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Intensive chemotherapy with idarubicin, cytosine arabinoside, and granulocyte colony-stimulating factor (G-CSF) in patients with secondary and therapy-related acute myelogenous leukemia. Club de Réflexion en Hématologie.

Using a combination of intensive chemotherapy and G-CSF, we conducted a prospective trial designed to improve the complete remission (CR) rate in patients with AML evolving from a primary documented myelodysplastic syndrome (sAML) and therapy-related AML (tAML). Thirty-four patients (median age 61 years) with sAML (25 patients) or tAML (nine patients) entered the study. Induction course consisted of idarubicin (12 mg/m2 of body-surface area per day for 3 days) and intermediate-dose (ID) cytarabine in the 24 younger patients (1 g/m2 of body-surface area as a 2 h infusion every 12 h for 5 days) or standard-dose (SD) cytarabine in the 10 older patients (100 mg/m2 of body-surface area per day as a continuous infusion for 7 days), followed by G-CSF until neutrophil recovery or treatment failure. Nineteen patients (56%, 13/24 in the ID group and 6/10 in the SD group) achieved a CR (14/25 sAML and 5/9 tAML). Early death occurred in four patients, but four additional patients died in CR from treatment-related toxicity (overall toxic death rate 24%). Initial cytogenetics was available in 33 patients. The CR rate was significantly lower in patients with unfavorable cytogenetics compared to patients with intermediate cytogenetics (37% vs 79%). Median remission duration and overall survival were 3 and 9 months, respectively and not different between ID and SD patients. Although the treatment-related toxicity is high, a high CR rate can be obtained in these poor-risk AML patients with the use of intensive chemotherapy in combination with G-CSF, although the role of the latter is still to be proven. Results remain especially poor in patients with unfavorable cytogenetics. New approaches are needed to maintain remission in these high-risk AML patients.

Adult↗

Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL(1).

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.

Antineoplastic Agents↗

The comparative values of bone marrow aspirate and trephine for obtaining bone scan-targeted metastases from hormone-refractory prostate cancer.

Samples of metastatic prostate cancer to bone are difficult to obtain. The aim of this study was to compare the results of bone marrow aspirate and trephine biopsy for obtaining metastatic hormone-refractory prostate cancer (HRPC) samples using previous diagnostic planar 99(m)Tc-HDP bone scans to guide the procedure. All samples taken were for the purposes of research and molecular studies on HRPC. Twenty patients with HRPC had bone marrow aspirate and trephines taken from lesions in the posterior superior iliac spine or sacro-iliac region when shown on diagnostic 99(m)Tc-HDP bone scans. Three patients also underwent plain X-ray, 18F-positron emission tomography bone scan, pelvic MRI scan and 99(m)Tc nanocolloid bone marrow scans. These images were used to assess if the extra imaging information provided, such as three-dimensional localisation of the bone metastases, was of value for target bone metastases. Cancer cells were obtained in 15/20 (75%) cases in which a trephine biopsy was attempted and 0/20 of cases in which a bone marrow aspiration was attempted. The additional information provided by the range of other imaging investigations was of little benefit in obtaining tumour samples, but did suggest why negative biopsies were obtained in some cases after targeting with planar bone scans. We recommend the use of bone marrow trephine biopsy alone, guided by previous diagnostic 99(m)Tc planar bone scan as a practical method to obtain prostate cancer cells from bone metastases.

Aged↗

Haemophagocytic lymphohistiocytosis in children.

OBJECTIVE: To evaluate the clinical and diagnostic features of children presenting with haemophagocytic lymphohistiocytosis (HLH), evolution of the disease and outcomes in response to treatment. METHODOLOGY: The medical records of 12 children, aged 5 weeks to 13 years at diagnosis, with HLH managed at a single institution were reviewed. RESULTS: Presenting features were fever, hepatosplenomegaly, pancytopenia and hypertriglyceridemia or hypofibrinogenemia. Nine patients (75%) developed central nervous system (CNS) disease. Only one child with CNS disease survived. Five children had complete responses to therapy (42%), but all relapsed at a median of 1.5 months after starting treatment (range 2 weeks to 5 months). Two of the children treated are long-term survivors (17%), both after allogeneic bone marrow transplantation. All deaths occurred in the context of active disease. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is a disease with a poor prognosis. Central nervous system complications are common and response to treatment usually is transient. This study provides support for the use of immunomodulatory therapy for remission introduction followed by consideration of allogeneic bone marrow transplantation.

Adolescent↗

[Differential diagnosis of a macrocytic, hyperchromic anemia following alcohol abuse and simultaneous therapy with triamterene and cotrimoxazole].

