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[Objectives] To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL)., [Patients and methods] In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB., [Results] Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB (n = 237) or placebo (n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group (P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group (P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo (P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB., [Conclusions] The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL., This study was funded by Gilead Sciences, Inc. M. B., W. G. and M. J. H. are employees of Gilead Sciences. All other authors or their institutions have received compensation for study participation from Gilead Sciences International Ltd.

The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, alpha-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate. D816V c-kit mutation is frequent and associated with resistance against Imatinib. Because of the rarity of these forms, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies.

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. “Salvage” therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30–50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based “salvage” attempt in a “real life” (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based “salvage therapy” in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).

Background: PICCs are vascular devices inserted from a peripheral vein of the upper third of the arm under ultrasound guide, and provide a central venous access (CVA) with an intermediate duration between short term central venous catheters (CVCs), such as jugular or subclavian CVCs, and long term ones (port-a-caths). PICC insertion is ease and safe with no pneumothorax or hemothorax risk. Their extremity reaches a central vein, and can be used for cytostatic drugs, hyperosmolar solutions, and antibiotics infusion. Furthermore, patients (pts) at high risk of hemorrhage for thrombocytopenia or coagulopathy are eligible for PICC insertion. Nevertheless, some concern exists about the risk of infectious and thrombotic complications associated with PICC use in immunocompromised cancer pts characterized by a prothrombotic state. In particular, few clinical data from large oncohematologic pts series are available on PICCs' implants and their complications. Aims: To analyze the results of a large multicenter, retrospective study of the REL group (Rete Ematologica Lombarda-Lombardy Hematologic Network, Italy) aimed at clinically characterizing PICC use in oncohematologic patients management. Methods: Four REL Hematology Centers participate to the study. The clinical data of 453 implanted PICCs from January 2010 to June 2015, were retrospectively collected, for a total of 44,577 catheter days. Pts median age was 61 yrs (range 10-88). Patients' diagnoses were 197 non-Hodgkin's lymphoma, 10 chronic lymphocytic leukemia, 105 acute myeloid leukemia, 45 acute lymphoblastic leukemia, 33 Hodgkin's lymphoma, 39 multiple myeloma, 12 myelodysplastic/myeloproliferative syndrome, 6 miscellaneous. All pts received intravenous chemotherapy, long term anti infectious drugs (antibiotics and antifungals), and hypertonic solutions. PICCs were inserted by ultrasound-guided puncture of a peripheral vein of the arm, by microintroducer technique, under strict asepsis. Chest X-ray was performed to verify correct tip location (ideally in the proximity of cavo-atrial junction). Data on PICCs' lumen number are available in 423 cases: 292 (69%) were single-lumen and 131 were double-lumen (31%). Results: Median PICC life-span was 90 days (range 1-760, Kaplan-Meier method). No major insertion-related complications were observed. Late complications occurred in 172/453 PICCs (38%, 3.8/1000 catheter days): 93 infectious (20%, 2/1000 catheter days), 38 thrombotic (8%, 0.8/1000 catheter days), 37 mechanical (8%, 0.8/1000 catheter days), 5 (1%, 0.1/1000 catheter days) miscellaneous complications (patient intolerance, local pain and hematoma). Among infectious complications, we reported 24 cases (5%, 0.5/1000 catheter days) of fever of unknown origin (FUO) and 69 (15%, 1.5/1000 catheter days) catheter-related bloodstream infections. Mechanical complications consisted of 3 (1%) catheter dislocations, 19 accidental removals (4%), 16 (3%) lumen occlusions and 3 (1%) breakages of the external section of PICC. In 376/453 (83%) cases PICC was removed due to end of intravenous therapy in 160 patients (35%), death in 98 (22%) and to various complications in 118 (26%) cases. Specifically, FUO lead to PICC removal in 10 (2%), infection in 40 (9%), venous thrombosis in 25 (5%) cases, catheter dislocation or accidental removal in 22 (5%), lumen occlusion in 13 (3%), breakage of the external section of PICC in 2 (0,5%), other mechanical complication in 4 (1%), local pain and miscellaneous 2 (0,5%) each. In the case of a complication occured, the incidence of PICC removal was 68% (118/172): FUO/infections represented the removal cause in 50/172 (29%), mechanical complications in 40/172 (23%), thrombosis in 25/172 (14%) cases. Conclusions: Traditional CVCs are associated with significant complications, reported at varying frequencies in highly heterogeneous oncohematologic pts series: infections are reported from 4.6 to 23% and thromboses from 1.2 to 30.2% of the cases. We have clinically characterized a large series of PICCs in oncohematologic patients. Our data suggest that their implant, as an alternative to traditional CVCs, is a safe and effective way to provide oncohematologic patients at high risk of hemorrhagic and infective complications with a CVA. PICCs compare favorably with traditional CVCs reported complications, and facilitate the proper management of complex and prolonged therapeutic programs. Disclosures No relevant conflicts of interest to declare.

