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Biomedical subjects

A Zander

Publications and source records attributed to A Zander.

At least 37 records · Page 2Linked to original sources
PubMed1999

Establishment of an optimised gene transfer protocol for human primary T lymphocytes according to clinical requirements.

Current gene therapeutic protocols directed towards the treatment of inherited disorders (eg ADA-SCID) and viral infections (eg AIDS), as well as adoptive immunotherapy approaches are based on the use of genetically modified lymphocytes. Since only insufficient transduction of T cells is obtained using existing techniques, the development of more efficient gene transfer protocols into these cells is of great importance. We present here a protocol for the highly efficient transduction of human primary T cells at high densities (1 x 106/ml) by retroviral infection. Using retroviral vectors encoding a truncated human low-affinity nerve growth factor receptor (DeltaLNGFR) as a gene transfer marker, we obtained transduction frequencies of more than 70% of CD3+ cells after two cycles of infection. Our protocol is based on the use of FBS-free media for both the production of retrovirus-containing supernatant and the cultivation of the primary T cells. Since the protocol presented here works just as efficiently under large-scale conditions, it may be easily adapted to clinical needs and 'good manufacturing practice' (GMP) standards.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation.

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patient's condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy.

Adolescent↗
PubMed1998

Analysis of nicotine and its oxidation products in nicotine chewing gum by a molecularly imprinted solid-phase extraction.

Chromatographic stationary phases showing exceptional selectivity for nicotine can be prepared by the technique of molecular imprinting. Such phases were used in the search for a rapid cleanup step for nicotine and some of its oxidation products in chewing gum formulations. Thus, using an organic mobile phase, the nicotine analytes from chewing gums dissolved in nonpolar solvent were retained, whereas the nonpolar matrix eluted close to the void peak. A subsequent switch to an acidic mobile phase resulted in elution of the analytes as one sharp peak. Due to weak binding of the less basic oxidation products, other imprinted polymers were tested, and the solid-phase extraction procedure was optimized. Polymers were prepared using various functional and cross-linking monomers, templates, porogens and thermal treatments. This resulted in phases that, when compared with a nonimprinted or a C18 reversed-phase column, showed significantly higher recoveries of the analytes. Furthermore, no bleeding of template from the phases could be detected. The cleanup step was coupled off-line to reversed-phase HPLC, and the efficiency of the analysis was compared with and without the cleanup step. Three out of four analytes were quantitatively recovered using the imprinted phase, whereas, using the nonimprinted phase, only nicotine was recovered. Without the cleanup step, none of the analytes could be determined using the reversed-phase HPLC method.

Chewing Gum↗
PubMed1998

Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation.

In a multicentre trial involving 20 transplant centres from 10 countries haematopoietic stem cells were obtained either from the bone marrow of 33 sibling donors or from the peripheral blood of 33 such donors after administration of filgrastim (10 microg/kg/day). The haematopoietic stem cells were infused into their HLA-identical recipients suffering from acute leukaemias in remission or chronic myeloid leukaemia in chronic phase. PBPC donors tolerated filgrastim administration and leukapheresis well with the most frequent side-effects being musculoskeletal pain, headache, and mild increases of LDH, AP, Gamma-GT or SGPT. Pain and haematoma at the harvest site and mild anaemia were the most frequent complaints of BM donors. Severe or life-threatening complications were not seen with any type of harvest procedure. Time to platelet recovery greater than 20 x 10(9)/l was 15 days (95% confidence interval (CI) 13-16 days) in the PBPCT group and 19 days (CI 16-25) in the BMT group. Time to neutrophil recovery greater than 0.5 x 10(9)/l was 14 days (CI 12-15 days) in the PBPCT group as compared to 15 days (CI 15-16 days) in the BMT group. The numbers of platelet transfusions administered to PBPCT and BMT patients were 12 (range: 1-28) and 10 (range: 3-39), respectively. Sixteen patients (48%) transplanted with bone marrow and 18 patients (54%) transplanted with PBPC developed acute GVHD of grades II-IV; acute GVHD of grades III or IV developed in six (18%) and seven (21%) patients, respectively. Kaplan-Meier plots for transplant-related mortality until day 100 and leukaemia-free survival at a median of 400 days after BMT or PBPCT showed no significant differences. Administration of filgrastim and leukapheresis in normal donors were feasible and well tolerated. The number of days with restricted activity and of nights spent in hospital was lower in donors of PBPC. Transplantation of PBPC to HLA-identical siblings with early leukaemia resulted in earlier platelet engraftment. The incidence of moderate to severe acute GVHD, transplant-related mortality, and leukaemia-free survival did not show striking differences. Further investigation of allogeneic PBPCT as a substitute for allogeneic BMT is warranted.

Adolescent↗
PubMed1998

Safety and efficacy of spinal vs general anaesthesia in bone marrow harvesting.