HISTORY AND ADMISSION FINDINGS: A 50-year-old woman was admitted to our emergency room because of progressive weakness. She collapsed the night before admission. Skin and mucosa were pale, she denied major infections or bleedings. An alcohol abuse was known for many years. Because of edema she received a therapy with triamteren, an infection of the urinary tract was treated with cotrimoxacol. INVESTIGATIONS: In addition to thrombocytopenia (50 Gpt/l) and leukocytopenia (1,51 10 (9)/l) we diagnosed a hyperchromic and macrocytic anemia (Hb 3,6 mmol/l [5,8 g/dl], Hk 0,17, MCH 2.52 fmol, 116,8 fl). Folic acid was decreased to 0.677 ng/ml, whereas levels of cobalamin, ferritin and iron were normal. Examination of bone marrow showed a hypercellular marrow with typical megaloblastic features of erythropoiesis and granulopoiesis. A systemic hematological disorder could be ruled out. The folic acid deficiency in our patient was the result of a long time alcohol abuse and a simultaneous therapy with mild folate antagonists (triamteren and cotrimoxacol). CLINICAL COURSE: The patient received folic acid (5 mg/d orally). Within one week the peripheral blood counts increased to normal, the follow up bone marrow examination showed a hyperplastic marrow with normal hematopoietic maturation. CONCLUSIONS: Folic acid deficiency can be aggravated because of simultaneous therapy with mild folate antagonists. In addition to megaloblastic anemia this can lead to thrombocytopenia and/or leukocytopenia. Therefore in patients with pancytopenia a deficiency of folic acid should be ruled out.

Alcoholism↗

Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation.

BACKGROUND: Patients whose leukemia relapses after allogeneic bone marrow transplantation have a poor prognosis; few respond to further chemotherapy, and almost none survive over the long term. We present preliminary observations on the use of filgrastim (granulocyte colony-stimulating factor) for relapse after transplantation. METHODS: Seven female patients with leukemia (one with chronic myelogenous leukemia, five with acute myelogenous leukemia, and one with a myelodysplastic syndrome that transformed into acute myelogenous leukemia) whose disease relapsed within 360 days after allogeneic bone marrow transplantation received filgrastim (5 micrograms per kilogram of body weight per day by subcutaneous injection) to reinduce remission by stimulating residual donor marrow cells. Cytogenetic analysis of bone marrow, fluorescence in situ hybridization, and determination of restriction-fragment--length polymorphisms were used to assess response and chimerism. RESULTS: Three of the seven patients had a complete hematologic and cytogenetic remission, with reestablishment of hematopoiesis of donor origin. Mild chronic graft-versus-host disease developed in one patient, and acute graft-versus-host disease in none. One patient had a relapse 12 months after treatment, and two others remained in remission after 10 and 11 months. In two of the patients with a response, fluorescence in situ hybridization demonstrated stimulation of donor cells without differentiation of the leukemic clone. CONCLUSIONS: Filgrastim may be effective in selected cases of leukemic relapse after allogeneic bone marrow transplantation.

Adolescent↗

Bone marrow-disseminated tumor cells in patients with carcinoma of the esophagus or cardia.

BACKGROUND: The long-term prognosis after surgical therapy for esophageal carcinoma depends on tumor stage and completeness of resection. Similarly to other epithelial tumors, the presence of micro deposits of neoplastic cells in the bone marrow may indicate residual disease and the potential for recurrence. This study assesses the prevalence of bone marrow-disseminated tumor cells in patients undergoing surgical resection for esophageal carcinoma. In addition, we investigated the agreement between immunohistochemical and molecular techniques for the detection of micrometastases in a subgroup of patients. METHODS: Between January 1998 and November 1999, forty-eight patients with adenocarcinoma of the esophagogastric junction (n = 29) or squamous cell carcinoma of the thoracic esophagus (n = 19) and no evidence of overt metastatic disease entered the study. An immunohistochemical assay (capable of detecting 1 carcinoma cell in 7 x 10(5) bone marrow cells) was used to test bone marrow obtained by flushing a resected rib or by needle aspiration either of the iliac crest or of a rib. A polymerase chain reaction (PCR) molecular technique was also used to identify bone marrow and peripheral blood epithelial cells. RESULTS: Cytokeratin-positive cells were found in 79.1% of the bone marrow samples obtained from the rib, and in only 8% of the needle aspirates either from the iliac crest or from a contiguous rib: This difference is probably explained by the improved removal of metastatic cells with the flushing of the rib. Comparable results were obtained at a qualitative level by the PCR technique on bone marrow. In addition, PCR-positive results were found in 3 of 18 peripheral blood samples. There was no association with tumor type, neoadjuvant therapy, or lymph node status. Patients with a pT3 or pT4 tumor showed, at a borderline statistical level, a higher proportion of cytokeratin-positive cells in the flushed rib. CONCLUSIONS: Bone marrow-disseminated tumor cells are present in the resected rib of a high proportion of patients undergoing esophagectomy for carcinoma, and immunohistochemistry seems to be the method of choice for their quantitative assessment. However, the prognostic and therapeutic implications of this finding need further investigation.

Adenocarcinoma↗

Application of interphase FISH on direct bone marrow smears for evidence of chimerism in pediatric sex mismatched bone marrow transplantation.

