Successful management of chronic disseminated candidiasis in hematologic patients treated with high-dose liposomal amphotericin B: a retrospective study of the SEIFEM registry.

PURPOSE: Chronic disseminated candidiasis (CDC) is a complication of Candida infection in immunocompromised patients, involving the liver and spleen, and rarely other organs. The aim of the study is to identify the best antifungal drug for hematologic immunocompromised patients with CDC. METHODS: In this multicentric retrospective study, the charts of 20 patients with CDC following cytotoxic agent protocols for hematological malignancies, diagnosed from 2003 to 2013, were analyzed. The response to systemic antifungal therapy within 90 days from CDC diagnosis and the possible delay in chemotherapy plan, due to the infection, were evaluated. RESULTS: Six patients were treated with high-dose (HD; 5 mg/kg/daily) liposomal amphotericin B (L-AmB), whereas three received standard-dose (SD) L-AmB (3 mg/kg/daily). Azoles were given to six patients; the remaining five were treated with echinocandins. All patients treated with HD L-AmB (6/6-100 %) achieved complete resolution of CDC; one of them had to interrupt the chemotherapy program for the infection. In the SD L-AmB group, treatment failed in the 100 % of cases and one patient had to delay chemotherapy for the infection. Of the six patients who received azoles, two achieved complete resolution of the infection, four experienced treatment failure, and only three performed chemotherapy as planned. Echinocandins treatment resulted in complete resolution of the infection in 2/5 cases, partial response in 2/5 cases, and failure in one case. In this group, 3/5 patients completed chemotherapy as planned. CONCLUSIONS: This study shows that HD L-AmB was particularly effective against CDC in hematologic patients, allowing most patients to continue cytotoxic agent program.

Autologous graft-versus-host disease after CD34+-purified autologous peripheral blood progenitor cell transplantation.

Autologous graft-versus-host disease (GVHD) has been frequently reported after cyclosporine A (CsA) administration in the autologous setting. This complication is related to the disruption of self-tolerance mechanisms induced by CsA and may exert an antitumor effect. We report the spontaneous occurrence of autologous GVHD after CD34+-purified peripheral blood progenitor cell transplantation (PBPCT) in 5 out of 24 consecutive patients (20.8%). The syndrome was characterized by skin rash (5/5), pruritus (5/5), eosinophilia (5/5), and fever (2/5) occurring at a median of 37 days (range 22-60) after transplantation. Diagnosis was confirmed by skin biopsy in all patients. The syndrome was self-limiting, lasted a median of 25 days, and did not require treatment. The rate of autologous GVHD was high after CD34+-purified autologous PBPCT. In fact, no autologous GVHD was documented in an historical control of 100 consecutive patients submitted to unmanipulated PBPCT at the same institution. The manipulation of the graft by the purging procedure causes a profound T lymphocyte depletion, thus possibly perturbing the equilibrium between autoregulatory cells and autocytotoxic T cells. These observations add new interest to the antitumor efficacy of autologous GVHD and suggest new questions regarding the role of transplantation for autoimmune diseases.

Long-term immune recovery after CD34+ immunoselected and unselected peripheral blood progenitor cell transplantation: a case-control study.

BACKGROUND AND OBJECTIVE: CD34+ stem cell selection induces extensive T-cell depletion as a consequence of ex vivo manipulation. The impact of T-cell depletion on long-term immunologic recovery after autologous CD34+ peripheral blood progenitor cell transplantation (CD34+ PBPCT) is not well characterized. We compared the long term immunologic recovery in two groups of patients submitted to CD34+ PBPCT or unselected autologous peripheral blood progenitor cell transplantation (uPBPCT). DESIGN AND METHODS: Eight patients in both groups were closely matched for diagnosis, age, disease status at transplantation and conditioning regimen and lymphocyte phenotype was prospectively evaluated during long-term post-transplantation follow-up. RESULTS: At a median of 18 months after transplantation, CD3+ lymphocyte subset remained below the normal range in both groups. CD19+ B lymphocytes subset after CD34+ PBPCT was within the normal range in both groups. CD4+ lymphocytes were depressed while the CD8+ lymphocyte subset was increased in group A and in the normal range in group B. As a result, inversion of CD4/CD8 ratio was documented in both groups. T-activated lymphocytes (CD3DR+) and natural killer (CD16/56+) cells were increased in both groups. INTERPRETATION AND CONCLUSIONS: Long-term immune recovery appears to be unaffected by extensive ex vivo manipulation in this adult population when compared to recovery after unmanipulated PBPCT. CD34+ selection, although causes an extensive depletion of T lymphocytes in the graft does not represent a risk factor for delayed CD4+ recovery late after transplantation. Elevated numbers of NK cells and activated T-cells, which have antineoplastic activity, are maintained late after autologous CD34+ transplantation.

