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Bone marrow transplantation for hematologic malignancies in patients aged 30 years or older.

During the past 10 years, 86 patients 30 to 54 years of age with hematologic malignancies were prepared with high-dose radiochemotherapy and received histocompatible bone marrow grafts. Thirty-four of these patients are surviving for 4 months to 9 years (median, 26 months) following marrow transplantation and 32 of them are in continuing complete remission (CR). Disease-free survival is 44% for 37 patients who were in first remission of acute leukemia or in the chronic phase of chronic granulocytic leukemia (CGL), 23% for 39 patients whose leukemia had relapsed at least once before transplantation or who had advanced stages of CGL, and 60% for ten patients who had hematologic malignancies other than leukemia. The median age of the surviving 34 patients is 36 years (range, 30 to 43 years). The incidence of moderate to severe acute graft-v-host disease (GVHD) was 48% and of chronic GVHD, 26%. The major causes of failure were interstitial pneumonia in 31 patients (24 of whom had antecedent acute GVHD) and recurrent leukemia in 12 patients (11 of whom had either never entered a CR or had relapsed at least once with acute leukemia or had progressive CGL before transplantation). Our data warrant further prospective studies in patients with hematologic malignancies who are older than 30 years.

Actuarial Analysis↗

[Detection of minimal residual disease in childhood hematological malignancies and its clinical significance].

OBJECTIVE: Exploring the detection of minimal residual malignant cells in bone marrow from children with hematological malignancies to predict the prognosis. METHODS: Seventy-five patients with acute lymphoblastic leukemia (ALL), stage IV non-Hodgkin's lymphoma or stage IV neuroblastoma were studied. Complete remission was maintained for over 3 months before the detection. Minimal residual disease was detected by polymerase chain reaction (PCR) for IgH and TcRgamma rearrangements in lymphoid tumors by reverse transcriptase-polymerase chain reaction (RT-PCR) for neuroblastoma patients. RESULTS: Thirty five patients were positive for minimal residual disease, and 21 of them (60%) relapsed 3 - 40 months later, while only 7 (17%) negative patients relapsed (chi(2) = 12.59, P < 0.01). CONCLUSION: Minimal residual disease detection in bone marrow by PCR might predict prognosis in some childhood hematological malignancies.

Adolescent↗

[Treatment of severe infections in hematologic malignancies with piperacillin sodium].

Combination antibiotic therapies using piperacillin (PIPC) were evaluated in 60 episodes of severe infections in 38 neutropenic patients with hematologic malignancies. 1. The overall efficacy rate was 46.7%. Efficacy rates were 30% in patients with pneumonia, 60% in patients with sepsis and 50% in patients with suspected sepsis in which causative organisms were not identified. 2. Eradication rates were 44.4% for Gram-negative bacilli, 50% for Pseudomonas aeruginosa and 22.2% for Gram-positive cocci. 3. Efficacy rates were 33.3% in patients with initial count of neutrophil less than 100/microliters, 60% in patients with those 100 to 500/microliters and 66.7% in patients with those higher than 500/microliters. Initial neutrophil counts correlated well with efficacies of PIPC on severe infection in patients with hematologic malignancies. 4. Mild increases of transaminase were observed in 2 cases. From these results it is concluded that PIPC is one of the most important antibiotics in the treatment of severe infections in neutropenic patients with hematologic malignancies.

Adolescent↗

An autopsy study of systemic fungal infections in patients with hematologic malignancies.

The aim of this study was to determine the incidence of fungal infections detected on autopsy in a group of 40 patients with hematologic malignancies treated with intensive chemotherapy or bone marrow transplantation, and to evaluate the risk factors for fungal infections. A control group included 38 patients with nonhematologic diseases and without granulocytopenia but with at least one of the known risk factors for fungal infections. Standard histopathological and microbiological methods were used. A higher incidence of invasive fungal infections was found in patients with hematologic malignancies as compared to the control group (p < 0.01). The predominant causes of fungal infections were Candida albicans and Aspergillus spp. The incidence of fungal infections caused by Aspergillus was higher (p < 0.05) in patients with hematologic malignancies than in the control group. The independent risk factors for fungal infections were fungal colonization, number of antibiotics and duration of antibiotic therapy, duration of fever and skin rash. A higher proportion of fungal infections was diagnosed on autopsy than during the patients' life (p < 0.01).

Adolescent↗

Anorectal and perianal complications of hematologic malignant neoplasms.