We report here our experience in the management of four children undergoing sex mismatched allogeneic bone marrow transplantation (BMT) who showed evidence of poor engraftment post BMT. Fluorescence in situ hybridisation (FISH) was performed on direct bone marrow smears with the X centromere and Y heterochromatin probes, to ascertain chimerism. Of 16 hybridisations, only one was unsuccessful, whereas routine bone marrow cytogenetics performed at the same time failed in five of eight cultures. The FISH results were available in one to two days. The FISH findings provided a valuable aid in the early management of these children.

Bone Marrow Examination↗

Parvovirus B19 infection associated with severe aplastic anemia in an immunocompetent patient.

Human parvovirus B19 (PVB19) infection may cause mild pancytopenia characterized by transient and spontaneous recovery in healthy subjects. Severe aplastic anemia associated with PVB19 infection in patients without an underlying disease has been described in a number of reports. Here, a previous healthy, 10-year-old girl with severe aplastic anemia associated with PVB19 infection is described. The patient underwent bone marrow transplantation from her HLA-identical sibling resulting in complete recovery. PVB19 infection should be considered as one of the causes of aplastic anemia in patients without an underlying disease.

Anemia, Aplastic↗

Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method.

Cell enrichment methods that deal with larger volumes of peripheral blood and BM are needed for increased sensitivity of detection, characterization and quantification of isolated tumor cells (ITC). This study was designed to evaluate a new procedure, the RosetteSep-Applied Imaging Rare Event (RARE) detection method, which depletes the majority of the erythrocytes and leucocytes in a peripheral blood (PB) sample, thereby negatively enriching tumor cells if present. This enrichment procedure allows for increased sensitivity, by analyzing a 5-10 fold larger volume of blood, compared with a direct immunocytochemical (ICC) technique, with minimal impact on laboratory workload. Model experiments showed comparable tumor cell recoveries between the two tested methods, both in PB and BM. Clinical samples were evaluated using paired PB and BM samples from 95 carcinoma patients. Analysis of PB results showed that 25.3% had > or = 1 tumor cell detected by the RARE procedure, compared with 5.2% after direct ICC analysis, analyzing a 10-fold larger volume by the RARE procedure. The direct ICC analysis of BM from the same patients revealed 16.8% positive. The ITC detection differed both quantitatively and qualitatively between BM and PB, as samples with high numbers of ITC in BM were still negative in PB. The clinical significance of ITC in blood still needs to be established. However, the easy access of peripheral blood, and the increased sensitivity obtained by increasing the sample volume with the RARE procedure, suggests that the value of peripheral blood analysis should be tested in parallel in studies where ITC detection in BM is performed.

Antibodies, Monoclonal↗

Aplastic anemia: the role of immunosuppression.

In a young, previously untransfused patient for whom a compatible donor can be found, marrow transplantation may be optimal. Otherwise, immunosuppression provides an effective therapeutic alternative.

Adult↗

Use of the polymerase chain reaction for the detection of tumor cell involvement of bone marrow and peripheral blood: implications for purging.

Bone marrow purging is being performed increasingly in an effort to deplete residual tumor cells from the graft prior to reinfusion. Several studies have suggested that the removal of tumor cells is an important clinical goal. In this review the utility of the polymerase chain reaction (PCR) for the detection of small numbers of tumor cells in bone marrow and peripheral blood is discussed. Using sensitive assays such as PCR, it is expected that the efficacy of bone marrow purging strategies will be improved and this will hopefully result in decreased relapse rates following autologous bone marrow transplantation.

Antineoplastic Agents↗

Can patients with early-stage diffuse large B-cell lymphoma be treated without bone marrow biopsy?

BACKGROUND: Data on the incidence of bone marrow (BM) involvement in early-stage diffuse large B-cell lymphoma (DLBCL) are lacking. Although BM biopsy is a safe procedure, it is often poorly tolerated. This analysis aims to assess the incidence of BM involvement and to identify parameters predicting BM involvement in early-stage DLBCL. PATIENTS AND METHODS: One hundred and ninety-two patients with radiological stages 1 and 2 disease were analysed. The data collected were age, sex, presence of B symptoms, white blood cell (WBC) count, platelet count, haemoglobin (Hb), serum lactate dehydrogenase level, serum beta(2)-microglobulin level, presence of extranodal disease, and the presence of bulky disease (defined as >7 cm). RESULTS: Overall incidence of BM involvement was 3.6%. Hb < 10 g/dl (P=0.02), WBC count < 4 x 10(9)/l (P=0.007) and bulky disease (P=0.06) were found to be predictive of BM involvement. Among the 120 patients without any of these three factors, only one patient had BM involvement (0.83%; 95% confidence interval 0.02% to 4.6%). The absence of all three factors gave a negative predictive value of 99.2%. Overall 3-year survival for patients without all three risk factors was 80%. CONCLUSIONS: BM biopsy may be safely omitted in selected patients with early-stage DLBCL.

Bone Marrow Examination↗