti‐coagulation regimen to coincide with changes in the inflammatory state.     

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.     

Bone marrow engraftment and associated dermatologic sequelae in a three‐yr‐old after liver transplantation

We present a case of a three‐yr‐old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft‐vs.‐host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post‐transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft‐versus‐host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described.     

Acute monoblastic leukemia that switched lineage at relapse to acute lymphoblastic leukemia: a case report

We herein present the case of an acute monoblastic leukemia infant who relapsed with acute lymphoblastic leukemia (ALL). Complete remission was achieved after an acute myeloblastic leukemia-directed chemotherapy, but the patient relapsed with pro-B ALL. As he did not respond to acute myeloblastic leukemia-type reinduction therapy, he was switched to ALL-type chemotherapy, and a complete remission was achieved. Unrelated cord blood stem cell transplantation was performed, but he relapsed with pro-B ALL again. After he received ALL-type chemotherapy, he underwent another bone marrow transplant from his human leukocyte antigen mismatch mother, and has been free from recurrence for over 8 months.     

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.     

Mini-hyper CVD + CRIB (condensed rituximab,inotuzumab ozogamicin,and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia

Relapsed or refractory pediatric patients with B-acute lymphoblastic leukemia (B-ALL) have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male child with high-risk B-ALL that was refractory to several re-induction regimens. He was put into minimal residual disease-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin, and blinatumomab, termed mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) plus CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab). This regimen was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.     

Low incidence of hepatic veno‐occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin,oral glutamine,and ursodiol at a single transplant institution

Lakshminarayanan S, Sahdev I, Goyal M, Vlachos A, Atlas M, Lipton JM. Low incidence of hepatic veno‐occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin, oral glutamine, and ursodiol at a single transplant institution.
Pediatr Transplantation 2010: 14:618–621. © 2009 John Wiley & Sons A/S. Abstract: We report the low incidence of hepatic VOD in pediatric patients with various diagnoses including hematologic malignancies and non‐malignant conditions transplanted at our institution. Retrospective review of 188 patients who underwent HSCT and received a combined prophylactic regimen of intravenous heparin, oral glutamine, and ursodiol was undertaken. Analysis of the outcome of VOD revealed only one clinical case with acute myeloid leukemia; the patient developed hepatic VOD 10 days after receiving myeloablative chemotherapy with busulfan and CTX followed by HLA‐matched related peripheral blood stem cell transplantation. The low incidence of hepatic VOD in an otherwise high‐risk pediatric transplant population is an important observation, which may be partly attributed to this prophylactic regimen, and warrants further randomized clinical trials for confirmation.     

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.     

Allogeneic hematopoietic cell transplantation in chemotherapy‐induced aplasia in children with high‐risk acute myeloid leukemia or myelodysplasia

Relapse remains the most common cause of treatment failure after hematopoietic cell transplantation for acute myeloid leukemia. Inability to achieve hematologic complete remission has been a barrier to transplant for patients with refractory disease. We describe six children with refractory myeloid disease undergoing transplant in chemotherapy‐induced aplasia, as a strategy to facilitate curative therapy in refractory patients. Clofarabine‐ or high‐dose cytarabine‐based chemotherapy regimens were used to achieve marrow aplasia, followed by reduced‐intensity conditioning and allogeneic transplant before hematologic recovery. Long‐term disease control was achieved in five, with one transplant‐related mortality, suggesting the feasibility of this approach.     

Successful long‐term hematological and immunological reconstitution by autologous cord blood transplantation combined with post‐transplant immunosuppression in two children with severe aplastic anemia

aUCBT is a valuable curative option in pediatric patients with refractory idiopathic SAA and no available matched sibling or unrelated donors. Experience in the use of autologous cord blood units in patients with SAA is limited and private for‐profit cord blood‐banking programs are controversial. We report the successful treatment of two patients with SAA, aged 15 and 24 months, with autologous cord blood combined with immunosuppression. After conditioning with 200 mg/kg cyclophosphamide and ATG, 7.5 mg/kg, 32.2 × 10⁷/kg, and 3.8 × 10⁷/kg autologous cord blood nucleated cells were infused, respectively. One of our patients underwent transplantation after failure of IST. Both patients received post‐transplant immunosuppression with cyclosporine for 12 months. They remain disease‐free 6 years post‐transplantation.     