Among 17 adults with hematologic malignant neoplasms in whom anorectal complications developed, the overall mortality was 53%; for those in whom the disease was not in remission the mortality was 69%, compared with zero for patients who were in remission. All but one of the deaths were directly attributable to septicemia secondary to the anorectal lesion. Over half of the patients had a history of previous anorectal problems or disordered bowel pattern preceding the anorectal complication. The anorectal lesions affecting these 17 patients included prolapsed hemorrhoids (in 5); discrete ulcers in the anal canal and surrounding cellulitis (8); necrosis of the anus and perianal area (2); and perirectal abscesses (2). Only the abscesses responded to surgical drainage. Treatment of the other lesions was conservative: bowel function was maintained as normal as possible, good perineal hygiene was practised and stool softeners were used, while efforts were directed towards achieving remission of the hematologic neoplastic disease.

Adult↗

Occupational risk for hematological malignancies.

A case-control study was conducted in 620 cases of hematological malignancies and in 1,240 age- and sex-matched controls in order to verify the possible association between occupation, toxic substances exposure, and the risk of hematological neoplasias. The results demonstrate that farmers and industrial workers have a significant risk for hematological malignancies. Exposure to asbestos, aromatic hydrocarbons, fertilizers, mineral oils, pesticides, and radiations is associated with a significant increase in the risk for these malignant diseases. These data are in agreement with previously reported data, and require a confirmation in larger, prospective studies.

Adult↗

Distribution of C3-step regulatory proteins of the complement system, CD35 (CR1), CD46 (MCP), and CD55 (DAF), in hematological malignancies.

The distribution and levels of three membrane proteins, CD35, CD46, and CD55, which serve as complement regulators, were examined in normal peripheral blood and hematologically malignant cells. CD35 was negative in most leukemia cells regardless of the type of leukemia, although granulocytes, monocytes, and some populations of lymphocytes were CD35+. CD46 was present in all blood cells except erythrocytes, and levels were 2-8 times higher in most leukemia cells than in their mature counterparts, particularly in CML and CLL cells, except for those of B cell lineage. CD55, a widely-distributed phosphatidyl inositol-anchored protein, was more frequently lost in NHL cells than in other types of hematological malignancies. In this review, we discuss the roles, mechanisms, and clinical applications of cell-associated complement regulatory proteins in hematological malignancies.

Antigens, CD↗

Imipenem-cilastatin for empirical therapy in neutropenic patients with fever: an open study in patients with hematologic malignancies.

In adult neutropenic patients with hematological malignancies, we explored imipenem-cilastatin as empirical antibiotic therapy in a dose of 500 mg four times daily. Changing to second-line treatment was only resorted to if clinical deterioration, new infections or recurrence of fever occurred. A clinically or microbiologically documented infection was apparent in 115 of 150 episodes studied (76.7%). Imipenem-cilastatin was successful in 70.7% of all episodes and in 67.8% of all proven infections. Modification was necessary and successful in 22.0% of all episodes. 11 patients died while still febrile, 6 of them by infection (4%) and 5 because of progressive disease (3.3%). Imipenem-cilastatin is safe initial therapy in neutropenic febrile patients.

Antibiotics, Antineoplastic↗

Phase I study of oral topotecan in hematological malignancies.

PURPOSE: In this Phase I, dose-seeking study, we investigated the dose-limiting toxicities (DLTs) and maximal tolerated dose (MTD) of oral topotecan in patients with hematological malignancies. EXPERIMENTAL DESIGN: Patients with myelodysplastic syndromes, myeloproliferative disorders, or relapsed acute myelogenous leukemia were treated with 0.6-1.9 mg/m(2)/day oral topotecan for 5 consecutive days on and 2 days off, for 3 weeks (15 doses/course) followed by 2-4 weeks of rest. The DLTs occurring during the first course of treatment were considered for defining the MTD. Preliminary results of antitumor activity were assessed by examining bone marrow status and peripheral blood cell counts. RESULTS: All 26 patients enrolled in the study were evaluable for toxicity, and 24 patients were evaluable for response. A total of 54 courses were administered. The most frequently reported nonhematological toxicities (percentage of courses) were diarrhea (57%), nausea/vomiting (50%), fatigue (24%), and mucositis (9%). DLTs included grade 3 or 4 nausea/vomiting and diarrhea at 1.9 mg/m(2)/day. The MTD for oral topotecan in patients with hematological malignancies was defined at 1.4 mg/m(2)/day. Hematological toxicity was noted in all 26 patients and with all courses but was not considered dose-limiting. Four (17%) patients achieved a complete response, and six (25%) patients experienced hematological improvement. CONCLUSIONS: Protracted administration of oral topotecan is safe and well tolerated in patients with hematological malignancies. At the dose-schedule used, single-agent oral topotecan has a definite activity in patients with myelodysplastic syndrome and acute myelogenous leukemia and warrants further investigation alone or in combination with other agents.

