Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (SCT) is the treatment of choice for many malignant hematological disorders. Following recent improvements in non-relapse-related mortality rates, relapse has become the commonest cause of treatment failure. Infusion of donor lymphocytes can potentially enhance immune-mediated antitumor activity and offers a salvage option for some patients. This paper reviews the current literature on the efficacy of this therapeutic strategy. AREAS COVERED: The biology of adoptive cellular therapy with allogeneic immune cells to treat relapse across a spectrum of diseases in both the full intensity and reduced intensity hematopoietic SCT settings is explored. The review discusses the current limitations of the approach and reviews several new experimental strategies which aim to segregate the desired graft-versus-tumor effect from the deleterious effects of more widespread graft-versus-host reactivity. EXPERT OPINION: Durable responses to DLI have been noted in chronic myeloid leukemia and responses have also been described in acute leukemia, multiple myeloma and chronic lymphoproliferative disorders. The new challenge in transplantation is to optimize DLI therapy in order to further improve patient outcomes.     

The use of monoclonal antibodies for the treatment of graft-versus-host disease following allogeneic stem cell transplantation

Introduction: Graft-versus-host disease (GVHD) remains the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Steroids along with calcineurin inhibitors remain the standard initial therapy, however, less than half of the patients completely respond and there is no uniformly accepted therapy for patients with steroid-resistant GVHD.

Areas covered: This paper reviews the current role and ongoing development of mAbs in the treatment of GVHD. Various mAbs to cell surface antigens on GVHD effector cells have been investigated for the treatment of acute GVHD: these include anti-TNF-α antibodies, IL-2 receptor antagonists, anti-CD3 and anti-CD52 mAbs, while anti-CD20 mAb has been extensively investigated in the setting of chronic GVHD. Overall, response rates have been reported to be greater than 60%, although it should be emphasized that the long-term survival still remains suboptimal, mainly due to the detrimental side effects of infectious complications, progressive GVHD and relapse of underlying malignancy.

Expert opinion: Future challenges will include more appropriate definition of these agents in the therapeutic scenario of GVHD. Combinations of mAbs or mAb combined with newer immunosuppressive drugs might potentially achieve greater success, especially if used early in the disease process.     

Clinical study on the relapsd leukemia patients with graft versus host disease after allogeneic hematopoietic stem cell transplantation

OBJECTIVE: To explore the dissociation of graft-versus-leukemia (GVL) effects from graft-versus-host disease (GVHD) in the patients who experienced GVHD during leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The primary disease, disease status, GVHD, response to donor lymphocyte infusion (DLI) and prognosis were analysed in 11 leukemia patients who relapsed with GVHD after allo-HSCT. RESULTS: Of the 11 relapsed, 5 were acute lymphoblastic leukemia and 6 acute myeloid leukemia. Five received DLI before relapse and all developed post-DLI GVHD, including 2 grade II acute GVHD (aGVHD), 1 limited chronic GVHD (cGVHD) plus grade II aGVHD, and 2 extensive cGVHD. After relapse of the 5 patients, 2 received Chemo-DLI, one achieved CR with extensive cGVHD and then relapsed again, the other didn't achieved CR. The other 6 patients didn't received DLI before relapse and also developed post-HSCT GVHD while relapsing, including 3 extensive cGVHD, 1 grade I aGVHD and 2 grade II-IV aGVHD. After relapse, these 6 patients received Chemo-DLI, 2 achieved CR and then relapsed again, 4 didn't achieved CR. CONCLUSION: The elicited GVHD after allo-HSCT may not accompany effective GVL effects inhibiting leukemic relapse.     

