An artificial intelligence-driven predictive model for pediatric allogeneic hematopoietic stem cell transplantation using clinical variables.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a procedure with high morbidity and mortality. Identifying patients for maximum benefit and risk assessment is crucial in the decision-making process. This has led to the development of predictive risk models for HSCT in adults, which have limitations when applied to pediatric population. Our goal was to develop an automatic learning algorithm to predict survival in children with malignant disorders undergoing HSCT. METHODS: We studied allogenic HSCTs performed on children with malignant disorders at a third-level hospital between 1991 and 2021. Survival was analyzed using the Kaplan-Meier method, log-rank test for the univariate analysis, and Cox regression for the multivariate analysis. A prognostic index was constructed based on these findings. Lastly, we constructed a predictive model using a random forest algorithm to forecast 1-year survival after HSCT. RESULTS: We analyzed 229 HSCTs in 201 patients with a median follow-up of 1.64 years. Variables that impacted on the multivariate analysis were older age (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.76, p = .003), oldest period of HSCT (HR 0.46, 95% CI 0.29-0.73, p < .001), and mismatched donor (HR 2.65, 95% CI 1.51-4.65, p = .001). Our prognostic index was associated with 3-year overall survival (OS; p < .001). A random forest was developed using as variables: diagnosis, age, year of HSCT, time from diagnosis to HSCT, disease stage, donor type, and conditioning. This achieved 72% accuracy in predicting 1-year OS. CONCLUSIONS: Our index and random forest was effective in predicting 1-year survival. However, further validation in diverse populations is necessary to establish their generalizability.

Embryonic cerebrospinal fluid formation and regulation.

The vertebrate brain is organized, from its embryonic origin and throughout adult life, around a dynamic and complex fluid, the cerebrospinal fluid (CSF). There is growing interest in the composition, dynamics and function of the CSF in brain development research. It has been demonstrated in higher vertebrates that CSF has key functions in delivering diffusible signals and nutrients to the developing brain, contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the patterning of the brain. It has also been shown that the composition and the homeostasis of CSF are tightly regulated following the closure of the anterior neuropore, just before the initiation of primary neurogenesis in the neural tissue surrounding brain cavities, before the formation of functional choroid plexus. In this review we draw together existing literature about the composition and formation of embryonic cerebrospinal fluid in birds and mammals, from the closure of the anterior neuropore to the formation of functional fetal choroid plexus, including mechanisms regulating its composition and homeostasis. The significance of CSF regulation within embryonic brain is also discussed from an evolutionary perspective.

Subarachnoid cerebrospinal fluid is essential for normal development of the cerebral cortex.

The central nervous system develops around a fluid filled space which persists in the adult within the ventricles, spinal canal and around the outside of the brain and spinal cord. Ventricular fluid is known to act as a growth medium and stimulator of proliferation and differentiation to neural stem cells but the role of CSF in the subarachnoid space has not been fully investigated except for its role in the recently described "glymphatic" system. Fundamental changes occur in the control and coordination of CNS development upon completion of brain stem and spinal cord development and initiation of cortical development. These include changes in gene expression, changes in fluid and fluid source from neural tube fluid to cerebrospinal fluid (CSF), changes in fluid volume, composition and fluid flow pathway, with exit of high volume CSF into the subarachnoid space and the critical need for fluid drainage. We used a number of experimental approaches to test a predicted critical role for CSF in development of the cerebral cortex in rodents and humans. Data from fetuses affected by spina bifida and/or hydrocephalus are correlated with experimental evidence on proliferation and migration of cortical cells from the germinal epithelium in rodent neural tube defects, as well as embryonic brain slice experiments demonstrating a requirement for CSF to contact both ventricular and pial surfaces of the developing cortex for normal proliferation and migration. We discuss the possibility that complications with the fluid system are likely to underlie developmental disorders affecting the cerebral cortex as well as function and integrity of the cortex throughout life.

A retrospective study of treosulfan versus busulfan-based conditioning in pediatric patients.