Adult↗

Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies.

Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin's disease, 22 non-Hodgkin's lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52-289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P < 0. 001) and BCV regimen (P < 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309-313.

Adolescent↗

[Splenectomy: surgical indications in malignant hematologic diseases].

Indications for splenectomy in malignant hematological diseases are discussed for relief of symptoms (splenomegaly, cytopenias), for staging (M. Hodgkin) or improvement of survival (hairy cell leukemia). The role of splenectomies is also evaluated for Non-Hodgkin lymphomas, chronic lymphatic leukemia, myelofibrosis and for chronic myeloic leukemia.

Hematologic Diseases↗

[Treatment of elderly patients with hematological malignancies].

Treatment of elderly patients with hematological malignancies is difficult and a matter of controversy. Low responsiveness to therapy and high risk of mortality have been reported. The risk of chemotherapeutic death increases after age 60, and an age-adjusted chemotherapy schedule is needed. In stage III and IV Hodgkin's disease, for example, an age-adjusted COPP regimen may be adopted. Many non-Hodgkin lymphomas (NHL) of elderly patients have a slow course. However, for intermediate to high grade aggressive NHL, dose-reduced CHOP regimen, or non- or low-dose methotrexate-containing programs like BECALM, CNOP, and low dose-ACOP-B are acceptable. MACOP-B regimen with G-CSF may be used for patients under age 65. For the treatment of elderly patients with AML, it is reported that a reduced-dose DAT regimen is better than the standard dose for inducing CR in patients older than 60. In elderly AML patients over 60, the dose-adjustment reported by Mori, or low-dose cytarabine with G-CSF, is recommended. Information about elderly patients with acute lymphoblastic leukemia is scarce. Aggressive treatments like L-17 M regimen are not tolerable by elderly patients, and a combination chemotherapy consisting of vincristine and prednisolone is recommended.

Aged↗

Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies.

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti-CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC-mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC-mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Adolescent↗

[Phase II study with methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU) in hematological malignancies].

Forty-two cases of hematological malignancy (18 cases of CML, three cases of polycythemia vera, 10 cases of malignant lymphoma and 11 cases of multiple myeloma) were treated with MCNU. The results obtained were as follows. MCNU was markedly effective on CML cases, being especially useful during the chronic phase, and a partial remission was observed in one of three patients with CML blastic crisis. A good response was observed in all cases with polycythemia vera. In some cases of malignant lymphoma, a fair response was observed. No response was observed in any of the cases of multiple myeloma. Myelosuppression was a major side effect of MCNU, but other side effects other than melena were not severe.

Adult↗

Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy.

The high relapse rate of hematologic malignancy treated with autologous bone marrow transplantation (ABMT) may reflect the absence of a graft-versus-leukemia (GVL) effect usually associated with graft-versus-host disease (GVHD). The purpose of this study was to determine whether administration of interleukin-2 (IL-2) early after ABMT might induce or exacerbate acute skin GVHD. Fourteen patients at high risk for post-transplant relapse, eight with NHL and six with AML > or = first relapse, were conditioned with chemotherapy and total body irradiation (13) or chemotherapy alone (1), and received purged (10) or unpurged (4) marrow. A median of 35 days (range 25-58) after ABMT, they received a 5-day induction course of Roche IL-2 (9 x 10(6) U/m2/day) followed by apheresis, reinfusion of LAK cells, and a 10-day maintenance course of IL-2 (0.9 x 10(6) U/m2/day), all by continuous i.v. infusion. Serial skin biopsies were obtained before and after IL-2 therapy and were read blindly. Patients were studied prospectively for the development of acute cutaneous GVHD as reflected by rash ( > or = 25% body surface area), skin biopsy ( > or = grade II histologic changes) and T cell infiltration as assessed by staining of the biopsy with antibodies UCHL-1 and TIA-1. No patient had a rash before IL-2 therapy, but 12 of 14 (85%) developed a rash during the IL-2 induction course. Before IL-2 therapy, biopsies from three of 10 patients (30%) revealed histologic GVHD; after induction IL-2, biopsies from 11 of 14 patients (79%) revealed grade II acute GVHD. Biopsies from all patients with histologic GVHD after IL-2 therapy contained TIA-1 positive T cells. HLA-DR was negative in the keratinocytes of these paraffin-embedded sections. One patient died early of sepsis, one patient required and responded to topical corticosteroids and 12 had spontaneous resolution of the rash. Six patients relapsed at 3-13 months, while seven remain in complete remission 32+ to 41+ months after ABMT. The results demonstrate that IL-2 therapy after ABMT can induce effects which histologically and clinically mimic cutaneous acute GVHD in most patients. Prospective, randomized trials of IL-2 vs observation after transplantation of autologous marrow or stem cells for high-risk NHL and AML have been initiated which may allow us to determine whether this phenomenon is associated with a clinical GVL effect as reflected by a decreased relapse rate.

