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Trichosporon beigelii pneumonia in patients with hematologic malignancies.

Trichosporon beigelii is a causative agent of hypersensitivity pneumonia in immunocompetent individuals and of invasive pneumonia in immunocompromised patients. The actual incidence and clinical manifestations of T beigelii pneumonia are obscure because the diagnosis is sometimes difficult. We studied eight patients with T beigelii pneumonia diagnosed by immunohistochemical investigation of lung tissue sections and/or isolation of the organism from the lung, sputum, or blood. All patients had underlying hematologic malignancies for which they had received cytotoxic chemotherapy, resulting in profound neutropenia. The clinical manifestations were persistent fever unresponsive to broad-spectrum antibiotic therapy, cough, bloody sputum, and rapidly progressive dyspnea. The chest radiographs showed diffuse alveolar infiltrates in four patients, diffuse interstitial infiltrates in one, patchy reticulonodular infiltrates in one, and focal alveolar infiltrates in two. Histopathologic examination demonstrated numerous centrally necrotic foci with minimal cellular inflammatory reaction, intra-alveolar hemorrhage, and edema. Trichosporon beigelii consisting of both yeast and hyphal forms was located predominantly in the alveolar vessels. In neutropenic patients with hematologic malignancies, this fungus appears to enter the lung not only through the airways but also via the hematogenous route. In vitro susceptibility testing indicated borderline susceptibility to amphotericin B and showed that some azoles were active against T beigelii at safely achievable serum concentrations.

Aged↗

Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies.

BACKGROUND AND OBJECTIVES: The hematopoietic system is controlled by growth factors (cytokines) which can influence cell survival, proliferation, differentiation and functional activation. The study of cytokine receptor expression by flow cytometry could allow us to differentiate between normal and tumoral cells. DESIGN AND METHODS: We analyzed the expression of the interleukin-3 (IL-3) receptor a chain (CD123) in 22 normal samples and in a wide panel of hematologic malignancies using flow cytometry. We found that CD123 was expressed in the myeloid progenitor subpopulation but in contrast, normal lymphoid progenitors lacked CD123. We analyzed the CD123 expression pattern in 64 patients with acute leukemia, 45 with acute myeloid leukemia (AML) and 19 with acute lymphocytic leukemia (ALL) (13 B-cell lineage ALL and 6 T-cell lineage ALL). RESULTS: All the AML cases except two patients with M7 and all the B-cell lineage ALL patients were CD123 positive. In contrast, all the T-cell lineage ALL cases tested were CD123 negative. We also studied the CD123 expression pattern in 122 patients with a B-cell chronic lymphoproliferative disease (B-CLPD). CD123 was positive in three situations: 1) typical cases of hairy cell leukemia showed a specific, strong CD123 expression, 2) a subgroup of atypical chronic lymphocytic leukemia with a marked CD11c expression was also CD123 positive, and finally 3) transformed B-CLPD showed the phenomenon of transition from CD123 negativity to CD123 positivity simultaneuosly with morphologic changes. INTERPRETATION AND CONCLUSIONS: In summary, our data show high expression of IL-3 receptor a chain in hematologic malignancies. Given the high frequency of CD123 reactivity in blast cells in contrast to in normal precursors, this antigen could be applied to the study of minimal residual disease in acute leukemia. CD123 is expressed with a characteristic pattern in cases of hairy cell leukemia.

Acute Disease↗

Evaluation by multivariate analysis of the differentiation inhibitory factor nm23 as a prognostic factor in acute myelogenous leukemia and application to other hematologic malignancies.