OBJECTIVES: To compare the outcomes of treosulfan-based vs busulfan-based conditioning regimens in allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. METHODS: Retrospective study of all consecutive patients (2012-2019) treated with allogenic HSCT and treosulfan- or busulfan-based conditioning regimens at a single center. RESULTS: A total of 101 HSCT were included: 66 HSCT with busulfan and 35 with treosulfan. In malignant diseases (n = 62), busulfan-based conditioning was more commonly employed than treosulfan: 82.3% vs 17.7%. However, the use of treosulfan for malignant diseases increased over time: 6.5% of HSCT in 2012-2015 vs 29% of HSCT in 2015-2019 (p = .02). The cohort of treosulfan had more children under 1-year of age than the busulfan cohort (31 vs 13%; p = .033). The percentage of patients who received serotherapy was 73 and 89% in the nonmalignant and malignant groups, respectively. The engraftment, time to neutrophil, and platelet engraftment were not significantly different between the busulfan and the treosulfan cohorts. Rate of grade II-IV acute GvHD was significantly higher in the busulfan cohort than the treosulfan cohort (39% vs 15%; p = .016). No differences were observed in endothelial damage complications, chronic GvHD, relapse, overall survival, and transplant-related mortality. CONCLUSIONS: Busulfan-based conditioning regimens are used more frequently for children undergoing allogenic HSCT, but treosulfan-based conditioning is gaining acceptance. Treosulfan-based conditioning is associated with lower rates of acute GvHD, and no significant differences on overall survival were observed compared with busulfan.

Clinical and histopathological evaluation of 50 acantholytic cutaneous squamous cell carcinomas: Analysis outcome in a retrospective case-control study.

BACKGROUND: Acantholytic cutaneous squamous cell carcinomas (aCSCCs) have been classically considered as a high-risk variant of CSCC. However, more recent studies show that aCSCC does not confer more aggressiveness. This study aims to establish whether the prognosis of the aCSCC is worse than that of the non-acantholytic (naCSCC) or not. METHODS: Retrospective case-control study with 50 aCSCCs and 50 naCSCCs. For each aCSCC, an naCSCC with similar high-risk features to the aCSCC but with no acantholysis was selected. Prognosis between both groups was compared. RESULTS: The mean age was 86 years (SD 9.61). Sixty-one patients were men. Thirty-nine CSCCs were located in high-risk head and neck areas. Twenty CSCCs exhibited a poor degree of differentiation, and 36 showed an infiltrative growth pattern. The tumor diameter was 18.71 mm (interquartile range, IQR 35), and the tumor thickness was 6.72 mm (IQR 15.50). Twelve CSCCs exhibited perineural infiltration, and eight CSCCs exhibited invasion beyond the subcutaneous fat. Positive margins after excision of the tumor in 22 aCSCCs vs eight naCSCCs (P < 0.02). Nineteen poor-prognosis events were observed (local recurrence, lymph node metastasis, and death from CSCC). However, no differences were observed between both groups when comparing poor-prognosis events. CONCLUSION: The proportion of unfavorable events is similar in aCSCC and naCSCC. The acantholytic histopathological subtype is not associated with a poorer prognosis than the non-acantholytic CSCC in our cohort.

Failure of Viral-Specific T Cells Administered in Pre-transplant Settings in Children with Inborn Errors of Immunity.

PURPOSE: Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few patients. We report our experience, reviewing all the cases previously reported. METHODS: We report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported. RESULTS: Taking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis [mean time 28 days (IQR; 17-52 days)], and the VST was followed shortly thereafter by HSCT [mean time 28 days (IQR; 10-99 days)]. Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration [mean time from viral diagnosis to VST infusion was 176 days (IQR; 54-1687)]. CONCLUSIONS: In patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.

The role of early natural killer cell adoptive infusion before engraftment in protecting against human herpesvirus-6B encephalitis after naïve T-cell-depleted allogeneic stem cell transplantation.