供者淋巴细胞输注治疗HLA不合造血干细胞移植后白血病复发

目的 观察HLA不合造血干细胞移植(HSCT)后白血病复发患者中进行供者淋巴细胞输注(DLI)的有效性及安全性.方法 对HLA不合HSCT后复发患者进行G-CSF动员的DLI联合移植物抗宿主病(GVHD)预防、部分联合化疗,并观察GVHD发生、白血病缓解以及长期生存情况.结果 24例HSCT后白血病复发患者DLI后8例发生Ⅲ～Ⅳ度GVHD.短期GVHD预防可显著减少重度GVHD发生(P=0.020).8例发生慢性GVHD.3例出现骨髓抑制.16例白血病患者获完全缓解.9例无病存活,随访时间1310(961～1914)d.移植后1年和2年无病存活率分别为60%和40%.复发时骨髓幼稚细胞数量影响DLI后的缓解率和生存率,DLI后发生慢性广泛型GVHD与白血病完全缓解呈正相关(P=0.046).3例Ph阳性急性淋巴细胞白血病全部死于复发.结论 经G-CSF动员的DLI联合GVHD预防、部分联合化疗可以作为HLA不合HSCT后白血病复发的治疗手段.     

Infusion of allogeneic natural killer cells in a patient with acute myeloid leukemia in relapse after haploidentical hematopoietic stem cell transplantation

BACKGROUND: Allogeneic donor natural killer (NK)‐cell infusion (NK‐DLI) is a promising immunotherapy for patients with hematologic disorders. CASE REPORT: This report describes the case of a patient who received a single haploidentical NK‐DLI for a relapse of acute myeloid leukemia (AML) after haploidentical hematopoietic stem cell transplantation. He underwent a cytoreductive, immunosuppressive regimen before NK‐DLI and received high‐dose interleukin‐2 in vivo for 8 weeks afterward. RESULTS: No major adverse effect was observed. Prospective phenotypic and functional studies of the NK cells showed major expansion of infused NK cells and, more importantly, of the alloreactive KIR2DL1+KIR2DL2/DL3–NKG2A– subset, which reached 117 × 10⁶ cells/L on Day +14 after NK‐DLI, the greatest expansion of infused alloreactive NK cells reported so far. Infused NK cells conserved their lytic capacities against K562 target cells and primary AML‐mismatched blasts. CONCLUSION: We review the literature to clarify these data and to detail the indications for allogeneic NK‐DLI, the criteria for determining the most suitable donor, the types of conditioning regimens, and the procedures for selecting and activating NK cells.     

Gene therapy for lysosomal storage disorders

Introduction: Lysosomal storage disorders (LSDs) encompass more than 50 distinct diseases, caused by defects in various aspects of lysosomal function. Neurodegeneration and/or dysmyelination are the hallmark of roughly 70% of LSDs. Gene therapy represents a promising approach for the treatment of CNS manifestations in LSDs, as it has the potential to provide a permanent source of the deficient enzyme, either by direct injection of vectors or by transplantation of gene-corrected cells. In this latter approach, the biology of neural stem/progenitor cells and hematopoietic cells might be exploited.

Areas covered: Based on an extensive literature search up until March 2011, the author reviews and discusses the progress, the crucial aspects and the major challenges towards the development of novel gene therapy strategies aimed to target the CNS, with particular attention to direct intracerebral gene delivery and transplantation of neural stem/progenitor cells.

Expert opinion: The implementation of viral vector delivery systems with specific tropism, regulated transgene expression, low immunogenicity and low genotoxic risk and the improvement in isolation and manipulation of relevant cell types to be transplanted, are fundamental challenges to the field. Also, combinatorial strategies might be required to achieve full correction in LSDs with neurological involvement.     