High‐dose chemotherapy with autologous stem cell rescue for treatment of retinoblastoma: Report of five cases

RB is a primarily pediatric cancer arising from the retina, initiated by biallelic loss of the RB1 gene. We report five children with bilateral RB (n = 3), extra‐ocular disseminated RB, or disseminated relapsed RB, who were treated with tandem high‐dose chemotherapy and autologous stem cell rescue. All patients received at least 2.2 × 10⁶/kg CD34⁺ (median, 3.9 × 10⁶/kg) cells. The preparative regimen for course 1 was carboplatin, thiotepa, etoposide, and for course 2, CM and melphalan. ANC of at least 0.5 × 10⁹/L occurred at a median of 11 days (range, 10–12) and 15 days (range, 12–16) after the first and second procedure, respectively. Platelet engraftment occurred at a median of 13 days (range, 12–17) and 15 days (range, 14–22) after the first and second procedure, respectively. All of the five patients treated remain alive and disease free at the last follow‐up time, ranging between 21 and 44 months after completion of autologous transplant. Additional therapy was required in one patient, in whom enucleation had to be performed because of early disease relapse, refractory to local therapy. Intensification of chemotherapy with repeated high‐dose chemotherapy and autologous rescue appears an acceptable choice in selected cases with bilateral or extra‐ocular disease, either recurrent or refractory.     

Long‐term response of juvenile idiopathic arthritis after conditioning with 8 Gy total body irradiation followed by autologous peripheral blood stem cells: Case report

Woolfrey A, Storek J, Bowyer S, Nelson R, Robertson M, Wallace C. Long‐term response of juvenile idiopathic arthritis after conditioning with 8 Gy total body irradiation followed by autologous peripheral blood stem cells: Case report.
Pediatr Transplantation 2010: 14:E65–E69. © 2009 John Wiley & Sons A/S. Abstract: Investigations of HCT for refractory JIA have employed high dose immunosuppressive drugs, such as CY and ATG with or without low dose TBI. Initial disease response has been observed in approximately two‐thirds of patients; however, relapse occurs in about half of the responders. The current report describes a regimen with substantially increased dose of TBI, previously shown to be associated with high rate of disease response in adult patients with refractory MS and severe SSc. We report outcome of the lead patient in this pilot study, who remains in complete remission now, five yr after HCT. This regimen should be considered for patients with JIA refractory to medical therapies, including previous low intensity regimen HCT.     

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.     

Alemtuzumab,Fludarabine, Low‐Dose TBI,and Double Umbilical Cord Transplant for Primary Graft Failure in a Patient with Recurrent HLH

Graft failure occurs at relatively low frequency, but commonly in hemophagocytic lymphohistiocytosis (HLH), especially with umbilical cord blood transplant (UCBT). No standard approaches to management of graft failure exist. We present a challenging case of relapsed HLH following first UCBT with primary graft failure following second UCBT. We report a novel reduced intensity conditioning regimen of alemtuzumab, 4 Gy total body irradiation and fludarabine for salvage of primary graft failure followed by double UCBT. The reported patient successfully engrafted with 100% donor chimerism following salvage UCBT with no occurrence of acute or chronic graft‐versus‐host disease.     

HHV‐6 encephalitis in pediatric unrelated umbilical cord transplantation: A role for ganciclovir prophylaxis?

