Juliana Folloni Fernandes

Oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: Clinical outcomes in a context of specialized oral care using low‐level laser therapy

OM is a painful inflammatory condition of the oral mucosa, derived from the toxic effects of chemotherapy and radiotherapy. High OM severity is frequently present in HSCT pediatric patients, who exhibit multiple painful ulcers that limit their mastication and swallowing, leading to poor nutritional status. Few studies have demonstrated OM clinical outcomes in young patients undergoing HSCT. Feasibility of oral care and LLLT on OM prophylaxis and treatment is also poorly discussed. The aim of this study was to describe a specialized oral care protocol that included LLLT for pediatric patients undergoing transplantation and to demonstrate the clinical outcomes after OM prevention and treatment. Data from OM‐related morbidity were collected from 51 HSCT pediatric patients treated daily with LLLT, followed by standard oral care protocols. All the patients, even infants and young children, accepted the daily oral care and LLLT well. The majority (80.0%) only exhibited erythema in the oral mucosa, and the maximum OM degree was WHO II. Patients who had undergone autologous and HLA‐haploidentical transplants showed OM with the lowest severity. The frequency of total body irradiation and methotrexate prescriptions was higher in adolescents when compared with infants (p = 0.044), and adolescents also exhibited OM more severely than infants and young children. We found that good clinical outcomes were obtained using this therapy, mainly in regard to the control of OM severity and pain reduction in the oral cavity. Specialized oral care, including LLLT, is feasible and affordable for HSCT pediatric patients, although some adaptation in the patients oral hygiene routine must be adopted with help from parents/companions and clinical staff.

Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias

B+NK+SCID (severe combined immunodeficiency) due to IL7Rα deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Rα deficiency, we describe two unrelated IL7Rα-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect.

Haploidentical bone marrow transplantation with post transplant cyclophosphamide for patients with X-linked adrenoleukodystrophy: a suitable choice in an urgent situation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment that enhances survival and stabilizes neurologic symptoms in X-linked adrenoleukodystrophy (X-ALD) with cerebral involvement, a severe demyelinating disease of childhood. Patients with X-ALD who lack a well-matched HLA donor need a rapid alternative. Haploidentical HSCT using post transplant cyclophosphamide (PT/Cy) has been performed in patients with malignant and nonmalignant diseases showing similar outcomes compared to other alternative sources. We describe the outcomes of transplants performed for nine X-ALD patients using haploidentical donors and PT/Cy. Patients received conditioning regimen with fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and 2 Gy total body irradiation (TBI) with or without antithymocyte globulin. Graft-vs.-host disease prophylaxis consisted of cyclophosphamide 50 mg/kg/day on days +3 and +4, tacrolimus or cyclosporine A and mycophenolate mofetil. One patient had a primary graft failure and was not eligible for a second transplant. Three patients had secondary graft failure and were successfully rescued with second haploidentical transplants. Trying to improve engraftment, conditioning regimen was changed, substituting 2 Gy TBI for 4 Gy total lymphoid irradiation. Eight patients are alive and engrafted (17–37 months after transplant). Haploidentical HSCT with PT/Cy is a feasible alternative for X-ALD patients lacking a suitable matched donor. Graft failure has to be addressed in further studies.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x‐linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long‐term outcome of the 2 main treatments in long‐term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow‐up of 2.7 years (range, 1 week‐15 years). Patients receiving chronic IS (n = 34) had a median follow‐up of 4 years (range, 2 months‐25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4–83.0) and after IS was 65.1% (95% CI, 62.8–95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long‐term disease‐free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Identification of a novel fusion TBL1XR1–PDGFRB in a patient with acute myeloid leukemia harboring the DEK–NUP214 fusion and clinical response to dasatinib

Paulo Vidal Campregher, Nathalia da Silva Halley, Gabriela Amaral Vieira, Juliana Folloni Fernandes, Elvira Deolinda Rodrigues Pereira Velloso, Siraj Ali, Tariq Mughal, Vincent Miller, Cristov~ao Luis Pitangueira Mangueira, Vicente Odone and Nelson Hamerschlak Department of Hematology and Clinical Pathology, Research Institute, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil; Foundation Medicine, Cambridge, MT; Department of Hematology, University of Campinas (Hemocentro Unicamp), Campinas, S~ao Paulo, Brazil; Department of Pediatric, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil; Hematology and Bone Marrow Transplantation Program, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil; Hematology Service, Hospital das Cl ınicas, Faculdade de Medicina da Universidade de S~ao Paulo, S~ao Paulo, Brazil; Cytogenetics Laboratories, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil; Tufts University Cancer Center, Boston, MA, USA; Department of Pediatric Oncology, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil; Department of Hematology, Hospital Israelita Albert Einstein, S~ao Paulo, Brazil

Eosinophil chimerism in the differential diagnosis between DEK-NUP214-positive acute myeloid leukaemia relapse and chronic graft-versus-host disease

Eosinophilia is a rare, recurrent finding in acute myeloid leukaemia (AML). The classic cases include core-binding factor AMLs with chromosome 16 abnormalities and AMLs with rearrangements of the platelet derived growth factor (PDGF) receptor A and B genes ( PDGFRA and PDGFRB ) and the fibroblast growth factor receptor 1 gene ( FGFR1 ). AML with t(6;9)(p23;q24) is a rare entity (0.7%–1.8% of all AMLs), characterised by multilineage dysplasia, basophilia and an unfavourable prognosis.1–3 This cytogenetic alteration leads to the formation of the DEK-NUP214 hybrid protein, and usually presents as a single abnormality, but it can also be associated with a complex karyotype.4 There are currently no descriptions of eosinophilia associated with DEK-NUP214+ AML. We report the case of a 16-year-old male patient who presented with generalised cutaneous pruritus and fever, associated with peripheral blood eosinophilia (absolute count 7830 cells/μL) in August 2010. After ruling out common causes of secondary eosinophilia, the patient was submitted to bone marrow aspiration, which showed erythroid hyperplasia (58.8%) with dyserythropoiesis, eosinophilia (16.4%), dysgranulopoiesis and 9.6% blast cells. These findings were compatible with the diagnosis of AML-M6, according to the French–American–British classification. A cytogenetic study showed the presence of t(6;9) (p23;q34) as the sole anomaly. Fluorescence in-situ hybridisation (FISH) was negative for inv(16), and molecular studies showed wild-type sequences for the fms-related tyrosine kinase 3 ( FLT3 ) and nucleophosmin ( NPM1 ). FISH was also negative for PDGFRA rearrangement. The patient was treated with two cycles of cytarabine-based chemotherapy, achieving haematological remission; nevertheless, peripheral …

Simultaneous Occurrence of Biphenotypic T Cell/Myeloid Lesions Involving t(12;13)(p13;q14) in a Pediatric Patient

This paper chronicles a 2-year-old girl who presented with acute leukemia/lymphoma syndrome of the T cell immunophenotype. At this time, the cytogenetic analysis of her bone marrow cells showed a reciprocal translocation between the short arm of chromosome 12 and the long arm of chromosome 13, t(12;13)(p13;q14). The immunophenotyping of bone marrow blast cells by flow cytometry revealed a population of cells positive for CD56, CD117, CD45, partial CD33, partial HLA-DR, CD13, CD7, CD2 and CD5. Therefore, a diagnosis of acute leukemia with a mixed T cell/myeloid phenotype was made. The patient had a poor response to classic T cell acute lymphocytic leukemia/lymphoma therapy; thus, her treatment was changed to a myeloid leukemia protocol, which produced a good response. She underwent a successful cord blood transplantation from an unrelated HLA partially matched donor. The coexistence of these two phenotypes prompts questions about the existence of clonal instability, which might influence the choice of therapy. The rarity of the t(12;13)(p13;q14) and the coexistence of T cell/myeloid markers suggest a nonrandom association. To the best of our knowledge, this is the first reported case in which a cell clone bearing a t(12;13)(p13;q14) translocation in a mixed T cell/myeloid lesion was detected.