Highly fluorescent reticulocyte count predicts haemopoietic recovery after immunosuppression for severe aplastic anaemia.

Highly fluorescent reticulocyte (HFR) counts are the most reliable and sensitive index of haemopoietic recovery after bone marrow or peripheral blood stem cell transplantation. We report the behaviour of HFRs during haemopoietic recovery in two patients who were affected by severe aplastic anaemia (SAA) and treated with horse antithymocyte globulin (ATG), cyclosporin A (CsA) and granulocyte colony-stimulating factor (G-CSF). A HFR value > 5% of the total reticulocyte count, a reticulocyte count > 30 x 10(9)/l, and a polymorphonuclear (PMN) count > 0.5 x 10(9)/l were found after 9 and 8, 20 and 46, and 16 and 22 days, respectively, after the end of ATG. HFR recovery to > 5% anticipated the rise of PMN > 0.5 x 10(9)/l by at least 7 and 14 days, respectively. Thus, HFR evaluation could be used as a reliable and early marker of response to immunosuppression in severe aplastic anaemia.

Factor V Leiden and allogeneic bone marrow transplantation: chimerism as a confounding factor in genetic test interpretation.

Factor V Leiden is one of the most common genetic conditions predisposing to venous thrombosis. Diagnosis is currently made by plasma activity assay for activated protein C (APC) resistance or polymerase chain reaction (PCR)-based DNA assay. The occurrence of factor V Leiden is reported in a patient affected by acute myeloid leukaemia submitted to allogeneic bone marrow transplantation from an HLA identical sister. The donor was not affected by the factor V mutation. The patient did not develop thrombosis during induction and consolidation chemotherapy and the post-transplantation course was not complicated by thrombosis or veno-occlusive disease. At engraftment, PCR analysis showed the disappearance of factor V Leiden. Genetic tests on DNA after allogeneic marrow transplantation should be carefully interpreted as a result of donor chimerism.

[Sudden death by sleep apnea syndrome associated with myxedema. A case report and a review of the literature]. / Morte improvvisa da sindrome delle apnee durante il sonno associata a mixedema. Presentazione di un caso e revisione della letteratura.

The case is presented of a 48-year old, slightly overweight, brachymorphic male affected by undiagnosed myxedema, admitted for nocturnal dyspnea present for several years but worsened in the last few weeks. At the age of 19, a paranoid schizophrenia diagnosis was indicated leading to repeated admissions to psychiatric hospitals and continued pharmacological therapy. His sensorium was lucid albeit with a slight psycho-motor slowing down; pharyngeal edema and macroglossia were also apparent, blood O2 saturation was 97%. After the first emergency exams, a hypothyroid condition associated with multinodular goiter and tracheal dislocation was found. Administration of triiodothyronine p.o. and hydrocortisone i.v. was thus initiated. In the doubt of sleep apnea syndrome (SAS) occurrence, pulse oximetry was performed, but after 7 hours, the patient suddenly deceased. Data showed waves of deep O2 desaturation secondary to periods of prolonged apnea. A literature review shows that such a case has never been reported. A posteriori analysis of the patient's clinical management indicates that the obstructive form of SAS, associated with myxedema is a condition which needs to be promptly diagnosed; due to the possible seriousness of its functional evolution, the need for intensive or sub-intensive therapy, with continuous nasal airway positive pressure or with oro-tracheal intubation and assisted ventilation, should be carefully taken into consideration; continuous cardiac monitoring should also be carried out, given the risk for acute coronary complications and ventricular arrhythmias in the early phases of substitutive therapy with thyroid hormone.

Long-lasting complete remission in plasma cell leukemia after aggressive chemotherapy and CD34-selected autologous peripheral blood progenitor cell transplant: molecular follow-up of minimal residual disease.

Plasma cell leukemia is a rare disease associated with very poor survival with standard treatment. We report a patient affected by plasma cell leukemia treated with aggressive chemotherapy and autologous CD34-selected PBPC who achieved a complete remission now lasting more than 2 years. Molecular studies confirmed the presence of minimal residual disease (MRD) despite the absence of disease activity. High-dose chemotherapy with stem cell rescue may be applied to selected patients considering the impact of the treatment on survival. The meaning of molecular MRD in this setting is unclear.

Bulky lymphadenopathy in acute myeloid leukemia.

Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later.

The Hohn catheter in the management of haemopoietic stem cell transplant recipients.

