Remission With Donor Lymphocyte Infusion in a Child With Marrow Relapse After Haploidentical Stem Cell Transplantation for Relapsed Stage 4 Neuroblastoma

A 7‐year‐old male with Stage 4 neuroblastoma was treated with chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), resulting in partial response with residual bone and marrow disease. He proceeded to haploidentical‐HSCT with his mother as donor and achieved remission. The patient developed marrow relapse 2 years after haploidentical‐HSCT with cytopenia and dropping donor chimerism. Donor lymphocyte infusion (DLI) using mother's whole blood was given resulting in clearance of marrow disease, resolution of cytopenia, and full donor chimerism. This is the first report of successful treatment for neuroblastoma relapse after haploidentical‐HSCT using DLI alone, supporting the role of adoptive cell therapy post‐HSCT in neuroblastoma.     

Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia

Jasinska A, Kalwak K, Trelinska J, Borowiec M, Piatosa B, Zeman K, Mlynarski W. Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia. Abstract: HIGM syndrome is a group of primary immunodeficiency disorders characterized by recurrent bacterial and opportunistic infections; it is also associated with normal to elevated serum IgM levels and a concomitant deficiency of IgG, IgA, and IgE. In this report, we give account of a boy with X‐linked HIGM and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia as the dominating symptom. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. This boy suffered from life‐threatening infections and required high doses of rhG‐CSF, and a haploidentical PBSCT was also successfully performed, thus leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). Two low‐dose T‐cell addbacks were required to re‐establish full donor chimerism and clear CMV reactivation. The report demonstrates that in select cases, alternative donor allogeneic HSCT supported by DLI may be effective in correcting the defect in X‐linked HIGM, and HSCT in HIGM children is not necessarily limited to matched sibling donor transplantation.     

Chronic granulomatous disease: Clinical,molecular, and therapeutic aspects

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X‐linked recessive (XR‐CGD) form caused by mutations in the CYBB gene encoding the gp91^phox protein, and an autosomal recessive (AR‐CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22^phox, p47^phox, p67^phox, and p40^phox, respectively. Patients suffering from this disease are susceptible to severe life‐threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR‐CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN‐lentiviral vectors targeting gp91^phox expression in myeloid cells to increase the safety and efficacy of the GT protocols.     

Successful treatment of post‐transplant thrombocytopenia with romiplostim in a pediatric patient with X‐linked chronic granulomatous disease

Thrombocytopenia is a frequent complication following HSCT in pediatric patients. Romiplostim is a TPO receptor agonist that has been utilized successfully in the treatment of pediatric patients with immune thrombocytopenia. We describe a three‐yr‐old male with X‐linked CGD treated with an unrelated donor bone marrow transplant. His course was complicated by the development of symptomatic thrombocytopenia. He was started on romiplostim with prompt improvement in his thrombocytopenia. We found the use of romiplostim to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of immunosuppressive agents such as corticosteroids.     

Low‐dose total‐body irradiation and alemtuzumab‐based reduced‐intensity conditioning regimen results in durable engraftment and correction of clinical disease among children with chronic granulomatous disease

HSCT with MAC is associated with durable donor engraftment for patients with CGD; however, MAC is limited by high rates of RRT. We used a novel RIC regimen with LD‐TBI (200 cGy × two doses), fludarabine (30 mg/m² × three doses), and proximal alemtuzumab (0.5 mg/kg/dose × one dose) and unrelated donor grafts for consecutive patients with high‐risk CGD who were not candidates for MAC at our institution. Among four children with CGD transplanted at our institution, three PBSC recipients are alive with sustained donor engraftment (median follow‐up: two yr) and resolution of pre‐HSCT active infections while one patient with bone marrow graft is alive after graft failure and autologous recovery. RIC may be a curative option for children with high‐risk CGD.     

T cell replete–haploidentical second hematopoietic stem cell transplantation for primary graft failure in pediatric patients with hematologic malignancies

GF is one of the fatal complications of allogeneic HSCT. To rescue patients with primary GF, a second HSCT should be conducted as soon as possible, but the optimal donor source and technique have yet to be established. In this study, we retrospectively analyzed six children with hematologic malignancies who received TCR‐haploidentical second HSCT for primary GF. The median interval between the prior HSCT and the second HSCT was 37.5 days. All patients received fludarabine and ATG containing reduced‐intensity re‐conditioning before the second HSCT. All patients, except one who died early, achieved both neutrophil and Plt engraftment at a median time of 15 and 33 days, respectively. Chimerism analysis showed that all engrafted patients achieved complete donor chimerism within 3 weeks. Four patients developed acute GVHD, and three patients developed chronic GVHD. TRM occurred in two patients. Median follow‐up of the four survivors was 6.8 years, and all remained in sustained remission until the last follow‐up. These results suggested that a TCR‐haploidentical second HSCT for pediatric patients is feasible, and this approach may provide a potent option for children with primary GF.     