异基因造血干细胞移植后白血病复发伴活动性移植物抗宿主病患者的临床研究

目的 探讨异基因造血干细胞移植(allo-HSCT)后白血病复发伴活动性移植物抗宿主病(GVHD)患者GVHD与GVL效应的分离.方法 分析11例接受allo-HSCT后在白血病复发时存在活动性GVHD的患者其原发病、疾病状态、复发时GVHD类型、供者淋巴细胞输注(DLI)疗效及转归等对GVL效应的影响.结果 11例患者包括急性淋巴细胞白血病5例,急性髓系白血病6例,其中5例曾行预防性DLI,复发时伴有活动性DLI后GVHD,包括2例Ⅱ度急性GVHD(aGVHD),1例原局限型慢性GVHD(cGVHD)加重+新发Ⅱ度aGVHD,2例广泛型cGVHD;这5例患者复发后,2例行化疗+治疗性DLI,DLI后在广泛型cGVHD反复加重情况下,1例达完全缓解(CR)后再次复发,1例未达CR.另6例患者复发前未行预防性DLI,白血病复发时亦均存在活动性GVHD,包括3例广泛型cGVHD、1例Ⅰ度aGVHD及2例Ⅲ～Ⅳ度aGVHD,复发后行化疗+治疗性DLI,之后2例达CR后再次复发,4例未达CR.结论 allo-HSCT后活动性GVHD不一定伴随可抑制白血病复发的有效GVL效应.     

Programmed death-1 checkpoint blockade in acute myeloid leukemia

Introduction: Immune checkpoints are regulatory pathways induced in activated T lymphocytes that regulate antigen responsiveness. These immune checkpoints are hijacked by tumors to promote dysfunction of anti-tumor effector cells and consequently of tumor escape from the host immune system.

Areas covered: Programmed death-1/programmed death ligand (PD-1/PDL-1), a checkpoint pathway, has been extensively investigated in leukemia mouse models. Expression of PD-1 on the surface of activated immune cells and of its ligands, PD-L1 and PD-L2, on leukemic blasts has been documented. Clinical trials with PD-1 inhibitors in patients with hematological malignancies are ongoing with promising clinical responses.

Expert opinion: Therapy of hematological cancers with antibodies blocking inhibitory receptors is expected to be highly clinically effective. Checkpoint inhibitory receptors and their ligands are co-expressed on hematopoietic cells found in the leukemic milieu. Several distinct immunological mechanisms are likely to be engaged by antibody-based checkpoint blockade. Co-expression of multiple inhibitory receptors on hematopoietic cells offers an opportunity for combining blocking antibodies to achieve more effective therapy. Up-regulation of receptor/ligand expression in the leukemic milieu may provide a blood marker predictive of response. Finally, chemotherapy-induced up-regulation of PD-1 on T cells after conventional leukemia therapy creates a solid rationale for application of checkpoint blockade as a follow-up therapy.     

Donor lymphocyte infusion in myeloid disorders

A number of modalities including both pharmaceutical and cell-based treatments have long been tested and developed to prevent and treat relapses after allogeneic stem cell transplantation (allo-HSCT). The ability of donor T cells to recognize antigenic structures on leukemic cell surfaces and destroy them is a well-known fact. Based on this fact, the idea of using donor T cells to contribute to the development of adoptive immunotherapy has emerged. Donor lymphocytes are easy to obtain and donor lymphocyte infusions (DLI) have a simple rational while this treatment modality is an effective example of cellular therapy. The group of chronic myeloid leukemia patients who are more likely to benefit from DLI include: a) patients in the chronic phase of hematologic relapse and b) patients with molecular/cytogenetic relapse. DLI appear to be an appropriate treatment option to be used in combination with conventional chemotherapy or hypomethylating agents in the treatment of post-allo-HSCT relapse for acute myeloid leukemia and myelodysplastic syndrome, if:) the burden of tumor is low b) the relapse is at a molecular level rather than an overt hematologic relapse c) the patient has favorable cytogenetic characteristics d) time interval between transplantation and relapse is relatively longer (>5 months) e) response could be obtained after salvage therapies. In the event that minimal residual disease (MRD) or increasing mixed chimerism is detected, prompt administration of DLI for prophylactic purposes without waiting for a manifest relapse, was found to be effective in inducing a full donor chimerism and overcoming MRD and eventually preventing a manifest relapse.     

