Rita Balter

Recombinant human G‐CSF‐mobilized peripheral blood stem cells for second allogeneic transplant after bone marrow graft rejection in children

Two children affected by severe aplastic anaemia and sickle cell anaemia rejected the allogeneic bone marrow transplantation from an HLA‐matched unrelated volunteer and an HLA‐identical sibling, respectively. In both cases a second transplant using granulocyte‐colony stimulating factor (G‐CSF) mobilized peripheral blood stem cells (PBSC) was performed. Donors were the HLA‐haploidentical mother and the same HLA‐identical sibling who was employed for the first marrow allograft, respectively. Treatment with G‐CSF and PBSC collection were well tolerated. Both patients had engraftment of donor haemopoiesis and did not experience severe graft‐versus‐host disease. These cases confirm that PBSC transplant should be considered as a feasible treatment to reverse graft failure in paediatric patients.

Infant Ependymoma in a 10-Year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) Experience With Omitted or Deferred Radiotherapy

PURPOSE The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003. PATIENTS AND METHODS After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m(2), and cyclophosphamide 1.5 g/m(2) alternating with cisplatin 90 mg/m(2) plus VP16 450 mg/m(2) for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m(2), and cyclophosphamide 3 g/m(2)) for 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression. RESULTS We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT. CONCLUSIONS Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT.

Intensive short-term chemotherapy regimen induces high remission rate (over 90%) and event-free survival both in children and adult patients with advanced sporadic Burkitt lymphoma/leukemia.

The optimal treatment of advanced sporadic Burkitt lymphoma in adults is still a matter of debate. The salutary results of pediatric therapies did open the road for improving the adult outcome. Between May 1988 and March 2009, 71 consecutive patients—46 adults, 25 children—affected by Burkitt lymphoma/leukemia were treated with the same intensive pediatric protocol alternating vincristine, adriamycine and fractionated ciclophosphamide (phase A) with high dose methotrexate and high dose cytarabine (phase B) in four Italian institutions. Eighty‐nine per cent of patients were in Stage III–IV or had L3 leukemia. Complete remissions were 67/71 (94.4%), 24/25 (96%) in children, and 43/46 (93.5%) in adults. Toxic deaths were 3/71 (4.2%), all in adults. There were nine relapses (one in children, eight in adults), all but one observed early. After a median observation of 94 months (range 23–275), the Event–Free Survival rate is 92% in children and 71.7% in adults (P = 0.067). The 23 more recent adults received also rituximab, without differences in outcome as compared to patients who did not. Our experience confirms that such an intensive pediatric‐derived chemotherapy is feasible and improves the long‐term outcome of adults with advanced Burkitt lymphoma. Am. J. Hematol., 2012.

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Congenital Cystic Mesoblastic Nephroma

Congenital mesoblastic nephroma is a relatively rare infantile renal tumor. It comprises 3–6% of renal masses in childhood and 50% during the neonatal period. Most mesoblastic nephroma occur in the newborn period, with 80% of the cases being reported within the first month of life. Macroscopically the tumor is composed of a solid mass of different sizes tending to invade the surrounding structures and renal parenchyma. The authors report a case of cystic mesoblastic nephroma of the cellular subtype, with diffuse areas of hemorrhage and necrosis. The tumor was treated by surgical excision with radical nephrectomy and the child is doing well 4 years after the operation.

A Randomized, Non-Inferiority Study Comparing Efficacy and Safety of a Single Dose of Pegfilgrastim versus Daily Filgrastim in Pediatric Patients after Autologous Peripheral Blood Stem Cell Transplant

PURPOSE To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT). METHODS The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes. RESULTS Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression. CONCLUSIONS We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.

Vincristine-Related Neuropathy Versus Acute Inflammatory Demyelinating Polyradiculoneuropathy in Children With Acute Lymphoblastic Leukemia

The objective of this study was to evaluate whether electroneurography could help in differentiating between vincristine-induced neuropathy and acute inflammatory demyelinating polyradiculoneuropathy. We performed electroneurography in 7 children from September 2006 to March 2009 admitted to receive chemotherapy including vincristine for acute lymphoblastic leukemia, in whom severe acute limb weakness developed, suggesting vincristine-induced neuropathy. Three of 7 patients had electroneurography, suggesting acute inflammatory demyelinating polyradiculoneuropathy. They received intravenous immunoglobulins without discontinuing chemotherapy, and within 10 days their electroclinical conditions improved. Although electroneurography showed only absent F waves, preventing us from reaching a definitive neurophysiological diagnosis of acute inflammatory demyelinating polyradiculoneuropathy, children’s presenting clinical manifestations, their disease course, and rapid and complete recovery after intravenous immunoglobulins argued strongly in its favor. A prompt, correct differential diagnosis of vincristine neuropathy and acute inflammatory demyelinating polyradiculoneuropathy in patients with acute lymphoblastic leukemia receiving vincristine is essential to improve disease outcome and prolong life expectancy.

