摘要:

It is now known that syngeneic transplantation, T lymphocyte depletion and absence of graft-versus-host disease all increase the risk of relapse following allogeneic transplantation for the myeloid leukemias, both acute and chronic. Leukemia-specific immune responses appear to play a major role in the therapy of the myeloid leukemias. In recent years attempts have been made to better characterize and effectively utilize these antileukemic immune responses, concentrating on clinical states of minimal residual disease. This review will discuss the role of such immunotherapy following autologous bone marrow transplantation for myeloid leukemias, and will focus on recent experience and ongoing clinical trials using the novel immunomodulator Linomide.

ISSN:1042-8194    

DOI:10.3109/10428199309067922

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Chronic exposure of humans to benzene (BZ) affects hematopoietic progenitor cells in intermediate stages of differentiation which can lead to aplastic anemia and/or acute myelogenous leukemia and some of its variant forms. We studied the effects of BZ and hydroquinone (HQ), a toxic bone marrow metabolite, on the human HL-60 promyelocytic leukemic cell line. Because the HL-60 cell is bipotential and can be induced to differentiate to monocytes or granulocytes it has been used in many studies as a surrogate for the granulocyte/macrophage committed cell, GM-CFU. Treatment of HL-60 cells with BZ specifically induced differentiation along the granulocytic lineage as measured by morphology, induction of superoxide production and chloroacetate esterase activity and the appearance of the LI2–2 surface antigen. Differentiation was induced via the activation of protein kinase C and the phosphory-lation of several proteins known to be involved in HL-60 cell differentiation. Subsequent to kinase C activation, arachidonic acid was released from membrane phospholipids and the 5-lipoxygenase pathway was activated for the production of leukotriene D4(LTD4) required for granulocytic differentiation. BZ induction of granulopoiesis was prevented by preincubation of HL-60 cells with inhibitors of protein kinase C, 5-lipoxygenase,γ-glutamyl transpeptidase required for the conversion of LTC4to LTD4, or LTD4receptor antagonists. Treatment of HL-60 cells with tetraphorbol myristate acetate (TPA), lα, 25-dihydroxyvitamin D3(1,25-(OH2)D3) or interleukin-1 (IL-1) induced HL-60 cells to differentiate to monocytes/macro-phages. Hydroquinone prevented induction to monocytes/macrophages induced by TPA or lα,25-dihydroxyvitamin D3, but not by IL-1 and significantly, had no effect on the induction of granulocytic differentiation by BZ or any other inducer. A mechanism for the induction of granulocytic differentiation by BZ is proposed.

ISSN:1042-8194    

DOI:10.3109/10428199309067923

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

X-linked clonal analysis (XLCA) either using Glucose-6-phosphate dehydrogenase (G-6-P-D) polymorphisms or restriction fragment length polymorphisms (RFLP) and methylation analysts has provided considerable understanding of haematologic malignancy. Acute Promyelocytic Leukemia (APL) is characterized by a unique cytogenetic translocation t(15;17), frequent achievement of remission without a preceding phase of marrow hypocellularity after induction chemotherapy and a high rate of clinical response to all-trans retinoic acid (ATRA). In limited studies XLCA has provided insight into the pathogenesis and mechanism of drug action in this disease.

ISSN:1042-8194    

DOI:10.3109/10428199309067924

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Myelodysplastic syndrome (MDS) has been thought to be an identifiable early stage in mul-tistep leukemogenesis. Considerable numbers of patients with MDS eventually develop acute myelogenous leukemia (AML), which is very much more difficult to manage than typical de-novo AML. There are several differences in both the clinical and biological behavior of AML with and without prior MDS. We have established an unique long-term bone marrow culture (LTBMC) system which allows abnormal cells to grow in preference to normal cells, based on the method originally described by Dexteret al. Leukemic transformations occur more frequently in MDS patients with abnormal karyotypes, and particularly those with multiple abnormalities. New cytogenetic abnormalities were occasionally observed at the time of transition to AML. We have applied this LTBMC system for cytogenetic and molecular studies on the leukemic transformation from MDS. Among the 32 patients with MDS studied thus far, novel abnormal karyotypes were detected during the LTBMCs in 15 patients. Furthermore, 6 out of 23 novel karyotypes detected during the in-vitro cultures emerged in vivo, one to 11 months later in 4 patients. In addition, point mutation of the N-ras proto-oncogene was observed in 3 of 18 cases. The signal of the dot-blot hybridization was increased in one examined case after 2 weeks in culture. Thus, this LTBMC system may provide some promising information with respect to understanding the multistep process from the preleukemic stage to the development of overt leukemia as well as its prognostic relevance.

ISSN:1042-8194    

DOI:10.3109/10428199309067925

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

We studied the efficacy and safety of itraconazole for the prevention of fungal infection in neutropenic patients given cytotoxic chemotherapy for hematologic malignancies. Patients were randomly allocated to receive either itraconazole (200 mg bd) or placebo in addition to oral amphotericin B until the patient either developed fungal infection or had completed an-tileukemic treatment. Forty six patients (83 neutropenic episodes) treated with itraconazole and 46 placebo treated patients (84 neutropenic episodes) were evaluable. No specific toxicity was noted. Nine fungal infections developed in the itraconazole group, of which four were histologically or microbiologically proven and 15 in the patients given placebo (eight proven) (p>0.12). All these patients received IV amphotericin B. The incidence of Candida albicans infections tended to be lower in the itraconazole group, but overall, there was no measurable improvement in the prevention of fungal infections and mortality by itraconazole.