The differentiation inhibitory factor nm23 can inhibit the differentiation of murine and human myeloid leukemia cells. We recently reported that nm23 genes were overexpressed in acute myelogenous leukemia (AML), and a higher level of nm23-H1 expression was correlated with a poor prognosis in AML, especially in AML-M5 (acute monocytic leukemia). To evaluate the importance of nm23 expression as a prognostic factor in AML, we compared it with other putative prognostic factors in AML. An analysis of the correlation between nm23 expression and the clinical parameters of 110 patients with AML demonstrated that increased nm23-H1 mRNA levels were associated with resistance to initial chemotherapy and with reduced overall survival. Multivariate analysis using Cox's proportional hazard model also showed that elevated nm23-H1 mRNA levels significantly contributed to the prognosis of patients with AML. Especially in AML-M5, nm23-H1 status was the most important prognostic factor. Furthermore, to determine whether we can apply the results observed in AML to other hematologic malignancies, we investigated the relative levels of nm23-H1 and nm23-H2 transcripts in 149 patients with hematologic neoplasms, including 110 with de novo AML, 9 with de novo acute lymphoblastic leukemia, 14 with myelodysplastic syndrome, 16 with chronic myelogenous leukemia (CML), and 5 normal subjects by the reverse transcriptase-polymerase chain reaction. Expression of nm23-H1 was significantly higher in all the hematologic neoplasms, except CML in chronic phase, than in normal blood cells. nm23 may have a prognostic effect in these hematologic malignancies as well as in AML.

Acute Disease↗

Pilot study on the safety and efficacy of desmopressin for the treatment or prevention of bleeding in patients with hematologic malignancies.

BACKGROUND AND OBJECTIVES: Desmopressin is the treatment of choice for patients with von Willebrand's disease and mild hemophilia A. This compound is also useful in other congenital and acquired disorders of hemostasis, reducing the need for blood derivatives with the inherent risks of infections and alloimmunization. The following article presents a pilot study on the safety and efficacy of desmopressin for the treatment or prevention of bleeding in 15 patients with thrombocytopenia associated with hematologic malignancies. METHODS: Cases were consecutively recruited from February to June 1995. Fifteen patients were treated with desmopressin for prevention or treatment of bleeding. Desmopressin was diluted in 100 mL of isotonic saline and infused for 30 minutes. Bleeding time (BT) was carried out using the Simplate II device, making two standardized incisions on the forearm: the mean between the two incisions was recorded. RESULTS: Significant reduction of BT was observed in three out of four patients with myelodysplastic syndrome who were successfully treated for active bleeding or dental extraction. In the remaining patients, the effect of desmopressin on BT was not tested. Nevertheless, in all of them bleeding mainly due to epistaxis or persistent gum oozing was stopped by a single infusion of desmopressin. In three patients, desmopressin infusion had been successfully administered on a different occasion. No side effects were observed. INTERPRETATION AND CONCLUSIONS: Desmopressin could be a safe and immediately effective option for the treatment or prevention of bleeding in selected patients with hematologic malignancies.

Adult↗

Outcome of 5651 hematopoietic stem cell transplants for hematological malignancies carried out in Europe in 1993: a reliability study of the registry.

Outcome results of observational databases are frequently criticized as relying on incomplete information from incomplete patient populations. Few data are available to dispute these arguments of selection bias. The European Group for Blood and Marrow transplantation (EBMT) decided to address this question by evaluating the hematopoietic stem cell transplants performed in 1993. A comprehensive survey was launched in an effort to collect informations on all transplants for hematological malignancies performed throughout Europe during the year 1993. The main goals of this effort were to compare the group of spontaneously reported patients with the group of retrospectively solicited patients, and to give an accurate estimate of the outcome of all patients. For the year 1993, the annual EBMT activity survey indicated 6336 transplants performed for hematological malignancies in Europe. A total of 5651 transplants could be analyzed; 2595 were reported spontaneously by the teams (group A) and 3056 were retrieved on solicitation (group B). Patients and transplant characteristics for group A and B were very similar for most parameters with a few exceptions. There was no statistical difference for outcome at 3 years between groups A and B: disease-free survival (DFS) was 45 +/- 1% and 44 +/- 1%, relapse incidence (RI) 41 +/- 1% and 42 +/- 1%, transplant-related mortality (TRM) 23 +/- 1% and 23 +/- 1%, and overall survival (OS) 54 +/- 1% and 55 +/- 1%, respectively, for group A and group B. The real outcome at 3 years for the 5651 patients (group A + group B) transplanted in 1993 was 44 +/- 1%, 41 +/- 1%, 23 +/- 1%, and 54 +/- 1%, for DFS, RI, TRM and OS, respectively. The outcome at 3 years by transplant modality, autologous or allogeneic transplants, and by disease categories showed no difference between groups A and B.

Bias↗

Hormone replacement therapy and chronic graft-versus-host disease activity in women treated with bone marrow transplantation for hematologic malignancies.

Several lines of experimental evidence suggest that sex hormones may influence the development and activity of chronic graft-versus-host disease (cGVHD), which frequently occurs in patients undergoing allogeneic bone marrow transplantation (ABMT). Following ABMT, young women are commonly treated with hormone replacement therapy (HRT) because of irreversible gonadal failure. It seemed therefore worthwhile to investigate the effects of this therapy on the activity of cGVHD. Premenopausal women treated with ABMT for hematological malignancies between January 1997 and December 2000 were evaluated for cGVHD activity. They were divided into two groups, depending on whether or not they were treated with HRT. Seventy-one women qualified for the present study: 39 received HRT (treated group), while 32 did not (controls). In both groups of patients, cGVHD activity score was comparable before the start of HRT. No differences were observed in cGVHD activity score between the HRT group and controls after 3, 6, 12, and 24 months from the start of HRT. Furthermore, HRT did not induce any increase in the cGVHD activity score in the treated group of patients at any time from the start of HRT. According to present data, HRT did not appear to influence the activity of cGVHD in young women who underwent ABMT for hematological malignancies. Therefore, we can safely propose this therapy for women with gonadal failure after ABMT.

Adult↗

Transforming growth factor beta is increased in plasma of patients with hematologic malignancies after transfusion of platelet concentrates.

BACKGROUND: Transforming growth factor beta 1 (TGF-beta 1) acts as a potent inhibitor of bone marrow proliferation. High concentrations were found in human platelets, which release this cytokine during storage. STUDY DESIGN AND METHODS: TGF-beta 1 levels during a storage period of 5 days were compared in the plasma of platelet concentrates prepared by apheresis or by the buffy coat method. In addition, TGF-beta 1 plasma levels were monitored in patients with hematologic malignancies before and after transfusion. RESULTS: TGF-beta 1 levels in the supernatant of platelet concentrates were found to be 55 times higher than those in the plasma of healthy volunteer donors. During storage, an additional increase was observed. Accordingly, the transfusion of platelet concentrates resulted in a significant increase of plasma TGF-beta 1 levels in patients with hematologic malignancies (before transfusion: 2.2 +/- 0.5 ng/mL; after transfusion: 2.9 +/- 0.6 ng/mL), and these higher levels persisted for at least 4 hours. CONCLUSION: Because TGF-beta 1 reduces the clonogenic capacity of hematopoetic progenitor cells, a myelosuppressive effect of platelet transfusions is suggested.

Adult↗

Bax mutations in cell lines derived from hematological malignancies.

Many genes are involved in cell cycle control, DNA repair and induction of cell death. Alterations in these genes have been responsible for the development of cancer as well as for resistance to cancer therapy. Recently, an emerging family of bcl2-like genes has been identified that plays a role in the regulation of cell death. Its members are highly conserved in several domains which have been shown to be important for homodimerization or heterodimerization. The ratio between BAX/BCL2 heterodimers and BAX/BAX homodimers appears to be pivotal in deciding the life of death of a cell. We recently detected mutations in evolutionary highly conserved domains of the bax gene in cell lines derived from hematologic malignancies. Similar artificially generated mutations in other bcl2-like family members bcl2, bclxl, or ced9 have been shown to alter their function. This suggests a role for bax mutations in the multi-step pathogenesis of hematological malignancies.