Hematopoietic stem cell transplantation for hematologic disorders

There have been a great progress in hematopoietic stem cell transplantation (SCT) for hematologic malignancies in various aspects including stem cell sources, supportive care, infrastructure, stem cell mobilization, etc., which has lead SCT from experimental therapy to standard medical practice. The most prominent is the advent of SCT with reduced-intensity conditioning (RIC) regimen. It has not only expanded the eligibility for SCT to patients of older age or with co-morbidities, but also highlighted the impact of graft-versus-tumor (GVT) effects in some malignant disorders such as follicular lymphoma, peripheral T-cell lymphoma, and chronic myeloid or lymphocytic leukemia. RIC will provide a possibility for myriads of newly developed molecular-targeted or antibody-based agents to be incorporated in SCT as pre- or post-SCT therapies.     

Breast and dorsal spine relapse of granulocytic sarcoma after allogeneic stem cell transplantation for acute myelomonocytic leukemia: A case report

BACKGROUNDGranulocytic sarcoma (GS) is a rare malignant tumor, and relapse is even rarer in the breast and dorsal spine following allogeneic hematopoietic stem cell transplantation. Currently, a standard treatment regimen is not available.CASE SUMMARYA rare case of GS of the right breast and dorsal spine after complete remission of acute myelogenous leukemia is reported here. A 55-year-old female patient presented with a palpable, growing, painless lump as well as worsening dorsal compressive myelopathy. She had a history of acute myelomonocytic leukemia (AML M4) and achieved complete remission after chemotherapy following allogeneic hematopoietic stem cell transplantation. Imaging examinations showed the breast lump and C7-T1 epidural masses suspected of malignancy. Histologic results were compatible with GS in both the right breast and dorsal spine, which were considered extramedullary relapse of the AML treated 4 years earlier.CONCLUSIONA rare case of GS relapse following allogeneic hematopoietic stem cell transplantation and guidelines for treatment are discussed.     

Ofatumumab,a human anti-CD20 monoclonal antibody

Importance of the field: Since relapse of chronic lymphocytic leukemia (CLL), and refractoriness to treatment following relapse, is inevitable after initial treatment, development of novel treatment strategies is necessary.

Areas covered in this review: CD20 as a therapeutic target for CLL, successes and limitations of current anti-CD20 monoclonal antibody (mAb) therapy, and implications of preclinical and clinical developments of novel alternatives, including ofatumumab, that may enhance anti-CD20 mAb therapy are reviewed. The literature reviewed encompasses papers and congress abstracts from the past 13 years.

What the reader will gain: While rituximab combined with chemotherapy has considerably improved outcomes for some but not all CLL patients, single-agent use is limited in relapsed/refractory CLL. Novel anti-CD20 mAbs in development, such as ofatumumab, may bypass some limitations by virtue of alternative epitope binding and modified effector functions. Ofatumumab induces significant complement-dependent cell lysis in vitro, particularly in cells with low CD20 expression. The FDA recently approved ofatumumab for treatment of CLL refractory to fludarabine and alemtuzumab.

Take home message: CD20-targetting chemoimmunotherapeutic options have advanced treatment of CLL. Results for single-agent ofatumumab and other new CD20 mAbs, in different lines of therapy and in combination with chemotherapy, will guide optimal use of these alternative therapies for B-cell malignancies.     

Does transcutaneous electrical nerve stimulation (TENS) produce 'dose-responses'? A review of systematic reviews on chronic pain

Abstract

Background: This review aimed to examine existing systematic reviews regarding the clinical efficacy of transcutaneous electrical nerve stimulation (TENS) in reducing pain in patients with chronic pain conditions.

Methods: Data concerning the methods and conclusions of the reviews and individual trials were extracted. The data from the individual trials were subcategorised according to the validity of outcome measures, methodological quality, sample size, and 'dose response' (if any) of TENS.

Results: Two of the six reviews concerning TENS and chronic pain reported that high intensity TENS applications were more effective compared to placebo than low intensity applications. However, the reviews and the authors' conclusions were based on a total of eight high quality trials which reported positive findings on a visual analogue scale or numeric rating scale which measured pain relief/intensity.