Familial haemophagocytic lymphohistiocytosis: Survival of a premature twin with immuno-chemotherapy and bone marrow transplantation from an HLA-identical unrelated donor

UNLABELLED We describe a premature twin born at 30 wk of gestational age, affected with familial haemophagocytic lymphohistiocytosis. Two different mutations were identified in his DNA: one inherited from the mother and one from the father. Haemophagocytosis had been confirmed in his twin brother, who died soon after birth, as well as in the re-evaluation of the autopsy of his older sister, who died 1 y earlier. At 26 d of age, chemotherapy and immune-suppressive treatment were started according to the HLH-94 protocol. At 6 mo of age, a bone marrow transplant from an HLA-identical, unrelated volunteer was performed. Now at 32 mo of age, the infant is healthy and without signs of graft-versus-host disease. CONCLUSION This case report shows that immuno-chemotherapy and allogenic bone marrow transplant are feasible even in premature infants affected with familial haemophagocytic lymphohistiocytosis, which should be ruled out in unknown bleeding disorders of neonates.

Ewing Sarcoma of the Bone in Children under 6 Years of Age

Background Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy. Methods The records of all the children diagnosed with osseous ESFT in centres members of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) from 1990 to 2008 were reviewed. The Kaplan–Meier method was used for estimating overall and progression-free survival (OS, PFS) curves; multivariate analyses were performed using Cox proportional hazards regression model. Results This study includes 62 patients. An axial primary localization was present in 66% of patients, with the primary site in the chest wall in 34%. Fourteen (23%) patients presented metastatic disease. The 5-year OS and PFS were 73% (95% confidence interval, CI, 58–83%) and 72% (95% CI 57–83%) for patients with localized disease and 38% (95% CI 17–60%) and 21% (95% CI 5–45%) for patients with metastatic disease. Metastatic spread, skull/pelvis/spine primary localization, progression during treatment and no surgery predicted worse survival (P<0.01), while patients treated in the last decade had better survival (P  = 0.002). In fact, the 5-year OS and PFS for patients diagnosed in the period 2000–2008 were 89% (95% CI 71–96%) and 86% (95% CI 66–94%), respectively. Conclusion The axial localization is the most common site of ESFT in pre-scholar children. Patients treated in the most recent period have an excellent outcome.

Recurrent episodes of anaphylaxis in a patient with haemophilia B: a case report

Haemophilia B is an X-linked disorder resulting in coagulation factor IX (FIX) deficiency that is treated with the administration of exogenous FIX obtained from plasma of healthy donors or by a DNA recombinant technique1. The development of an inhibitor antibody against exogenous FIX is a serious complication and occurs in 1–3% of patients with haemophilia B and in 25–30% of patients with haemophilia A. Interestingly, in patients with haemophilia B, inhibitor development is associated with the risk of anaphylactic reaction to FIX administration. This reaction can occur concurrently with inhibitor detection or weeks or months apart regardless of which source of FIX replacement is used, plasma or recombinant. For this reason, the guidelines recommend that the first 20 administrations of FIX concentrate should be performed in hospital1,2. Common features of patients who develop a factor IX inhibitor are occurrence of an allergic/anaphylactic reaction early in life, a high inhibitor titre (>5 Bethesda units [BU]), exposure to various types of factor IX products, and the presence of abnormalities of the factor IX gene (F9)3. Patients with complete gene deletions or rearrangements of F9 have an approximately 50% risk of inhibitor development, while those with nonsense or frame shift mutations have a risk of approximately 20%4–5. This suggests that the greater the impairment of FIX synthesis, the higher the risk of anaphylaxis, although this phenomenon may occur in patients with nonsense mutations4–6. The precise mechanism of this adverse reaction remains unclear and the various hypotheses that had been considered include extracellular distribution of the small FIX protein with potential mast cell activation7,8, complement activation by IgG1 antibody formation9, an IgE-mediated hypersensitivity response10, higher amounts of exogenous protein (the concentration of FIX is much higher than that of factor VIII)11 and the absence of tolerance to FIX in patients with mutations resulting in a complete absence of FIX production12. Moreover, in contrast to antibodies against FVIII, antibodies against FIX may form circulating immune complexes that can initiate anaphylaxis when the individual is re-exposed to FIX concentrate6. We describe a case of three anaphylactic reactions in a patient with haemophilia B after exposure to FIX of different origins.