BACKGROUND: Naïve T-cell-depleted grafts have been employed as an ex vivo T-cell depletion (TCD) platform to prevent graft-versus-host disease (GvHD) and improve immune reconstitution by providing rapid donor memory T-cell reconstitution after allogenic hematopoietic stem cell transplantation (allo-HSCT). CD45RA- memory T cells confer protection against viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)-6B encephalitis among pediatric allo-HSCT patients. METHODS: We report the first 18 consecutive allo-HSCT, 16 haplo-HSCT, and two human leukocyte antigen-matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34+ stem cell product; second, a CD45RA+ TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10 days after HSCT. The study's primary endpoint was the incidence of HHV-6B encephalitis. RESULTS: Engraftment was achieved in 94.5% of cases; 2-year overall survival, event-free survival, and GvHD/relapse-free survival were 87.2% (95% CI 78.6-95.8), 67.3% (95% CI 53.1-81.5), and 64% (95% CI 50.5-78.1), respectively. HHV-6B reactivation occurred in 7 of the haplo-HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis. CONCLUSIONS: In this clinical study, we show that early adoptive NK cell infusion after a 45RA+ TCD allo-HSCT graft is safe and can prevent HHV-6B encephalitis. We recommend infusing adoptive NK cells after allo-HSCT using CD45RA+ TCD grafts.

Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).

OBJECTIVE: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs). METHODS: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT. RESULTS: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαß+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%. CONCLUSION: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise.

Ruxolitinib for steroid-refractory graft versus host disease in pediatric HSCT: high response rate and manageable toxicity.

Ruxolitinib, a selective Janus Kinase (JAK) 1/2 inhibitor, is a promising treatment for the steroid-refractory graft-vs-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT). Most studies have been performed in the adult population showing efficacy against GvHD. In this retrospective study, we evaluated the outcomes of 19 children who received ruxolitinib for refractory acute or chronic GvHD (cGvHD) after HSCT from two Pediatric Hemato-Oncology Departments in Spain between March 2017 and December 2018. Patients received a median number of 4 (IQR 2) previous lines of treatment before starting ruxolitinib. The overall response rate in acute GvHD (aGvHD) and cGvHD was 87% and 91%, respectively. Complete response (CR) was observed in 37% of aGvHD and 8.3% of cGvHD. Remarkably, 43% and 40% of patients with steroid-refractory gastrointestinal aGvHD and lung cGvHD achieved CR. During ruxolitinib treatment, there were 36%, 31%, and 10% infections caused by viruses, bacteria, and fungi, respectively. Overall, four patients interrupted ruxolitinib due to infectious complications, hematological, and liver toxicity. The 2-year overall survival was 71.9% (CI 95% 58.6-85.2). Our experience supports the use of ruxolitinib as an effective treatment for steroid-refractory acute and cGvHD in children with a moderate toxicity profile.

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+ CD19+ depletion, TCRαß+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.

Pseudolymphomatous Atypical Fibroxanthoma.

Atypical fibroxanthoma is a rare mesenchymal skin tumor of intermediate malignancy that typically occurs on sun-damaged skin of elderly patients. Histologically, it is composed of pleomorphic cells with hyperchromatic nuclei and abundant cytoplasm, commonly arranged in a spindle cell pattern. Different histologic variants have been described during the past years. We present a case of atypical fibroxanthoma containing a dense inflammatory infiltrate, which in conjunction with the existence of immunoblast-like and Reed-Sternberg-like neoplastic cells could be misinterpreted as a lymphoid neoplasm. Immunohistochemical studies revealed strong positivity of tumor cells for CD10 and negativity for cytokeratins, p63, p40, S100, SOX10, ERG, actin, desmin, B and T-cell markers, BCL6, CD15, and CD30. The inflammatory infiltrate contained a mixed reactive T- and B-cell population with negative T-cell receptor and immunoglobulin heavy rearrangements. We discuss the differential diagnosis of this entity in which clinical, immunohistochemical, and molecular features are essential to avoid the diagnosis of a lymphoproliferative disease.

Indeterminate Dendritic Cell Tumor as Cutaneous Involvement of Chronic Myelomonocytic Leukemia Successfully Treated With Phototherapy.

Indeterminate dendritic cell tumor (IDCT) is a rare disease composed of so-called indeterminate cells, a dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells, but lacking Birbeck granules. We report a case of cutaneous IDCT occurring in a patient with chronic myelomonocytic leukemia (CMML) successfully treated with UV-A phototherapy. Next-generation sequencing studies of the CMML demonstrated mutations in TET2, ASXL1, and ZRS2 genes, also detected in the IDCT, demonstrating a clonal relationship between both tumors and confirming IDCT as a specific subtype in the spectrum of CMML-related cutaneous lesions.