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.     

A single-center study of hematopoietic stem cell transplantation for primary immune deficiencies (PIDD)

DiNardo L, Brown V, Perez E, Bunin N, Sullivan KE. A single‐center study of hematopoietic stem cell transplantation for primary immune deficiencies (PIDD).
Pediatr Transplantation 2012: 16: 63–72. © 2011 John Wiley & Sons A/S. Abstract: PIDD are rare inherited disorders that can result in life‐threatening infections. Allogeneic HSCT is the only cure for many primary immune deficiencies; however, the specific diseases and optimal type(s) of transplants are not clear. This study compares transplant outcomes in a large cohort with a relatively uniform pre‐ and post‐transplant management strategies. We conducted a retrospective analysis of 39 pediatric patients who underwent HSCT for SCID (n = 25) or other immune deficiencies (n = 14) from 1986 to 2010. A structured case report form was used to collect clinical information. The outcomes of survival, immune reconstitution, engraftment, incidence of GvHD and IVIG dependency were tabulated. Overall survival rates were 88% for SCID and 86% for other primary immune deficiencies, which are high compared to other historical series. No single variable was associated with mortality. Immunoglobulin dependence occurred only in patients who had X‐linked SCID and a parental donor haploidentical transplant. Because of improved supportive care and use of alternative donors and conditioning regimens, HSCT has become an acceptable option for an increasing number of PIDD subtypes not previously transplanted with high frequency. This study encourages greater use of transplantation.     

Persistent Multiyear Control of Relapsed T‐Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report

There are few therapeutic options for patients with T‐cell acute lymphoblastic leukemia (T‐ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T‐ALL. We present the case of a now 9‐year‐old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life.     

Successful treatment of BCG‐related immune reconstitution inflammatory syndrome following ex vivo T‐cell–depleted haploidentical hematopoietic stem cell transplantation: A case report

IRIS is a phenomenon describing localized inflammatory reactions at BCG vaccination site and development of lymphadenopathy as immune system recovers. It is a rare entity in children following haploidentical HSCT. We represent the successful treatment of a case with fluctuating lymphadenopathy due to BCG vaccine during immune reconstitution period following ex vivo T‐cell–depleted haploidentical HSCT.     

Two‐year‐old boy with cervical and liver abscesses

Pyogenic liver abscesses are rare in children but relatively common in those with chronic granulomatous disease (CGD). We present a case of a 2 year old boy who initially presented with BCGitis and Staphylococcus aureus cervical adenitis, and then subsequently developed liver abscesses. A diagnosis of X‐linked CGD was confirmed. This case demonstrates the typical radiological features of liver abscesses in CGD, its management without surgical intervention, and the increasingly recognised complications of BCG vaccination in CGD.     

Autoimmune thyroiditis following HLA‐matched sibling hematopoietic stem cell transplantation for Wiskott‐Aldrich syndrome

WAS is a fatal X‐linked combined immunodeficiency syndrome, the only cures for which are HSCT or gene therapy. AID occur in up to 72% of patients with WAS who do not receive HSCT, likely arising secondary to impaired multilineage immune autoregulatory function; AITD is not typically seen. In this article, we describe the case of a male patient who underwent HLA‐matched HSCT for WAS at the age of 5 months, with his sister (a WAS carrier) acting as his donor and subsequently developed AITD 12 months post‐transplant, with marked elevation of antithyroid peroxidase antibody titer. His donor sister was subsequently found to have elevated antithyroid peroxidase antibody titer with increasing trend and normal thyroid function. Although several mechanisms exist by which our patient may have developed AITD, we suggest the transfer of autoreactive donor immune cells as the most plausible explanation.     