Haploidentical non‐myeloablative stem cell transplantation as Salvage for graft failure in a patient with juvenile myelomonocytic leukemia

To the Editor: A 2-year-old male, with del(7q) juvenile myelomonocytic leukemia (JMML) was treated with an unrelated umbilical cord blood transplantation (UCBT) after intravenous busulfan, fludarabine, and thymoglobulin conditioning regimen, but had primary graft failure with autologous recovery at 31 days post-transplant. First regimen was intravenous busulfan (19 mg/ kg), fludarabine (160 mg/kg), and rabbit thymoglobulin (10.5 mg/ kg). Nine months later he underwent a second UCBT following intravenous busulfan (20 mg/kg), cyclophosphamide (120 mg/ kg), and melphalan (140 mg/m). No neutrophil recovery was seen until 60 days post-transplant, and bone marrow biopsy showed hipocellular marrow, confirming engraftment failure. The patient then underwent a haploidentical transplant, receiving peripheral blood stem cells collected from his mother. The conditioning regimen consisted of fludarabine (30 mg/m/day, from day 5 to 2), cyclophosphamide (500 mg/m/day, from day 5 to 2) and alemtuzumab (3 mg/day from day 4 to day 0). Total number of infused CD34þ cells was 30.90 10/kg. The patient had neutrophil engraftment on day 14 post-infusion with no major toxicities. Cytomegalovirus reactivation was the only infection observed. Donor chimerism of 100% was observed on day 30 post-transplantation. The patient developed grade II acute graft-versus-hostdisease (GVHD) of the skin on day 30, which was responsive to oral prednisone. On day 95, cyclosporine was switched to tacrolimus due to microangiopathic anemia. At 7 months post-transplant, the patient developed progressive increase of alkaline phosphatase and bilirubin. Severe vanishing bile duct syndrome secondary to chronic hepatic GVHD was diagnosed by liver biopsy. The patient was started on prednisone and mycophenolate mofetil with partial response. Daclizumab was added to the regimen and resulted in normalization of hepatic function. The patient is now 22 months after transplantation and in complete remission. He is still on immunosuppressive therapy (prednisone, tacrolimus, and sirolimus), doses being tapered. He is now 5 years old, shows a satisfactory cognitive development, started going to school, and has no sign of chronic GVHD. He is still hypogammaglobulemic and intravenous immunoglobulin is replaced monthly. The boy has a short stature due to premature closure of epyphisis. Graft failure is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) [1] and is more frequent following UCBT [2]. When graft failure occurs, a second transplant from the most available source is a therapeutic option [3]. Haploidentical related donor is a possible approach, since most patients have a potential donor readily available. However, the toxicity of the conditioning regimen, the increased immunosuppression necessary to overcome HLA disparity and the need for graft T-cell depletion can increase the chance of disease relapse and infections [4,5]. The use of non-myeloablative regimens may decrease the toxicity of haploidentical transplants. One report described the feasibility and efficacy of non-myeloablative regimens using fludarabine and alemtuzumab [6]. The study was conducted in adults, and we adapted the regimen for our patient. An adjusted dose of alemtuzumab was used based on previous reports with this drug in children [7]. Our case illustrates that non-myeloablative haploidentical transplant without ex vivo T-cell depletion is a possibly useful strategy in primary graft failure after UCBT.

Convergence properties of an optimal filter design with correlated output noise

This note studies the convergence and stability properties of an optimal filter for systems with Markov measurement noise. The convergence and stability conditions for the design analysed are the same as those for the optimal filter when the measurement noise is assumed to be a nonsingular white noise process.