Patients undergoing bone marrow transplantation require a reliable venous access. The authors have tested the feasibility and safety of a new, silicone, open-ended, non-tunnelled central venous catheter (CVC), the Hohn catheter (Bard Access System, USA). From January 1994 to December 1996, 58 Hohn were inserted into 56 bone marrow transplant (BMT) patients (26 women: 30 men; mean age 38 years, range 19-62 years). The CVC was inserted percutaneously at the bedside by puncture of the subclavian or the internal jugular vein. No early complications were observed. Significant late complications were infection (documented only in 14%) and accidental removal (11%). The median life of the CVC was 30 days (range 15-180 days). Major causes of removal were end of use (25 patients) and fever (19 patients; but infection was documented only in eight patients). In spite of the relatively small gauge (5 Fr), the Hohn catheter was adequate for rapid or high density infusion. In our experience, the unique features of the Hohn CVC (versatility, optimal biocompatibility, bedside management, low cost) may contribute to making the BMT procedure safer and less expensive.

Acute myeloid leukemia after iodine-131 treatment for thyroid disorders.

Leukemia has rarely been reported as a late complication of 131I therapy, occurring mostly after cumulative doses of 800 mCi. We observed two cases of acute myeloid leukemia (AML) after 131I therapy for hyperthyroidism and thyroid carcinoma, respectively. The first patient was a 45-year-old woman treated with a single dose of 27 mCi 131I for hyperthyroidism. She developed AML (FAB M2) 14 months after receiving 131I; the second patient was a 44-year-old man affected by refractory thyroid carcinoma who received a total dose of 1 Ci 131I plus radiotherapy and developed AML (FAB M6) 8 years after the first exposure to 131I. Although it is a very rare event, the occurrence of leukemia after 131I treatment should be kept in mind, considering the widespread use of 131I, particularly in the treatment of hyperthyroidism, and the unfavorable outcome of secondary leukemia.

Incidence of sepsis after peripheral blood progenitor cells transplantation: analysis of 86 consecutive hemato oncological patients.

The incidence of documented infections after autologous peripheral blood progenitor cells transplantation (PBPCT) was retrospectively evaluated in 86 consecutive patients (47 males 39 females; median age 36 years, range, 18-63) treated in our institution; 83 patients had refractory hematological malignancies (40 non-Hodgkin's lymphoma, 19 Hodgkin's disease, 17 multiple myeloma, 7 acute myeloblastic leukemia) and 3 had solid tumors (1 rabdomyosarcoma, 1 neuroblastoma, 1 osteosarcoma). All patients developed fever after transplantation lasting a median of 2 days (range 1-17); 20 instances of documented sepsis developed in 17 patients (19.7%). Gram positive microorganisms were implicated in all but 4 cases. There were no fatalities directly due to infections and no correlation was found between the risk of infection and reaching PMN > 0, 1 x 10(9)/L, PMN > 0.5 x 10(9)/L. In addition no specific risk factors related to age, disease, conditioning regimen, use of central venous catheter (CVC), type of transplant, and isolation measures were identified.

Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation.

Prevention of uterine bleeding after stem cell transplantation was attempted in 30 consecutive premenopausal women affected by hematological malignancies. This was with luteinizing hormone-releasing hormone (LHRH) leuprorelin acetate depot 3.75 mg administered subcutaneously at least 30 days before the conditioning regimen and then 28 days after the first dose. Complete prevention resulted in all but one patient (96.5%) during the phase of profound thrombocytopenia. No side-effects related to leuprorelin were observed. All patients developed amenorrhea after transplantation. Gonadal function was periodically assessed by means of luteinizing hormone (LH), follicular stimulating hormone (FSH) and estradiol serum levels. Hormone levels were consistent with menopause in all patients. After transplantation, patients required hormone replacement with estroprogestinics or estrogens alone when indicated. Leuprorelin is highly effective in preventing uterine bleeding in premenopausal women undergoing stem cell transplantation and has an excellent toxicity profile and virtually no interface with hemostatic balance and hepatic function. The role of leuprorelin in gonadal protection is currently unclear and deserves further investigations.

Assessment of hematological and immunological function during long-term follow-up after peripheral blood stem cell transplantation.

BACKGROUND AND OBJECTIVE: Long-term hemopoietic and immunological profile after autologous peripheral blood progenitor cells transplantation (PBPCT), in patients affected by hematological malignancies is largely unknown. The aim of this work was to detect the impact of high dose chemotherapy and PBPCT on hemopoietic and immunological function compared to conventional chemotherapy. DESIGN AND METHODS: Patients had to fulfill the following criteria: continuous complete remission after PBPCT, follow-up longer than 12 months, no chemo or radiotherapy or biological response modifiers after PBPCT. Twenty-five patients were considered eligible for this analysis. Stable and complete hemopoietic reconstitution (Hb > 12 g/dL, WB > 4.0 x 10(9)/L, ANC > 1.5 x 10(9)/L and Pits count > 150 x 10(9)/L), morphological examination of peripheral blood and bone marrow, cytogenetic analysis and immunological profile were evaluated at 12 months and yearly thereafter. RESULTS: Immunological reconstitution showed a persistent reduction of CD4/CD8 ratio up to five years after PBPCT. This reduction was related to a persistent increase of CD8+ lymphocytes and a constant reduction of CD4+ lymphocytes. INTERPRETATION AND CONCLUSIONS: Defects observed in PBPCT patients are induced by the procedure itself, by the conditioning regimen or both. The different behavior in the immune reconstitution of CD8+ subset after PBPCT may be favored by an extrathymic origin of these cells while CD4+ subset recovery which is thymus-dependent is impaired after PBPCT in adult population. Long-term hemopoietic reconstitution after PBPCT is rapidly obtained and is stable over the years, long-term immunological function seems to be abnormal in these patients and these abnormalities are long-lasting.

Highly fluorescent reticulocytes after CD34+ peripheral blood progenitor cell transplantation.

Highly fluorescent reticulocyte (HFR) counts were evaluated in 13 consecutive patients affected by hematological malignancies and submitted to autologous selected CD34+ peripheral blood progenitor cell (PBPC) transplantation. Results were compared with a historical group of patients comparable for age, disease and conditioning regimen submitted to unfractionated PBPC transplantation. HFR counts of the CD34+ group declined to an undetectable level from day +4 to day +10 when they became detectable and reached 5% of total reticulocyte count by day +12. In the historical group, the nadir was identical but the recovery was faster (day +9). Total reticulocyte count > 1% was achieved at days +17 and +11, respectively. The absolute neutrophil count (ANC) recovery was identical in both groups, achieving a value > 0.5 x 10(9)/l at day +13 after reinfusion. Hence, in the historical group, HFR count gave advance notice of complete and stable hemopoietic engraftment while in the CD34+ group HFR and ANC count showed almost simultaneous recovery.

Immunophenotypic profile of peripheral blood eosinophils in acute graft-vs.-host disease.

We used a flow cytometry technique, the "FOG" method (formaldehyde and octylglucopyranoside), to investigate the expression of activation antigens, i.e., CD4, CD23, CD25, HLA-DR, and the EG2 epitope of eosinophilic cationic protein, on peripheral blood eosinophils (PBEs) in leukemic patients who had developed acute graft-vs.-host disease (aGVHD) with eosinophilia after allogeneic bone marrow transplantation (alloBMT) or leukocyte buffy coat infusion. A comparative analysis was performed in transplanted patients not affected by aGVHD and in other conditions commonly associated with peripheral eosinophilia, i.e., interleukin (IL)-2 immunotherapy and allergy. CD25, recognizing the p55 subunit of IL-2 receptor, was detected in all patients with aGVHD except two who, at the onset of eosinophilia, were already receiving methylprednisolone intravenously. The specificity of our findings is confirmed by the absence of reactivity with anti-CD25 mAb in PBEs from transplanted patients not affected by aGVHD. Interestingly, the expression of CD25 progressively declined after steroid therapy. CD25 was also expressed after rhIL-2 administration, probably reflecting analogous mechanisms of eosinophil activation. No aGVHD or rhIL-2-treated patient showed reactivity with anti-CD4, CD23, or HLA-DR. CD25 and CD23 antigens were detected in 29% and 36% of allergic patients only. The accessibility of the EG2 epitope was significantly enhanced in all study groups compared with controls. In vitro activation of normal eosinophils with phorbol 12-myristate 13-acetate upregulated CD9 and EG2 expression but failed to induce the CD25 antigen, suggesting that selective activating stimuli may be required. The functional significance of in vivo CD25 expression and the role of activated PBEs in the development of cellular and cytokine-mediated tissue destructive processes in aGVHD remain to be clarified.

Granulocyte colony-stimulating factor-primed leukocyte transfusions in candida tropicalis fungemia in neutropenic patients.

Optimal management of fungemia in neutropenic patients is still controversial. Several reports have already stressed the poor prognosis in invasive candidiasis (80% mortality in several reports). Therefore granulocyte transfusions would appear to be useful in the management of these infections. We report the use of rhG-CSF-primed granulocyte transfusions plus amphotericin B in two neutropenic patients who developed life-threatening systemic fungal infections. This approach was successful and both patients fully recovered from the infection.