ISSN:1042-8194    

DOI:10.3109/10428199309067926

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

In a retrospective analysis of T cell depleted bone marrow transplantation, we have looked at different parameters in order to determine risk-factors of graft-failure after allogeneic bone marrow transplantation for leukemia. Fifty-one patients with acute leukemia or chronic my-eloid leukemia have been analysed. For 33 of them, the pretransplant conditioning regimen consisted of fractionated total body irradiation (TBI) at 12 Gy prior to cyclophosphamide (120 mg/kg). The other patients received various reinforced preparative regimens. T-cell depletion consisted of treating marrow cells with pan-T monoclonal antibodies (CD2+CD3 or CD2-CD5-CD7) followed by complement mediated cytolysis. No post-transplant immu-nosuppressive prophylaxis was administered except for the first nine patients who received Methotrexate alone. In this group of 51 patients, 12 died within 3 months from graft-related complications and 10 developed graft failure (no engraftment or rejection). Among the possible risk factors associated with this failure, two graft-related parameters appeared significant: the number of CFU-GM progenitors and the number of viable T cells injected with the marrow inoculum. No correlation with graft failure was found with other parameters including diagnosis, disease status at transplant, conditioning regimen, age, sex, and CMV status of donor/host pairs. However, the interpretation must remain cautious because of the relatively small samples in each group.

ISSN:1042-8194    

DOI:10.3109/10428199309067927

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The purpose of this study was to investigate the biologic activity of DAB486IL-2 when administered three times daily, in terms of toxicity, pharmacokinetics, and anti-tumor effects in patients with IL-2R expressing hematologic malignancies, especially mycosis fungoides. 20 patients were enrolled in this dose escalation phase I trial. Patient cohorts were treated at levels of 0.03 mg/kg, 0.05 mg/kg, 0.07 mg/kg and 0.09 mg/kg every 8 hours for a total of 12 doses, every 21 days as toxicity and response warranted. Eight patients experienced transient fevers associated with DAB486IL-2 administration. One patient experienced grade 3 hypotension, and a second developed fluid retention manifested as weight gain/pedal edema. Dose limiting toxicity consisted of one episode of transient grade 4 hepatic transaminase elevation, and 8 episodes of transient asymptomatic grade 3 hepatic transaminase elevation. At the maximum tolerated dose DAB486IL-2 exhibited biphasic clearance kinetics; transient receptor saturation may be one mechanism for this observation. Initial serum concentration and apparent steady state level (plateau) directly correlated with the dose administered, but no difference in area under the concentration curve with greater dose was observed. Biologic activity was noted in patients with mycosis fungoides with skin lesion clearing and relief of pruritus. One patient with mycosis fungoides, and one patient with a relapsed intermediate grade non-Hodgkin's lymphoma achieved partial responses. The novel mechanism of action, toxicity profile, and evidence of biologic activity in refractory cancer patients, support development of more active constructs of this agent; such trials are underway.

ISSN:1042-8194    

DOI:10.3109/10428199309067928

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Chromosomal analysis of stimulated whole blood cells and purified B lymphocytes was performed in 13 stage A(0) and 1 stage C(1V) chronic lymphocytic leukemia (B-CLL) patients. Abnormal clones were found in 6 cases in purified B lymphocytes cultures and in a single one in whole blood cultures. In situ hybridization with a chromosome 12 probe was in accordance with the chromosomal analysis of purified B-CLL lymphocytes and not with the results obtained using whole blood culture. Cytogenetic analysis of isolated B cells is simple and sensitive. It enhances the detection of abnormal clones in B-CLL and applied to larger series of patients, it should allow a precise evaluation of the incidence of chromosomal abnormalities in CLL and of their clinical (prognostic) significance.

ISSN:1042-8194    

DOI:10.3109/10428199309067929

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The 5 q deletion is frequently found in myelodysplastic syndromes and acute non lymphoid leukemia, but this anomaly is usually found in secondary diseases and associated with many other chromosomal aberrations. This report describes four cases of“de novo”acute leukemia with a sole 5q- anomaly. They had no cytological, genetic or clinical characteristics of secondary disorders. It is important to note that of the four patients studied, three had proliferation of immature blast cells. One case was classified as a MO AML and two as“undifferentiated”acute leukemia. Furthermore, these four cases of acute leukemia showed a deletion of the same portion of the long arm of chromosome 5: q22q33. On the same part of this chromosome many hematopoietic growth factor genes have been located, like IL3 and GM-CSF which have early undifferentiated hematopoietic stem cells as a their target.

ISSN:1042-8194    

DOI:10.3109/10428199309067930

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Twenty-nine adult patients with relapsed (21) or refractory (8)de novoacute leukemia (12 ALL and 17 ANLL) were treated with a remission-induction salvage chemotherapeutic protocol including vindesine, mitoxantrone, cyclophosphamide, intermediate-dose cytosine arabinoside, prednisolone and methotrexate. Ten of seventeen (59%) ANLL and 8/12 ALL (67%) achieved complete remission (CR). Seven of eight (86%) cases refractory to first-line remission-induction therapy (3/4 ANLL and 4/4 ALL) entered complete remission. The most frequent non-hematologic side effects were gastrointestinal. All patients experienced severe pancytopenia, with median times to recovery of granulocyte and platelet counts of 28 and 29 days, respectively. Nine of twenty-nine (31%) patients suffered febrile episodes of unknown origin and 13/29 (45%) suffered documented infections. Five patients (17%) died while aplastic, four from infection and one from cardiotoxicity. Four patients who entered CR were submitted to a bone marrow transplantation (BMT), two autologous and two allogeneic BMT. Sixteen of the 18 patients who entered CR relapsed, with a median remission duration of 3.5±2.9 months. Two patients remain in remission at 5+ and 17+ months. These results suggest that this protocol is an effective remission-induction salvage therapy for adult acute leukemias.

ISSN:1042-8194    

DOI:10.3109/10428199309067931

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor