Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.

BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with 85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m 2 , alemtuzumab 54 mg/m 2 (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.Bone Marrow Transplantation (2014) 49, 913-920;

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Rhizomucor variabilis and Hormographiella aspergillata rarely cause human infections. This report details a fatal case of a 14-year-old female with leukemia posthematopoietic cell transplant and relapse with refractory pancytopenia. The patient first developed an R. variabilis var. regularior palate infection and later developed a cutaneous H. aspergillata infection while on posaconazole and caspofungin therapy. CASE REPORTThe patient was a 14-year-old female with a history of acute myelogenous leukemia diagnosed in July 2007. The patient underwent an allogeneic HLA-matched bone marrow transplant in December 2007 and experienced relapse in April 2008, with a bone marrow aspirate showing a preponderance of blasts, and later failed reinduction chemotherapy. In September 2008, a computed tomography (CT) scan of the chest 2 weeks prior to admission revealed patchy ground-glass opacities with tiny peripheral nodular densities in both lung fields (sparing the left upper lobe) and a 1.2-cm nodule in the right upper lobe. The patient's condition was deemed too fragile to tolerate a diagnostic lung biopsy. She was empirically treated with broad antibacterial and antifungal coverage that included voriconazole. Of interest, the patient also started drinking an herbal tea remedy of an unknown variety. Shortly afterwards, the patient presented with a 2-week history of odynophagia and persistent febrile neutropenia. An examination showed that the patient had white plaques involving the soft palate and pharynx. A smear stained with calcofluor white from a throat culture showed hyphal elements and conidiophores. A biopsy of the palate lesion showed submucosa and mucosa infiltrated with hyphal forms with sparse septation, rare branching, and chlamydoconidia. The patient was started empirically on 800-mg oral (p.o.) doses of posaconazole twice a day (BID). A CT scan of the head and sinuses was negative, while a CT scan of the lungs confirmed pulmonary nodules that had been previously visualized. Serial galactomannan assay results were negative. The fungal isolate obtained in culture from palate biopsy was tentatively identified as a Rhizomucor sp. by the Mount Sinai clinical microbiology laboratory. The isolate was sent to the Mycology Laboratory of the New York State Department of Health for further characterization. The option of surgical debridement was declined by the family due to potentially severe morbidity. At week 2 of therapy, caspofungin was added as an adjunct therapy. By week 2 of therapy, the lesion had decreased in size, with improved symptoms. At week 3 of therapy, she began receiving a new regimen of chemotherapy, along with granulocyte infusions. By week 4, the patient's symptoms had resolved. By week 5 of therapy, the palate lesion was no longer visualized. Throughout, the patient had persistent severe refractory pancytopenia. One and onehalf months after initiation of therapy, she developed an altered mental status and had a generalized seizure. A CT scan of the brain showed multiple hypodense lesions of the c...

Summary:We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA) þ steroids7MMF (7) or CsA þ methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 Â 10 7 /kg (1.1-11); median CD34 þ : 2.3 Â 10 5 /kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/ 6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of Xgrade II acute graft-versus-host disease (aGVHD) by day þ 60 27%, Xgrade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P ¼ 0.024), CD34 þ /kg (P ¼ 0.038) and gender (P ¼ 0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.