Discussion: Data from chronic pain trials that use these outcome measures show that any dose-related responses of TENS cannot be conclusively demonstrated as a result of the number of confounding variables (e.g. inadequate design, low statistical power and the many differences in TENS protocols such as repeated versus single treatments).

Conclusion: To address these issues, recommendations are made for future systematic reviews and randomised controlled trials. Such recommendations include the need for more comprehensive and rigorous tools in assessing substantive trials within systematic reviews.     

Advances in umbilical cord blood cell therapy: the present and the future

Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy.

Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB.

Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.     

Genotoxicity of retroviral hematopoietic stem cell gene therapy

Introduction: Retroviral vectors have been developed for hematopoietic stem cell (HSC) gene therapy and have successfully cured X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy, and Wiskott-Aldrich syndrome. However, in HSC gene therapy clinical trials, genotoxicity mediated by integrated vector proviruses has led to clonal expansion, and in some cases frank leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity with the aim of developing safer vectors and safer gene therapy protocols. These genotoxicity studies are critical to advancing HSC gene therapy.

Areas covered: This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced.

Expert opinion: Continued research on virus–host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols.     

Promise of gene therapy to treat sickle cell disease

ABSTRACT

Introduction: Sickle cell anemia (SCA) is a hereditary blood disease caused by a single-gene mutation that affects millions of individuals world-wide. In this review, we focus on techniques to treat SCA by ex vivo genetic manipulation of hematopoietic stem/progenitor cells (HSPC), emphasizing replacement gene therapy and gene editing.

Areas covered: Viral transduction of an anti-sickling β-like globin gene has been tested in pre-clinical and early-phase clinical studies, and shows promising preliminary results. Targeted editing of endogenous genes by site-directed nucleases has been developed more recently, and several approaches also are nearing clinical translation.

Expert commentary: The indications and timing of gene therapy for SCA in lieu of supportive care treatment and allogeneic hematopoietic cell transplantation are still undefined. In addition, ensuring access to the treatment where the disease is endemic will present important challenges that must be addressed. Nonetheless, gene therapy and gene editing techniques have transformative potential as a universal curative option in SCA.     

异基因造血干细胞移植治疗复发难治性急性淋巴细胞白血病的临床研究

目的 探讨异基因造血干细胞移植(allo-HSCT)对复发难治性急性淋巴细胞白血病(ALL)患者的疗效及治疗相关毒性.方法 观察并分析47例复发难治性ALL患者对allo-HSCT治疗的耐受情况、移植相关并发症、总生存率以及无病存活率.其中HLA相合同胞间移植(sib-HSCT)19例,HLA相合的无血缘关系移植(URD-HSCT)18例,单倍型移植(Hi-HSCT)10例.预处理方案:42例采用改良TBI+CY方案,5例采用改良BU/CY方案.移植物抗宿主病(GVHD)的预防:环孢素(CsA)联合短程甲氨蝶呤(MTX)、Hi-HSCT和URD-HSCT加用霉酚酸酯(MMF)及抗胸腺细胞免疫球蛋白(ATG).定期监测微量残留病变(MRD),明确有分子生物学或细胞遗传学复发趋势的患者接受供者淋巴细胞输注(DLI).结果 所有患者均完成移植治疗,出现了不同程度黏膜炎;2例患者在应用CsA过程中有肾功能损害;1例患者发生药物性癫痢.移植后出现Ⅲ～Ⅳ度急性GVHD 7例;慢性GVHD22例;致命性肺部感染9例(包括间质性肺炎3例);出血性膀胱炎4例.有13例患者移植后再次复发.移植后造血重建的中位时间为移植后第17天.术后有19例接受DLI,6例疾病未再进展.中位随访期43(10～77)个月,预期5年总生存率为49.65%,无病存活率为46.55%.结论 统 allo-HSCT能有效治疗复发难治性ALL,改善其预后,治疗失败的主要原因是移植后复发,其次为致命性肺部感染和重度急性GVHD.DLI可能有助于减少移植后复发.     

siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis

Importance of the field: Gene silencing mediated by siRNA has been widely investigated as a potential therapeutic approach. The success of these therapies depends on effective systems capable of selectively and efficiently conveying siRNA to targeted cells/organs with minimal toxicity.

