Chiara Cugno

Treosulfan‐based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti‐thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft‐versus‐host disease. Cumulative incidence (95% confidence interval, CI) of transplantation‐related mortality and graft failure was 5% (95% CI, 0–34%) and 11% (95% CI, 3–43%), respectively. Two‐year probability of survival and thalassaemia‐free survival was 95% (95% CI, 85–100%) and 85% (95% CI, 66–100%), respectively. This regimen might find elective application in patients at high risk of developing life‐threatening complications.

Epidemiology, risk factors, and therapy of candidemia in pediatric hematological patients

Invasive fungal infections (IFI) are an important cause of morbidity, increased hospitalization and healthcare costs in critically ill or immunocompromised children. The mortality is comprised between 5 and 20%. In the last 2 decades, the epidemiology of candidemia has changed with an increase of episodes caused by non-Candida albicans species. Central venous catheter, diagnosis of malignancy, and receipt of either vancomycin or antimicrobials with activity against anaerobic organisms for >3 days have been associated with the development of candidemia in the pediatric intensive care unit (PICU). Additional risk factors found in hematological patients were the diagnosis of aplastic anemia, performing an unrelated bone marrow or cord blood transplant, the occurrence of a graft versus host disease and the use of steroids. Early antifungal treatment is recommended to reduce mortality. In neutropenic patients, liposomal amphotericin B, an echinocandin (caspofungin, micafungin), and voriconazole are considered the best option especially for C. glabrata and C. krusei. Fluconazole remains a valid option for infection by Candida albicans in patients not exposed to fluconazole prophylaxis. Amphotericn B deoxy-cholate is generally not recommended because of its nephrotoxicity.

Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498)

Congenital amegakaryocytic thrombocytopenia (CAMT, OMIM 604498) is an autosomal recessive disorder characterized by absent or reduced number of megakaryocytes in the bone marrow (BM) since birth, elevated serum levels of thrombopoietin (TPO), and very low platelet count. Prognosis of CAMT patients

Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology–Oncology)

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy‐two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow‐up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow‐up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666–671, 2016.

Successful T-cell-depleted Haploidentical Hematopoietic Stem Cell Transplantation in a Child with Dyskeratosis Congenita after a Fludarabine-based Conditioning Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure for marrow failure associated with dyskeratosis congenita (DC). Data on transplants from alternative donors are limited. We describe a boy with DC and severe aplastic anemia who underwent haploidentical T-cell depleted HSCT using a reduced-intensity conditioning regimen. He underwent engraftment without toxicity or GVHD. His posttransplant course was complicated by EBV reactivation, treated with rituximab and EBV-specific T lymphocytes. After 26 months, he is in complete chimerism, with normal blood count and no sign of GVHD or pulmonary dysfunction. To the best of our knowledge, this is the first report of DC successfully treated with allogeneic HSCT from a haploidentical family donor.

Successful treatment of a classic Hodgkin lymphoma-type post-transplant lymphoproliferative disorder with tailored chemotherapy and Epstein-Barr virus-specific cytotoxic T lymphocytes in a pediatric heart transplant recipient.

CHL type is the least common major form of EBV‐related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV‐associated, stage IV‐B, CHL arising in a heart allograft recipient eight yr after diagnosis of B‐cell polymorphic PTLD. The patient was successfully treated with adjusted‐dose HL chemotherapy and autologous EBV‐specific CTL, without discontinuation of maintenance immunosuppression. At two yr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL‐type PTLD, with decreased risk of organ toxicity or rejection.

Lethal sepsis and malignant transformation in severe congenital neutropenia: Report from the Italian Neutropenia Registry

To the Editor: The occurrence of lethal sepsis and myelodysplasia/acute myeloid leukemia (MDS/AML) may affect patients diagnosed with severe congenital neutropenia (SCN) at variable rates depending upon the cohorts studied [1]. The Severe Chronic Neutropenia International Registry (SCNIR) reported a cumulative incidence (CI) of sepsis/death of 10% after 15 years from the start of therapy with granulocyte colony-stimulating factor (G-CSF) [2]. The French Severe Chronic Neutropenia Registry (SCNFR) reported 6 septic deaths out of 101 SCN cases, while in the Swedish cohort nobody died of sepsis [3,4]. As for MDS/AML, the CIs after 15 years from the beginning of G-CSF therapy were 22%, 11% and 31%, respectively, in the SCNIR, SCNFR and Swedish cohorts [2,3,4]. In the present study, we evaluated the incidence of lethal sepsis and MDS/AML in patients registered in the Italian Neutropenia Registry (INR). Starting from 2003, the INR identified 350 patients affected with various type of neutropenia from 35 centers belonging to Associazione Italiana Ematologia-Oncologia Pediatrica (AIEOP). Among them, 23 had SCN and considered eligible for the study. Median age at diagnosis of SCN was 8.17 months (IQR: 2.83– 32.15) and median duration of follow up was 6.44 years (IQR; 2.99–12.05) (Table I). During the course of the study, two patients died of non-transplant related sepsis, after voluntary decision by the family to stop G-CSF treatment. The lethal sepsis CI was 10% after three years from the beginning of G-CSF treatment. One patient out of 23 developed MDS, while no leukemia cases were reported. The MDS CI was 6% (95% IC 1–35) at four years after the start of G-CSF. In our study, the incidence of MDS was far lower than that described in the Swedish cohort and in SCNIR patients treated with G-CSF doses greater than 8mcg/kg. On the contrary, it is closer to the French cohort and to the SCNIR group treated with G-CSF dosage lower than 8mcg/kg (15%). The reason for the low MDS incidence, could be the small size and the young age of the cohort; also, in some cases, the choice of “early” transplantion might have prevented the malignant transformation. Moreover, SCN cases (i.e., GATA2 gene defects) with a high transforming potential were not included in our cohort, possibly reducing the incidence of malignant events. On the other hand, the lethal sepsis risk in our cohort was similar to those described in SCNIR and in the French cohort. Deaths were mainly related to voluntary interruption G-CSF treatment, probably because underestimation of its vital importance and general lack of adherence to daily subcutaneous infusions. Even with the limitations of the small sample size and relatively short follow up, due to the young age of patients in the Registry and to the ongoing SCN cases registration, we emphasize that the management and follow up of patients with SCN remains a matter of concern. The education of patients and their families and strict follow up could minimize the risk of improper administration and help to perform early diagnosis of possible malignant evolution.

Immunophenotypic analysis of hematopoiesis in patients suffering from Shwachman-Bodian-Diamond Syndrome.

Shwachman–Diamond syndrome is a rare disorder characterized by exocrine pancreatic insufficiency, skeletal abnormalities, and bone marrow failure, with high risk of leukemic evolution. The aim of the study was the immunophenotypic characterization of bone marrow cells from patients with Shwachman–Diamond syndrome to assess the maturation pathway of blood progenitor cells and to identify the presence of recurrent abnormalities.