Base Sequence↗

Efficacy of etoposide, cyclophosphamide, and total body irradiation in allogeneic bone marrow transplantation for adult patients with hematological malignancies.

INTRODUCTION: A combination of fractionated total body irradiation (TBI) with etoposide (VP-16) and cyclophosphamide (CY) as a preconditioning regimen (VP/CY/TBI) has been reported to be safe and effective for both adults and children undergoing allogeneic bone marrow transplantation (allo-BMT). However, the reported doses of VP-16 were different. We evaluated the efficacy and safety of a VP-16 (at less than the usual dose)/CY/TBI regimen for adults with hematological malignancies who are required to receive allo-BMT. PATIENTS AND METHODS: Thirty-eight patients received VP-16, CY and TBI (VP/CY/TBI) as a preconditioning regimen for allo-BMT. Twenty-one patients were in first complete remission (1CR), six patients were in second remission (2CR) and 11 patients were in non-remission status (non-CR) before allo-BMT. These patients received allo-BMT from related donors (n=14) and unrelated donors (n=24). The preconditioning regimen consisted of VP-16 (15 mg/kg/d for 2 d), CY (60 mg/kg/d for 2 d) and 12 Gy TBI in six fractions for 3 d. RESULTS: Two patients died on day 30 after transplantation. The median follow-up period for all patients was 35.0 months (range 0.8-159.6 months). At the time of analysis, 10 patients had died. Seven of those 10 patients died because of relapse. The estimated 5-yr disease-free survival (DFS) rates for all cases and acute myelogenous leukemia and acute lymphoblastic leukemia cases were 73.6, 66.7 and 100%, respectively. The estimated 5-yr DFS rates for 1CR, 2CR and non-CR cases were 90.5, 83.3 and 40.9%, respectively (p < 0.05). CONCLUSION: Based on these findings, we suggest that a VP/CY/TBI regimen is effective and safe for adult patients with hematological malignancies in 1CR and 2CR.

Adolescent↗

The MAGE-A1 gene expression is not determined solely by methylation status of the promoter region in hematological malignancies.

Tumor antigens such as MAGE-A1 are aberrantly expressed in many human tumors and could be recognized by CTL. Thus, they could be targets for cancer immunotherapy. It is presently considered that the expression of the MAGE-A1 gene is regulated by methylation of its promoter region. To estimate the possibility of activating the MAGE-A1 gene with demethylating agents with a view toward clinical use, we assessed the methylation status of its CpG-rich promoter by sodium bisulfite mapping both of samples that express the gene and those that do not. Cell lines and samples from patients with hematological malignancies were examined. Surprisingly, the methylation status of the MAGE-A1 gene did not clearly correlate with the expression of the gene. Our results indicate that the MAGE-A1 gene expression is not determined solely by the methylation status of the promoter region in hematological malignancies.

Antigens, Neoplasm↗

Effects of mixed chimerism and immune modulation on GVHD, disease recurrence and survival after HLA-identical marrow transplantation for hematologic malignancies.