Areas covered in this review: This review discusses current experimental approaches to siRNA delivery strategies available for arthritis treatment and the management of other musculoskeletal disorders. The review covers literature on the subject from 2000 to 2010.

What the reader will gain: In the last decade, extensive improvements have been made to optimize siRNA-based gene therapy and have been tested on several arthritis and orthopedic conditions. However, except for Phase I – II DNA-based gene therapy trials on arthritis, no clinical studies have reported siRNA application in these domains.

Take home message: Most musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, fracture, aseptic loosening, cartilage and intervertebral disc degeneration are non-fatal and age-related chronic inflammatory conditions, but represent significant morbidity and a socio-economic burden. siRNA-based gene therapy offers treatment opportunities that are less invasive, more effective and less expensive than existing modalities. Future directions for siRNA therapy include the development of safe and more efficient delivery systems and the selection of optimal gene targets for disease control.     

混合骨髓移植后过继免疫治疗小鼠白血病

背景：急性白血病自体造血干细胞移植后复发率高,异基因造血干细胞移植后移植相关病死率高,混合造血干细胞移植及移植后过继免疫治疗有可能取长补短,提高疗效。目的：观察自体骨髓混合H-2半相合异体骨髓移植后供体淋巴细胞输注＋白细胞介素2治疗对小鼠白血病的疗效。方法：将Balb/c小鼠经直线加速器照射3Gy后分为白血病模型组、白血病模型照射组、混合移植组、自体骨髓移植组,均尾静脉注射5×10^5K562（GFP＋/NeoR＋）或K562（GFP-/NeoR-）细胞。7d后6Gy照射,自体骨髓移植组移植自体骨髓细胞或联合白细胞介素2治疗;混合移植组移植小鼠自体骨髓细胞混合1/10的H-2半相合异体骨髓细胞后应用白细胞介素2或联合供体淋巴细胞输注治疗。4周后行小鼠外周血及骨髓细胞形态检查,外周血细胞亚群、GFP及NeoR基因测定,肝、脾匀浆细胞GFP和NeoR基因测定。结果与结论：白血病模型组小鼠因骨髓造血功能衰竭于20d内全部死亡,白血病模型照射组小鼠因造血功能衰竭于14d内全部死亡;自体骨髓移植组、混合移植组均有多少不等小鼠无白血病存活超过28d,且混合骨髓移植后及自体骨髓移植后应用白细胞介素2治疗可提高白血病小鼠长期无病生存率,在此基础上联合供体淋巴细胞输注可更进一步提高白血病小鼠长期无病生存率。     

The clinical management of invasive mold infection in children with cancer or undergoing hematopoietic stem cell transplantation

Introduction: Invasive fungal disease (IFD) is a significant cause for morbidity and mortality in children receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). As compared to adults, children may differ from adults in specific aspects regarding epidemiology, diagnosis and management of IFD.

Areas covered: The review provides an overview over the epidemiology of IFD in children with cancer or undergoing HSCT, diagnostic tools, preventive and therapeutic strategies.

Expert opinion: Whereas the risk for IFD is highest in children with acute myeloid leukemia, relapse of acute leukemia, and allogeneic HSCT, the individual risk for IFD needs to be better defined in the large and heterogenous group of children with acute lymphoblastic leukemia. In contrast to galactomannan, pediatric data on beta-D-glucan and PCR testing are scarce. Findings of imaging studies in children are often not typical, but may prompt invasive diagnostic procedures. No substantial differences exist between children and adult regarding antifungal chemoprophylaxis, empirical, pre-emptive and specific therapy. However, antifungal strategies in children are limited as a number of antifungal compounds are not licensed for children or their pediatric dosage is unknown.