Comparing the eighth and the seventh editions of the American Joint Committee on Cancer staging system and the Brigham and Women's Hospital alternative staging system for cutaneous squamous cell carcinoma: Implications for clinical practice.

BACKGROUND: The new eighth edition of the American Joint Committee on Cancer staging system (AJCC-8) incorporates changes regarding cutaneous squamous cell carcinoma (CSCC). OBJECTIVES: We aimed to compare the AJCC-8 staging system with the previous seventh edition of the AJCC staging system (AJCC-7) and the Brigham and Women's Hospital (BWH) alternative staging system to identify their usefulness and the utility of their risk factors in defining prognostic groups in CSCC. METHODS: A series of 186 CSCCs of the head and neck were retrospectively collected. All 3 staging systems were compared from the standpoint of their ability to predict poor prognosis. Binary logistic regression models were built to determine which risk factors were most relevant. RESULTS: Poor prognosis was mainly associated with stage T2 of the AJCC-7, with stages T2b/T3 of the BWH system, and with stage T3 of the AJCC-8. The AJCC-8 and the BWH staging systems displayed overlap with each another in predicting poor prognosis, and both were superior to the AJCC-7. The new risk factors incorporated into the AJCC-8 and the poor degree of differentiation were independently associated with poor outcome. LIMITATIONS: Retrospective study and few cases with bone invasion. CONCLUSIONS: The AJCC-8 is more distinctive, monotonous, and homogeneous than the AJCC-7 and shows some overlap with the BWH system in stratification of tumors.

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell-Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients.

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.

How do we manufacture clinical-grade interleukin-15-stimulated natural killer cell products for cancer treatment?

BACKGROUND: Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. STUDY DESIGN AND METHODS: IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line. We analyzed the NK cell recovery and expansion, T cell depletion, phenotype, cytotoxicity, safety, and genomic stability of two good manufacturing practices (GMP)-grade IL-15-activated NK cell products. RESULTS: The number of NK cells obtained from NKIL15 cell and NKAE cell products was similar; however, there were significantly fewer T cells in the NKIL15 cell product. The haploidentical NKAE cell product contained more T cells than the autologous NKAE cell product. The surface expression of the activating receptors CD69, CD25, natural killer group-2 member D receptor, NKp44, NKp46, NKp30, and DNA accessory molecule 1 was up regulated in both NK cell products. NKIL15 cell and NKAE cell products had significantly higher lytic activity than unstimulated NK cells and showed no lytic activity against PBMNCs from healthy donors. No genetic alterations or potential oncogenic effects were found. CONCLUSION: Different GMP-grade procedures can be used to obtain large numbers of highly IL-15-activated NK cells with extremely low T cell content for clinical use.

Wiskott-Aldrich syndrome in a child presenting with macrothrombocytopenia.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease resulting from variants in the WAS gene, characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Despite the fact that WAS is traditionally differentiated from immune thrombocytopenia (ITP) by small size of WAS platelets, in practice, microthrombocytopenia may occasionally not be present, and in certain cases, WAS patients exhibit some parallelism to ITP patients. We characterized one patient presenting with the classic form of the disease but increased mean platelet volume. Molecular studies revealed a novel hemizygous 1-bp deletion in WAS gene, c.802delC, leading to a frameshift and stop codon at amino acid 308 (p.Arg268Glyfs*40). Next-generation sequencing of a total of 70 additional genes known to harbor variants implicated in inherited platelet disorders did not identify additional defects. The pathogenesis of macrothrombocytopenia in this case is not known, but probably the coexistence of a still unidentified additional genetic variant might be involved.

The embryonic blood-cerebrospinal fluid barrier function before the formation of the fetal choroid plexus: role in cerebrospinal fluid formation and homeostasis.