Dear Editor, Systemic mastocytosis (SM) comprises a heterogeneous group of disorders characterized by proliferation and accumulation of mast cells (MC) in one or more organs. Mast cell leukemia (MCL) is an extremely rare subtype of SM defined by leukemic infiltration of bone marrow and other organs by atypical neoplastic MC, morphologically characterized by cytoplasmic extensions, eccentric oval nucleoli and hypogranulated cytoplasm, which could exhibit a more immature blast-like morphology with no signs of maturation, prominent nucleoli and fine nuclear chromatin. Flow cytometric analysis of neoplastic MC reveals detection of CD2 and/or CD25 antigen, CD117/kit, CD68 [1, 2]. This infiltration may lead to bone marrow myelofibrosis with hemopoietic insufficiency, organ disfunction, bleeding and death after a median survival time of 6–7 months [2, 3]. Diagnostic criteria for MCL correspond to that used for diagnosis of SM, but also include a high percentage of bone marrow (≥20% of all nucleated cells) and circulating (≥10% of leukocytes) MC. According to the WHO consensus classification, cases of MCL with less than 10% circulating MC should be termed aleukemic variant [4]. The prognosis of disease is severe: Most patients (pts) survive less than 1 year and respond poorly to cytoreductive drugs or chemotherapy. A curative therapy is currently not available. Over the years 1995–2006, in collaboration with 17 Italian hematological divisions, 36 cases of SM were observed: 13 aggressive SM, ten MCL, seven indolent SM and six SM with associated hematopoietic non-mast cell lineage disease, particularly one acute myeloid leukemia, three myeloproliferative disorders (one idiopathic myelofibrosis, one polycythemia vera and one essential thrombocytemia) and two low-grade B-cell lymphoma; however, we focused the attention only on the ten cases of MCL. All centres were asked to report data about epidemiological, clinical features, treatments and outcome of their cases of MCL. Diagnostic features included hematological parameters with morphological examination of peripheral blood smears, bone marrow aspirate and bone marrow biopsy with an evaluation of MC infiltrate and immunophenotypic examinations of MC by flow cytometry. Furthermore, information about cytogenetic analysis, molecular biology analysis for the presence of the c-kit point Ann Hematol (2008) 87:505–508 DOI 10.1007/s00277-007-0430-3

Objective High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. Patients and methods Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1–5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 μg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. Results Eleven patients (44%, 95% CI: 23–65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P = 0.72). IDAol t 1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P = 0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. Conclusion Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.

Antifungal therapy may be unable to eradicate invasive mycosis in leukemia patients. The presence of persisting pulmonary nodules owing to mycosis seems to increase the risk of fungal relapse after chemotherapy and transplant procedures. Between 1997 and 2004, 10 acute leukemia patients underwent pulmonary surgery for invasive mycosis. The median time from diagnosis of mycosis to surgery was 135 days (range 21-147). Three patients underwent emergency surgery, owing to hemoptysis. In the other seven patients with nodule/cavitation remaining after antifungal treatment, surgery (three wedge resections, four lobectomies) was scheduled before transplant. Pathologic examination confirmed two aspergillosis and three zygomycosis. The only side effect was pneumothorax in one case. Nine patients were considered cured. Six patients underwent bone marrow transplantation (three allogeneic, three autologous) with antifungal prophylaxis without relapse during the transplant procedure. In selected patients scheduled for bone marrow transplantation, surgical resection of localized pulmonary fungus nodules combined with antifungal prophylaxis seem to be an effective treatment for preventing mycotic relapse.

A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography(ERCP). The bone marrow biopsy and the revision of liver biopsy using antitryptase stain diagnosed systemic mastocytosis. Because of the aggressive course of the disease the patient was treated with an acute myeloid leukaemia chemotherapy regimen without success.

Tacrolimus (FK506)-induced hematological toxicity, which has rarely been reported in transplant recipients, may result in anemia episodes, reported mainly in kidney and heart transplant recipients, sporadic cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, red cell aplasia (4 reported cases), and generalized bone marrow suppression (only 1 reported case). We describe a case of a liver transplant recipient with pancytopenia that appeared during immunosuppressive therapy with tacrolimus. This patient suffered from progressive anemia, leukopenia with severe neutropenia, and mild thrombocytopenia; bone marrow biopsy showed hypoplasia (20% of cellularity) without dysplasia. Bone marrow recovery was made possible by suspending tacrolimus and changing to immunosuppression with cyclosporine A, despite the two drugs being very similar in their mechanism of immunosuppression. Contrary to previously reported cases (pure red cell aplasia and bone marrow hypoplasia), the recovery of hemoglobin and neutrophil values was slow after tacrolimus suspension, even though in the first month transfusions were no longer necessary. ©2004 The Japanese Society of Hematology Indications:Graft rejection prophylaxis in 1 patient who underwent orthotopic liver transplantation. Concomitant disease: bone marrow hypoplasia caused by tacrolimus.Patients:One 17-year-old girl.TypeofStudy:Bone marrow hypoplasia in liver transplant recipient during tacrolimus therapy, characterized by a slow but complete recovery with replacement of tacrolimus with Sandimmun was described. Case report.DosageDuration:Dosage not stated. Duration for 15 months.ComparativeDrug:Tacrolimus 0.15 mg/kg, bid. Duration not stated.Results:In the following month after replacement of tacrolimus with Sandimmun, hemoglobin levels increased slowly but constantly, and the patient was no longer blood-transfusion dependent within a month after suspension. At the 12th month after tacrolimus suspension, her hemoglobin level reached 12.5 g/dL; neutrophils were 2.9 x 109/L, and platelets 245 x 109/L. A bone marrow biopsy performed 15 months after discontinuation of tacrolimus showed normal cellularity (>70%).AdverseEffects:No adverse events were mentioned.AuthorsConclusions:Finally, it is important to emphasize that the change to cyclosporin A permitted recovery from pancytopenia, a result showing that, despite the two drugs being very similar as to mechanism of immunosuppression, the side effects impacting on bone marrow probably do not have the same etiologic mechanism, as in patients affected by tacrolimus-induced TTP [thrombocytopenic purpura].FreeText:The patient underwent urgent orthotopic liver transplantation. Postoperative course was regular; the prophylactic treatment, consisted of gancyclovir, 15 mg/kg daily for 2 weeks, and oral pyrimethamine-sulfadiazine 500 mg daily with coadministration of folate for 1 month. Immunosuppression therapy with steroids, tacrolimus (0.15 mg/kg, bid), and azathioprine (50 mg daily). Thirteen days after transplantation, normochromic normocytic anemia (hemoglobin 7.2 g/dL) with low reticulocytes (10 x 109/L ) appeared. Azathioprine was suspended, and the patient received a transfusion. During the next 3 months the patient received regular monthly transfusions with 2 to 3 units of packed red blood cells. At the fourth month platelets and leukocytes also decreased, and severe neutropenia developed (leukocytes, 2.2 x 109/L; neutrophils, 0.4 x 109/L; platelets, 105 x 109/L). Physical examination results were consistently normal, and no significant hepatosplenomegaly was present. Coomb's test results were negative; haptoglobin, vitamin B12, folates, serum iron, and transferrin levels were normal; reticulocytes were low (5 x 109/L), and erythropoietin was slightly reduced. A bone marrow biopsy carried out showed reduced cellularity (20%) with depletion of myeloid and erythroid precursors; megakaryocytes were partially diminished. Because the patient did not show any sign of spontaneous recovery, but on the contrary hemochromocytometric values tended to worsen, tacrolimus was stopped and replaced with Sandimmun