Sonia Bonanomi

X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.

Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation

Background. Thrombotic microangiopathy (TMA) has been described as severe complication after hematopoietic stem cell transplantation (HSCT). The principal aim of this study was to focus the incidence and the outcome of TMA in the era of more complex HSCTs. Methods. We analyzed the role of some predicting factors for the incidence and the outcome of TMA after HSCT. We enrolled 539 consecutive patients (307 males, median age 31 years) undergoing HSCT from match or mismatch human leukocyte antigen family donor (314) or match/mismatch unrelated (195) and haploidentical donor (30) for malignant or nonmalignant diseases. TMA diagnosis was performed by homogeneous clinical and laboratory criteria. Results. Sixty-four of 539 patients presented TMA (11,87%) and the five-year cumulative incidence of TMA was 14% (HR=0.13). Fifty nine of 64 patients were affected by malignant and 5/64 by non-malignant diseases. On multivariate analysis, TMA occurrence was influenced by graft versus host disease >grade II (P=0.0001), donor type (P=0.029), gender (P=0.0233), total body irradiation based conditioning regimen (P=0.0041). Three factors for TMA outcome proved to be statistically significant by multivariate analysis: age (P=0.009), donor type (P=0.0187) and TMA index (P=0.029). The TMA mortality rate was 50%. The outcome was influenced by defibrotide (P=0.02 in univariate analysis). Conclusions. The study underlines the possibility of finding out which patients are more prone to developing post-HSCT TMA, and identifies which risk factors are more frequently associated with a dismal outcome after TMA.

Treosulfan-containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non-malignant disease and significant co-morbidities

Treosulfan is an immuno‐suppressive and myeloablative alkylating agent that has been introduced as a conditioning agent in stem cell transplantation (SCT). Most studies have been performed in adult patients with malignancy where a low incidence of regimen‐related toxicity has been reported. We report the use of treosulfan in 32 consecutive children undergoing SCT for non‐malignant disease. Patients received a total treosulfan dose of 36 or 42u2003g/m2/patient given in three daily, divided doses. A range of other conditioning agents and serotherapy was administered to patients who underwent family donor SCT (nu2003=u200311), or unrelated donor SCT (nu2003=u200321). One patient (3%) died early. Transplant morbidity was limited and mucositis was only mild. Dermatological toxicity was frequent but mild. Twenty‐eight patients (87·5%) established donor cell engraftment. In 25 patients (78%) there was adequate, stable donor engraftment. Four patients have required additional transplant procedures to maintain adequate donor‐derived haemopoiesis. Twenty‐seven patients (84%) survive with a median follow up of 417u2003d. There were four late deaths due to progression of the underlying disease, graft‐versus‐host disease or infection. Treosulfan‐based conditioning regimens achieve excellent engraftment with reduced regimen‐related toxicity in children with non‐malignant disease at high risk for both regimen‐related toxicity and graft failure.

Extracorporeal Photochemotherapy for the Treatment of Chronic Graft-Versus-Host Disease: Trend for a Possible Cell Dose-Related Effect?

Abstract:u2002 Extracorporeal photochemotherapy (ECP) has been progressively introduced into the treatment of both acute and chronic graft‐versus‐host disease (cGvHD) over the last decade. Nevertheless, its mechanisms of action, as well as the optimal treatment schedule, have not yet been defined. We retrospectively analyzed 25 patients with cGvHD unresponsive to conventional treatments who underwent ECP from 1997 until 2005. The impact of various factors (such as treated and infused nucleated cells, time from transplantation and cGvHD onset, and time from cGvHD and ECP treatment) on the probability of no response to ECP was therefore investigated. A positive response to ECP was achieved in 80% of the patients, after a median of 19 ECP treatments (with a range of 8–38). Eighteen out of the 20 patients responsive to the treatment maintained their response for a median of 30u2003months. We mainly focused on clinical response and yield composition. The analysis on mononuclear cell (MNC) dose suggested that an increase of MNC dose/kgu2003b.w. (body weight) induced a decrease in the odds of treatment failure, and that, if the MNC dose infused was at least 100u2003×u2003106/kgu2003b.w. per ECP treatment, a more positive and longer‐lasting response was achieved. Moreover, the mean dose of treated and infused monocytesu2003×u2003106/kgu2003b.w./ECP did not account for a clear dose‐related effect. These findings may eventually result in a more patient‐tailored approach to ECP. Prospective multicenter trials should be designed to investigate the real impact of MNC dose on ECP responsiveness.

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.

Successful outcome of allo-SCT in high-risk pediatric AML using chemotherapy-only conditioning and post transplant immunotherapy

We report successful outcome in 13 children (median age 2.2 years) with high-risk AML who received SCT from an unrelated (11) or identical sibling (2) donor after a preparative regimen consisting of BU, CY and melphalan. Three children were ‘poor’-risk in first CR, three in the second CR, five in PR and two had resistant disease. Immunotherapeutic strategies were employed to maximize a GVL response escalating through a reduced dose of alemtuzumab, early taper of CsA, donor lymphocyte infusion and treatment with α-IFN. Ten out of 13 (77%) children are alive in CR at a median of 41 months (range: 17–88) from SCT. There was no TRM, but three children relapsed and died 3, 4 and 17 months after SCT. These encouraging early results warrant further studies in children with very high-risk AML.

Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation

Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation

Neutropenia, hypogammaglobulinemia, and pneumonia: A case of WHIM syndrome

A 4-year-old girl was referred to the Pediatric Hematology Unit, MBBM Foundation, Monza, Italy due to leukoneutropenia (white blood cells, 500/lL; neutrophils, 20/lL) and recurrent pneumonia. Immunological evaluation indicated hypogammaglobulinemia (immunoglobulin [Ig]G, 413 mg/dL; IgM, 54 mg/dL; IgA, 48 mg/dL) and B and T CD8 lymphopenia (CD3, 948/lL; CD4, 731/lL; CD8, 158/lL; CD19, 59/lL; CD56, 889/lL; CD4CD8 ratio, 4.6). Bone marrow aspiration showed hypercellular marrow with granulocytic hyperplasia and myelokathexis (Fig. 1). Myelokathexis refers to retention and apoptosis of mature neutrophils with hypersegmented nuclei and cytoplasmic vacuolization associated with peripheral neutropenia. Figure 1 shows eyeglass-shaped neutrophils with pyknotic nuclear lobes connected by long filaments (arrows). On the basis of these clinical and laboratory features, a diagnosis of warts, hypogammaglobulinemia, recurrent infection, and myelokathexis (WHIM) syndrome was suspected. On molecular analysis of chemokine receptor 4 (CXCR4) in the family, a de novo heterozygous g.1000C>T mutation, known as R334X mutation, was detected, confirming the diagnosis of WHIM. Warts, hypogammaglobulinemia, recurrent infections, and myelokathexis syndrome is a rare autosomal dominant immune deficiency. Other symptoms include severe neutropenia, condyloma acuminate, malignancies (mainly carcinomas related to human papilloma virus infection), and B-cell lymphopenia with impaired antibody responses after vaccination. Patients may also present with or develop lymphopenia, monocytopenia, and deficiency of plasmacytoid dendritic cells in the circulation, with impairment in both innate and adaptive immunity. Mobilization of neutrophils can occur during acute infection. Thus, adequate neutrophil count should not rule out this condition, particularly if complete blood count is tested throughout the course of acute infections. Patients are heterozygous carriers of CXCR4 gain-of-function mutation. CXCR4, through interaction with its ligand CXCL12, is required for myelopoiesis, lymphopoiesis, leukocyte trafficking, and neutrophil adhesion in the bone marrow. Mutated cytoplasmic C-terminal tail of the CXCR4 receptor increases intracellular calcium release, thus affecting neutrophil retention in the bone marrow. Prompt recognition of this immune disorder is mandatory to start the proper treatment; granulocyte colony-stimulating factor (G-CSF) is generally used on demand, even if its long-term use seems not to be able to prevent recurrent infection. Immunoglobulins are used in the case of hypogammaglobulinemia but its early prophylactic use seems to have a role in preventing chronic pulmonary infection. Recently plerixafor, a CXCR4 antagonist with neutrophiland leukocyte-mobilizing capacity in the peripheral blood, was shown to have long-term safety and clinical efficacy, thus providing a rational alternative to G-CSF. Hematopoietic stem cell transplantation could be considered in patients refractory to G-CSF therapy. Although WHIM syndrome is rare, clinicians should be aware of it. In the case of recurrent infection, immunological evaluation may raise the index of suspicion (lymphopenia with or without neutropenia, hypogammaglobulinemia), and blood marrow aspiration (myelokathexis with eyeglass-shaped neutrophils) can support the diagnosis and lead to molecular analysis of CXCR4.

Autoimmune neutropenia of childhood secondary to other autoimmune disorders

To the Editor: As a sequel to our previous study, we would like to further comment on the topic of desiderosmia (olfactory cravings). We previously described three patients with iron deficiency anemia (IDA) presenting with symptoms of olfactory cravings, with compulsion to smell a variety of substances. We have designated the name, “desiderosmia,” for this novel symptom. After treatment for IDA, the patients’ olfactory craving symptoms resolved. In this article, we reviewed English medical literature and the World Wide Web to determine if such olfactory cravings associated with iron deficiency anemia had been previously reported. We searched the PubMed, Google, and Google Scholar to find publications, reports, presentations, or testimonies of individuals in online blogs using a combination of search terms including “nasal,” “olfactory,” “smell,” “craving,” “iron deficiency,” and “anemia.” Although this specific symptom has only been previously published once in medical literature, we did find a large number of online patients self-reporting such a phenomenon potentially corroborating our practice experience. Upon further exploration using Google search engine, we came across a number of online blog posts, mostly in pregnancy blogs, in which participants described this unique symptom. These women reported powerful cravings of olfaction, and were frequently overtaken by a strong desire to smell certain odors. The types of substances craved and their associated medical conditions (when reported) are summarized in Supporting Information Table S1. The effects of IDA on the olfactory system have only been minimally explored. It is known that several key enzymes necessary for proper olfaction such as neuronal nitric oxide synthase, tryptophan dioxygenase, and tyrosine hydrolase require either heme or inorganic iron for structure or activity. In an animal study, iron-deficient rats were observed to have prolonged exploratory time (sniffing) for attractive odorants compared to controls. The hypothesis was that IDA decreased the activity of these enzymes resulting in a net reduction of inhibitory olfactory inputs. Another study compared the olfactory function of IDA patients with healthy subjects and found a heightened sensitivity (lower threshold) in detecting odorant among patients with IDA. These reports support a plausible association between the physiological changes in olfaction and iron store. The mystery behind the pathophysiology of this symptom is a driving factor for further research and exploration. Additionally, it would be interesting to investigate what factors potentially account for the discrepancy between the volume of reports seen in online blogs and those documented in clinical practice. Perhaps these symptoms are being overlooked or not screened for in clinical encounters, and therefore leading to a misunderstanding of this symptom in practice. By placing a name to this symptom, we hope to contribute to a better understanding and recognition of these olfactory cravings by both patients and physicians.