Cerebrospinal fluid (CSF) has attracted interest as an active signaling milieu that regulates brain development, homeostasis, and course disease. CSF is a nutrient-rich fluid, which also contains growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). CSF constitution is controlled tightly and constituent concentrations are maintained narrow, depending on developmental stage. From fetal stages to adult life, CSF is produced mainly by the choroid plexus. The development and functional activities of the choroid plexus, and other blood-brain barrier systems in adults, have been extensively analyzed. However, the study of CSF production and homeostasis in embryos from the closure of the anterior neuropore, when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus has been largely neglected. This developmental stage is characterized by tightly controlled morphological and cellular events in the anterior part of the CNS, such as rapid brain anlagen growth and initiation of primary neurogenesis in the neural progenitor cells lining the cavities, events which are driven by specific molecules contained within the embryonic CSF. In this article, we review the existing literature on formation and function of the temporary embryonic blood-CSF barrier, from closure of the anterior neuropore to the formation of functional fetal choroid plexuses, with regard to crucial roles that embryonic CSF plays in neural development.

Use of Eculizumab in Pediatric Patients with High-Risk Transplantation-Associated Thrombotic Microangiopathy: Outcomes and Risk Factors Associated with Response and Survival. A Retrospective Study on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Transplantation-associated thrombotic microangiopathy (TA-TMA) is associated with high morbidity and mortality. Although survival has improved significantly with the introduction of eculizumab, the need for improvement remains, especially in high-risk patients. This study aimed to describe the results obtained with eculizumab in a pediatric cohort with the attempt to define which risk factors could determine the response to treatment. We designed a national multicenter retrospective study of children treated with eculizumab for high-risk TA-TMA. The study cohort comprised 29 patients who had undergone a first (n = 28) or second (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for malignant (n = 17) or nonmalignant (n = 12) disease. The median time from HSCT to TA-TMA diagnosis was 154 days (interquartile range [IQR], 103 to 263 days). Eleven patients (38%) who were initially diagnosed with low- to intermediate-risk TA-TMA progressed to high-risk TA-TMA (hrTA-TMA), within a median time of 4 days (IQR, 1 to 33 days). SC5b-9 was increased in 90% of 20 patients in whom it was measured. Renal (n = 12), pulmonary (n = 1), and intestinal (n = 1) biopsy confirmed the diagnosis in 12 of 14 patients (85%). Seventeen patients (58%) had extrarenal involvement with serositis (n = 13; 44,8%), pulmonary (n = 12; 41,4%), gastrointestinal (n = 8; 27.6%), cardiovascular (n = 7; 24.1%), or central nervous system (CNS) (n = 2; 6.9%) involvement. The median time from hrTA-TMA diagnosis to the initiation of eculizumab was 7 days (IQR, 1 to 8 days). Overall, 19 patients (65.5%) responded to eculizumab, of whom 17 (58.6%) achieved a complete response and 2 (6.9%) achieved a partial response. The remaining 10 patients (34.5%) did not show any of response. The overall response rate to eculizumab for TA-TMA was 27.59% (95% confidence interval [CI], 14.87% to 47.66%) at 1 month, 55.17% (95% CI, 38.43% to 73.48%) at 3 months, and 62.07% (95% CI, 45.10% to 79.13%) at 6 months after eculizumab initiation. In multivariate analysis, the pulmonary involvement decreased the probability of response (hazard ratio [HR], .18; P = .0298). The 1-year overall survival (OS) was 55.2% (95% CI, 35.6% to 71.0%) for the whole cohort and 83.3% (95% CI, 56.7% to 94.3%) for patients who responded to eculizumab. Pulmonary involvement (HR, 14.93; P = .0043) and CNS involvement (HR, 8.63; P = .0497) were associated with a statistically significant decrease in survival. We found that patients diagnosed with hrTA-TMA with pulmonary involvement had a poor response to eculizumab, and that patients with pulmonary and CNS involvement had significantly decreased survival. Given these results, we hypothesize that providing eculizumab therapy at an early stage of the disease before organ damage is established might significantly improve the response and, consequently, survival.

Severe Impairment of T-cell Immunity and Pulmonary GvHD Are Major Risk Factors for Nontuberculous Mycobacterial Infection After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplant recipients are prone to infectious complications. Infections caused by nontuberculous mycobacteria have increased in adults but literature in children is scarce. We report 6 episodes of disseminated or pulmonary nontuberculous mycobacteria infection among 5 pediatric hematopoietic stem cell transplant recipients. All but one were caused by Mycobacterium avium complex. Four patients died, 2 related to nontuberculous mycobacteria infection.