Cheng FWT, Lee V, Leung WK, Chan PKS, Leung TF, Shing MK, Li CK. HHV‐6 encephalitis in pediatric unrelated umbilical cord transplantation: A role for ganciclovir prophylaxis?
Pediatr Transplantation 2010: 14:483–487. © 2009 John Wiley & Sons A/S. Abstract: The role of ganciclovir as HHV‐6 prophylaxis in unrelated HSCT setting remains controversial. We performed an eight‐yr retrospective review of patients received unrelated HSCT from January 2000 to September 2008. From January 2002, ganciclovir prophylaxis 5 mg/kg twice daily for seven days for all unrelated HSCT before transplant was adopted. The prevalence of HHV‐6 encephalitis was studied before and after the change in policy. Fifty‐four unrelated HSCT were performed from January 2000 to September 2008. Four cases (7.4%) of HHV‐6 encephalitis were diagnosed. All of them were due to variant B infection. Two cases out of 16 cases (12.5%) were diagnosed before adoption of the policy; two cases out of 38 cases (5.3%) were diagnosed afterward. All of them were unrelated UCB transplant recipients. They were all seropositive to HHV‐6 before transplant. Two cases complicated with significant residual neurological deficit and refractory seizure. The other two cases died of other transplant‐related mortalities. We conclude that HHV‐6 encephalitis is still a rare complication of unrelated HSCT and may be more common in unrelated UCB transplant. Routine use of ganciclovir as HHV‐6 prophylaxis in all unrelated HSCT recipients may not be justified but may have a role in unrelated UCB transplant.     

无关脐血移植治疗儿童噬血细胞综合征

目的探讨脐血移植对儿童噬血细胞综合征的治疗效果。方法一例16月龄确诊为噬血细胞综合征的幼儿,经HLH-2004推荐方案进行化疗及免疫治疗7个月后,病情未缓解,行HLA基因位点5/6相合无关脐血移植。预处理采用BU/CY+VP16方案:马利兰(BU)1mg/kg,第6h一次,用4d共16次(-8~-5d);足叶乙甙(VP16)30mg/kg,用1天(-4d);环磷酰胺(CY)60mg/kg,用2d(-3~-2d)。输入脐血有核细胞(NC)5·66×107/kg,CD3+4细胞1·21×105/kg。GVHD预防采用环胞菌素A(CsA)+骁悉(MMF)+抗胸腺细胞球蛋白(ATG)。移植后应用G-CSF加速造血重建。结果脐血造血干细胞未植入,自体造血恢复。移植治疗后,患儿病情逐渐好转。随访至移植后14个月,病情持续完全缓解。结论噬血细胞综合征经化疗和免疫治疗不能缓解者,应及时进行移植治疗;供体细胞植入失败的移植,也有可能暂时或长期缓解病情。     

Successful induction of therapeutic urinary concentration by intravenous ganciclovir and oral valganciclovir with remission of adenoviral hemorrhagic cystitis after cord blood transplantation

AdV11‐HC is one of the major complications after allogeneic HSCT in Japan. We previously reported that the intravenous infusion of ganciclovir was effective against AdV11‐HC in a post‐transplant patient. We here report a case of a 10‐year‐old boy who underwent cord blood transplantation for the treatment of relapsed lymphoblastic lymphoma. He developed AdV11‐HC with an elevated AdV load in his urine and blood on day 14 after HSCT. He was immediately treated with intravenous ganciclovir; he rapidly achieved a remission of AdV11‐HC with a decreased AdV load in his urine and blood. He remained in remission of AdV11‐HC, even after we switched ganciclovir to oral valganciclovir on day 63. A pharmacokinetics study of his urine revealed that therapeutic concentrations of ganciclovir could be achieved by both intravenous ganciclovir and oral valganciclovir. These findings suggested that both intravenous ganciclovir and oral valganciclovir could be promising alternatives for the treatment of AdV11‐HC in post‐transplant patients.     

Successful treatment of refractory donor lymphocyte infusion‐induced immune‐mediated pancytopenia with rituximab

A 6‐year‐old male with chronic granulomatous disease, who was transplanted with bone marrow and exhibited increasing mixed chimerism, subsequently received two donor lymphocyte infusions (DLI). Two weeks after the second DLI, the patient developed acute graft‐versus‐host disease (GVHD) and progressive pancytopenia that was associated with autoantibody production. Conventional treatment did not improve the pancytopenia. However, administration of Rituximab (RTX) (375 mg/m²/week for four consecutive weeks) resulted in a rapid resolution of the pancytopenia. The patient achieved full donor chimerism without GVHD symptoms. RTX can be valuable for managing immune‐mediated cytopenias that arise after DLI and are refractory to conventional therapies. Pediatr Blood Cancer 2010;54:329–331. © 2009 Wiley‐Liss, Inc.