Acute Disease↗

Treatment of hematologic malignancies with alternate hemibody irradiation combined with high-dose chemotherapy: a single-center experience.

The objective of this study was to evaluate the clinical outcome of the treatment of hematologic malignancies with alternate hemibody irradiation (AHBI) combined with high-dose chemotherapy. Seventeen patients with hematologic malignancies were treated with AHBI combined with high-dose chemotherapy. Following high-dose chemotherapy, upper hemibody irradiation (UHBI) and lower hemibody irradiation (LHBI) were given sequentially in a dose of 6 to 9 Gy. UHBI was given 14 days (range, 12-22 days) after high-dose chemotherapy, and LHBI was performed 23 days (range, 7-34 days) after UHBI. Meanwhile, we treated a control group of 14 patients with acute lymphoblastic leukemia (ALL) with autologous hematopoietic stem cell transplantation (AHSCT). Hematopoietic reconstitution was observed in all of the patients. The median follow-up period was 927 days (range, 428-1446 days). The 3-year probabilities of disease-free survival (DFS) were 52.38% +/- 13.47% for the patients in complete remission who underwent AHBI. No patient died of AHBI-related toxicity. The 3-year DFS rates for the 2 groups of patients with ALL were not significantly different (47.73% +/- 17.55% in the AHBI group and 53.88% +/- 14.08% in the AHSCT group; P > .05). AHBI combined with high-dose chemotherapy is a feasible approach for patients with hematologic malignancies and has the advantages of a desirable effectiveness, low costs, simple operation, and acceptable side effects.

Adolescent↗

Documented and clinically suspected bacterial infection precipitating intensive care unit admission in patients with hematological malignancies: impact on outcome.

OBJECTIVE: To assess the impact of documented and clinically suspected bacterial infection precipitating ICU admission on in-hospital mortality in patients with hematological malignancies. DESIGN AND SETTING: Prospective observational study in a 14-bed medical ICU at a tertiary university hospital. PATIENTS: A total of 172 consecutive patients with hematological malignancies admitted to the ICU for a life-threatening complication over a 4-year period were categorized into three main groups according to their admission diagnosis (documented bacterial infection, clinically suspected bacterial infection, nonbacterial complications) by an independent panel of three physicians blinded to the patient's outcome and C-reactive protein levels. RESULTS: In-hospital and 6-months mortality rates in documented bacterial infection (n=42), clinically suspected bacterial infection (n=40) vs. nonbacterial complications (n=90) were 50.0% and 42.5% vs. 65.6% (p=0.09 and 0.02) and 56.1% and 48.7% vs. 72.1% (p=0.11 and 0.02), respectively. Median baseline C-reactive protein levels in the first two groups were 23 mg/dl and 21.5 mg/dl vs. 10.7 mg/dl (p<0.001 and p=0.001) respectively. After adjustment for the severity of critical and underlying hematological illness and the duration of hospitalization before admission documented (OR 0.20; 95% CI 0.06-0.62, p=0.006) and clinically suspected bacterial infection (OR 0.18; 95% CI 0.06-0.53, p=0.002) were associated with a more favorable outcome than nonbacterial complications. CONCLUSIONS: Severely ill patients with hematological malignancies admitted to the ICU because of documented or clinically suspected bacterial infection have a better outcome than those admitted with nonbacterial complications. These patients should receive advanced life-supporting therapy for an appropriate period of time.

Adult↗

Targeted therapy for hematologic malignancies.

BACKGROUND: The introduction of monoclonal antibodies, either as native molecules or conjugated to radioisotopes or other toxins, has led to new therapeutic options for patients with hematologic malignancies. In addition, the use of small molecules against specific cell surface receptors, enzymes, and proteins has become an important strategy in the treatment of such disorders. METHODS: The author reviewed the published clinical trials of monoclonal antibody and other targeted therapies in hematologic malignancies. RESULTS: Results from several trials demonstrate a therapeutic benefit for the use of monoclonal antibodies (either native or conjugated) and other targeted therapies, used alone or in combination with standard cytotoxic chemotherapy. CONCLUSIONS: Targeted therapy of hematologic malignancies seems to be an effective and less toxic approach to the treatment of such disorders. Nevertheless, additional studies are needed to determine where and when such management fits into a therapeutic regimen for any given disorder, whether upfront or as salvage therapy, alone or in combination with chemotherapy (concurrent or sequential).

Antibodies, Monoclonal↗