BACKGROUND: The success of allogeneic bone marrow transplantation(allo-BMT) is affected by underlying disease relapse. Although mixed chimerism(MC) is not necessarily a poor prognostic factor, several groups have suggested that MC is associated with an increased risk of disease relapse. There is evidence that patients with MC benefit from additional immunotherapy if the treatment is started in minimal residual disease status(mixed chimerism status), not in frank hematological relapse. The purposes of this study are to evaluate 1) the risk for relapse or graft rejection in correlation to persistent MC status after allo-BMT, and 2) the possibility of preventing relapse by immune modulation treatments (withdrawal or rapid taper-off of post-transplant immuno-suppression, additional interferon treatment, or the administration of donor lymphocytes) in hematologic malignancies. PATIENTS AND METHODS: Of 337 allogeneic donor-recipient pairs between March 1996 and August 1998, 12 patients who showed persistent or progressive MC and who received immune modulation treatments were evaluated. Twelve patients, median age 31 years(range 9 to 39 years), received an allo-BMT for: acute myelogenous leukemia(AML, n = 5), chronic myelogenous leukemia(CML, n = 4), acute lymphocytic leukemia(ALL, n = 3). Serial polymerase chain reaction(PCR) analysis of YNZ 22-, 33.6-minisatellites or Y chromosome-specific PCR analysis at short term intervals(pre- and post-transplant 1, 3, 6, 9, ... months) was performed. Once MC was detected, immune modulation treatments on the basis of increasing MC in an early phase of recurrence of underlying disease were started. RESULTS: Nine of 12 patients converted to complete chimerism(CC) (AML 5/5, CML 3/4, ALL 1/3). Four of 9 CC patients developed graft-versus-host disease(GVHD) grade < or = 2 during immune modulation. All were treated successfully with steroids. Three patients who were not converted to CC showed relapse of underlying diseases or graft failure. CONCLUSION: The results demonstrate that, in patients with hematologic malignancies after allo-BMT, persistent MC is associated with relapse of underlying diseases or graft failure. Furthermore, when patients receive early immune modulation treatment, MC can be changed to complete donor pattern chimerism and ultimately prevent relapse.

Adolescent↗

Clinical significance of breakthrough fungemia caused by azole-resistant Candida tropicalis in patients with hematologic malignancies.

A 5-year retrospective analysis of fungemia in patients with hematologic malignancies revealed that four patients, who received fluconazole and itraconazole during neutropenia, developed breakthrough candidemia due to azole-resistant Candida tropicalis isolates. This observation suggests that causative organisms of candidemia in neutropenic patients receiving azoles should be suspected of being azole-resistant.

Adult↗

Polymorphism of the proto-oncogene ETS-1 in hematological malignancies.

We studied a novel restriction fragment length polymorphism (RFLP) of the proto-oncogenes ETS-1 that we detected in a patient with an acute monocytic leukemia by the presence of two, 3.7 and 10 kb, Xbal fragments on Southern blots of DNA from blast cells and remission blood samples. RFLP analysis of a series of 114 normal donors revealed that only four (3.6%) shared the 10 kb fragment. By contrast, this unusual allele was found in 20 (all lymphocytic or monocytic) of 108 (18.5%) hematological malignancies (p less than 0.001). DNA sequence analysis indicated the disappearance in the rare allele of a Xbal site due to a single point mutation at the 3' end of ETS-1 locus. Molecular consequences of this mutation point to a possible pathogenic involvement of ETS-1 in these disorders and to the question of genetic susceptibility to hematological malignancies.

Anemia, Refractory, with Excess of Blasts↗

Piperacillin-tazobactam is more effective than ceftriaxone plus gentamicin in febrile neutropenic patients with hematological malignancies: a randomized comparison.

GOALS: Efficacy and costs of empirical antibacterial therapy in febrile neutropenic patients are important issues. Several strategies have been reported to be similarly effective: monotherapy with cefepime, ceftazidime or a carbapenem or duotherapy with an antipseudomonal beta-lactam antibiotic or ceftriaxone in combination with an aminoglycoside. Piperacillin-tazobactam monotherapy is promising, but its role in this setting still has to be defined. PATIENTS AND METHODS: Of 212 consecutive febrile episodes in 130 neutropenic patients with hematological malignancies randomized to receive either piperacillin-tazobactam (4.5 g every 8 h; group A) or ceftriaxone (2 g once daily plus gentamicin 5 mg/kg once daily; group B), 183 episodes (98 group A, 85 group B) were evaluable for response. RESULTS: Defervescence within 72 h without modification of the antibiotic therapy was achieved in 56/98 episodes (57.1%) in group A and in 30/85 (35.3%) in group B (P=0.0047). If fever persisted, teicoplanin plus gentamicin (group A) or teicoplanin plus ciprofloxacin (group B) were added. All patients still febrile then received meropenem, teicoplanin and amphotericin B. With these modifications of antibiotic therapy, 89.8% of patients in group A had responded at 21 days but only 71.8% in group B (P=0.005). The mean total antibiotic drug cost in group A was only 39.4% of that in group B (euro 445 versus euro 1129; P=0.010). CONCLUSION: Piperacillin-tazobactam monotherapy is significantly more effective and cost-efficient than ceftriaxone plus gentamicin as first-line therapy in febrile neutropenic patients with hematological malignancies.

Adolescent↗

Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Adult↗

The role of p73 in hematological malignancies.

The P73 gene is a homologue of the P53 tumor suppressor. Owing to its structural similarity with p53, p73 was originally considered to have tumor suppressor function. However, the discovery of N-terminal truncated isoforms with oncogenic properties showed a 'two in one' structure of its product, p73 protein. The full-length variants are strong inducers of apoptosis, whereas the truncated isoforms inhibit proapoptotic activity of p53 and the full-length p73. Thus, p73 is involved in the regulation of cell cycle, cell death and development. Moreover, it plays a role in carcinogenesis and controls tumor sensitivity to treatment. p73 is commonly expressed in tumor cells in hematological malignancies. Overexpression of p73 protein and aberrant expression of its particular isoforms, with very low frequency of P73 hypermethylation or mutations, were found in malignant myeloproliferations, including acute myeloblastic leukemia. In contrast, hypermethylation and subsequent inactivation of the P73 gene are the most common findings in malignant lymphoproliferative disorders, especially acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphomas. Assessment of P73 methylation may provide important prognostic information, as was confirmed in patients with ALL. This review summarizes some aspects of p73 biology with particular reference to its possible pathogenetic role and prognostic significance in hematological malignancies.

Alternative Splicing↗

Breakthrough fungemia caused by fluconazole-resistant Candida albicans with decreased susceptibility to voriconazole in patients with hematologic malignancies.

A 7-year retrospective analysis of candidemia in patients with hematologic malignancies demonstrated that ten patients, who received itraconazole and fluconazole during neutropenia, developed breakthrough fungemia caused by fluconazole-resistant Candida albicans (C. albicans) with decreased susceptibility to voriconazole. Eight of these ten patients died of candidemia despite amphotericin B administration. Karyotype analysis of C. albicans isolates revealed that all isolates were genetically unrelated? Our findings suggest that blood isolates of C. albicans in neutropenic patients receiving azoles could be azole cross-resistant, and that the patients should be treated by other antifungals such as echinocandins.

Candida albicans↗

TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate for combined treatment of hematological malignancies.

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF gene superfamily, which induces apoptosis through engagement of death receptors. TRAIL is unusual as compared to the other cytokines of this family, as it interacts with a complex system of receptors consisting of two pro-apoptotic death receptors (TRAIL-R1 and TRAIL-R2) and three decoy receptors (TRAIL-R3, TRAIL-R4 and osteoprotegerin). Moreover, with respect to other members of the TNF superfamily, such as CD95L and TNF-alpha, TRAIL has generated great interest as a potential tumor-specific cancer therapeutic because as a stable soluble trimer it selectively induces apoptosis in many transformed cells but not in normal cells. Of note, TRAIL cytotoxicity is at least partially independent of the major systems involved in resistance to chemotherapy, such as p53 wild-type function and multidrug resistance (MDR) genes. Since one fundamental problem of most cancers is the development of multiple mechanisms of resistance, which progressively reduce or suppress the therapeutic efficacy of conventional chemotherapy, new therapeutic approaches that either restore the pro-apoptotic activity of chemotherapeutic drugs or by-pass the mechanisms of resistance are highly desirable. This review will focus on the potential of TRAIL for its application in the therapy of hematological malignancies, used either alone or in combination with chemotherapy. The scenario emerging from the literature is that the treatment and management of hematological malignancies will require the rational combination of TRAIL plus conventional or new drugs in a regimen that would optimize the anti-neoplastic activity in malignant cells resistant to chemotherapy through restoration of the pro-apoptotic activity of TRAIL.

Animals↗