Cytomegalovirus reactivation posthematopoietic stem cell transplantation (HSCT) and type of graft: A step toward rationalizing CMV testing and positively impacting the economics of HSCT in developing countries

We aimed to determine a correlation between cytomegalovirus reactivation post hematopoeitic stem cell transplantation (post‐HSCT) with the type of graft source, defining children at risk. We analyzed data on children less than 18 years of age undergoing HSCT from 2002 to May 2016 (n = 464). Correlation between reactivation and graft source was analyzed statistically. Reactivation occurred in 3% of children with matched‐related donor (MRD) transplants, 33.3% with unrelated peripheral blood stem cells, 17.4% with unrelated cords, and 36.5% (15/41) with mismatched or haploidentical grafts (P = <0.0001). MRD does not warrant weekly PCR, unlike unrelated or haploidentical donors, thus defining protocols for developing countries with limited resources.     

Treosulfan‐based reduced toxicity hematopoietic stem cell transplantation in X‐linked agammaglobulinemia: A cost‐effective alternative to long‐term immunoglobulin replacement in developing countries

X‐linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan‐based regimen with resultant autologous reconstitution. At 6 months post‐HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow‐up of 20 months have 100% chimerism. Treosulfan‐based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.     

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.     

Mendelian susceptibility to mycobacterial disease—Challenges in hematopoietic stem cell transplantation

We present our experience in the hematopoietic stem cell transplantation (HSCT) in two children diagnosed with Mendelian susceptibility to mycobacterial diseases. The first child underwent a haploidentical HSCT with posttransplant cyclophosphamide using a reduced intensity conditioning following which he had primary graft failure. He was subsequently found to have interferon‐γ1 receptor deficiency. He had immune reconstitution and is on antitubercular therapy. The second child diagnosed with IL12RB1 gene mutation underwent matched sibling donor HSCT with myeloablative conditioning following pretransplant immunosuppression with fludarabine and dexamethasone. He is 13 months post‐HSCT with complete and remains disease free.     

Haploidentical stem cell transplantation with posttransplant cyclophosphamide for refractory systemic juvenile xanthogranuloma

Juvenile xanthogranuloma (JXG) is a generally benign, self‐limited histiocytic disorder, which belongs to non‐Langerhans cell histiocytoses (non‐LCH). However, systemic JXG can be fatal in rare cases. We present the case of an 11‐year‐old female with systemic JXG, who experienced repeated vertebral compression fractures and did not fully respond to systemic chemotherapy. Based on its reported efficacy in LCH, the patient underwent human leukocyte antigen‐haploidentical hematopoietic stem cell transplantation (HSCT) with posttransplant cyclophosphamide. The patient did not suffer major complications and has not experienced relapse for 13 months since HSCT. HSCT may be a potential treatment option for patients with refractory non‐LCH.     

Tolerance and effectiveness of nivolumab after pediatric T‐cell replete,haploidentical, bone marrow transplantation: A case report

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22‐year‐old female with multiple‐relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post‐haplo) HSCT. Anti‐PD‐1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft‐versus‐host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD.     

Successful treatment of idiopathic colitis related to XIAP deficiency with allo‐HSCT using reduced‐intensity conditioning

Recently, it has been reported that Crohn's‐like intractable colitis occurred in approximately 20% of the patients with XIAP deficiency, also known as X‐linked lymphoproliferative disease type 2. Because treatment used for Crohn's disease is not always effective for Crohn's‐like colitis related to XIAP deficiency, more effective treatment should be established. Although several studies reported allo‐HSCT might be promising even for Crohn's‐like colitis related to XIAP deficiency, the outcome of allo‐HSCT using MAC for XIAP deficiency is extremely poor due to frequent TRM. In addition, there is little information about the outcome of allo‐HSCT for intractable colitis related to XIAP deficiency. Herein, we describe a patient with intractable colitis related to XIAP deficiency who was successfully treated with allo‐HSCT using a reduced‐intensity conditioning regimen. Although allo‐HSCT using the RIC regimen might be a curative therapeutic option for intractable colitis with XIAP deficiency, the prognostic factors that will determine the success of allo‐HSCT require further clinical information of more patients.     

��Ѫ��ϸ����ֲ���ƶ�ͯ��Ѫ����չ

造血干细胞移植是目前治疗儿童白血病的重要手段之一。造血干细胞移植的适应证因白血病类型和供者种类不同而有所不同;供者以往以同胞供者为主,目前无关供者移植的生存率已接近同胞供者,半相合移植治疗白血病也越来越被临床所接受;各种细胞辅助治疗逐渐突显优势。造血干细胞移植治疗白血病进展迅速,临床应有所了解。