Bone marrow harvesting (BMH) can be performed with either general (GA) or spinal anaesthesia (SPA). Whether SPA is advantageous in BMH and if this technique is safe for procedures performed in the prone position is still controversial. To evaluate the safety and efficacy of both anaesthetic techniques in BMH, 37 allogeneic donors (nine female, 28 male; 34.3 +/- 9 years; ASA class 1-2) received either spinal (group 1, n =20) or general anaesthesia (group 2, n = 17) according to their personal wishes. Under standardised harvesting conditions, haematology parameters, cell counts (MNC, CD34+), haemodynamic parameters, adverse reactions and patient satisfaction were registered. No differences were seen between groups with respect to demographic data, harvesting time (55 +/- 17 vs 60 +/- 16 min) and bone marrow cell counts (MNC: 6.68 +/- 2.1 vs 5.7 +/- 1.7 ml/10(6)). The incidence of hypotension was higher in group 1 (45 vs 10.8%; P =0.042). Postoperative analgesic requirement and emesis were increased in group 2 (P < 0.04) in comparison to group 1. In conclusion, the present study failed to show superiority of spinal over general anaesthesia with regard to the quality of the harvested bone marrow. However, the lower incidence of complaints after spinal anaesthesia appears to offer an advantage over GA in healthy allogeneic bone marrow donors.

Adult↗
PubMed1997

[Transplantation of hematopoietic stem cells. II: Indications for transplantation of hematopoietic stem cells after myeloablative therapy].

The destruction of hematopoiesis and lymphopoiesis by total body irradiation or high dose chemotherapy for the treatment of malignancy can be reversed by the transplantation of allogeneic or autologous hematopoietic stem cells. In primary disorders of bone marrow or immune system, allogeneic stem cells replace deficient cells. Acute leukemias can be cured, with in 50 to 80% disease free survival after 5 to 8 years. The allogeneic graft versus leukemia effect by immunoreactive cells reduces the relapse rate in myeloid and lymphoid malignancies. 40 to 70% of patients with chronic myeloid leukemia remain disease free after more than 5 years. Patients with malignant lymphoma have a 40 to 70% chance of cure with autologous transplantation, which is not increased by allogeneic cells, because of a higher incidence of severe complications. An increasing number of patients without option for cure is treated with the aim of prolonging remission or retarding disease progression, such as in chronic myeloid leukemia, multiple myeloma and certain solid tumors. New studies suggest in breast cancer with axillary lymph node metastases, that adjuvant high dose chemotherapy with autologous stem cell support will significantly improve disease free survival from 30 to over 60% after 3 to 5 years. In congenital metabolic and storage diseases deficient enzymes are substituted by the allogeneic cells. Clinical trials explore the use of stem cell transplantation after myeloablative therapy in autoimmune disorders as well as in gene therapy with transfected hematopoietic stem cells.

Combined Modality Therapy↗
PubMed1997

[Transplantation of hematopoietic stem cells. I: Definitions, principle indications, complications].

The transplantation of hematopoietic and lymphopoetic stem and progenitor cells has become a standard procedure for the treatment of many malignant diseases. Autologous stem cells are derived from the patient himself, allogeneic cells from an HLA-identical or HLA-compatible family or unrelated donor. Hematopoietic stem cells can be obtained from bone marrow, blood and fetal cord blood. After 3 to 5 days treatment, the granulocyte-colony stimulating factor (G-CSF) mobilizes stem- and progenitor cells from the marrow into the blood. This method is now standard in autologous transplantation and is increasingly preferred in allogeneic transplantation. The time to hematopoietic recovery is shorter with blood stem cells than with bone marrow cells. With myeloablative high dose therapy followed by stem cell transplantation, long term disease free survival is possible in many cases and great proportions of patients can be cured (see part II). Improvements of supportive care have reduced toxicity of treatment substantially, however severe complications still occur at oropharynx, gastrointestinal tract, liver, lung, skin, kidney, urinary tract and nervous system. After allogeneic transplantation immunocompetent donor cells can react with the recipients tissue. In HLA-identical donor and recipients differences in the minor histocompatibility antigens account for this graft-versus-host-reaction (GvH), which is mainly mediated by transplanted T-cells. The GvH-reaction can affect skin, liver, gut and other organs and cause clinically relevant GvH-disease (GvHD). The GvHD is more severe in HLA-mismatched or unrelated transplantations. Immunodeficiency and organ dysfunction due to GvHD may predispose infections and impair the outcome of transplantation. Unrelated cord blood stem cells may have a minor risk of inducing acute GvHD, as stem and T-cells are immature. After allogeneic stem cell transplantation, the relapse rate of leukemia or lymphoma is significantly reduced by immunoreactive cells:graft-versus-tumor (GvT) or graft-versus-leukemia effect (GvL).

Graft vs Host Disease↗
PubMed1997

Long-term maintenance of hematopoiesis in irradiated mice by retrovirally transduced peripheral blood stem cells.

Mobilized peripheral blood stem cells (PBSC) are used as a source of hematopoietic stem cells for transplantation and gene therapy. It is still unclear, however, whether the PBSC are fully equivalent to normal bone marrow hematopoietic stem cells and whether they are able to provide long-term function of transgene in reconstituted mice. In the present study, mobilized PBSC from male mice were transduced with human adenosine desaminase gene (hADA) and were used for reconstitution of lethally irradiated female mice. At 1 1/2, 3, 6, 9, and 12 months after reconstitution, the bone marrow cells were repeatedly collected from each mouse under light anesthesia and the number of colony-forming unit-spleen (CFU-S), spleen repopulating ability (SRA), and the integration of human ADA gene were studied in CFU-S-derived colonies by polymerase chain reaction (PCR) and Southern blot hybridization analyses. After 9 months, the proportion of donor CFU-S detected by PCR with a Y-chromosome-specific probe in mice reconstituted with mobilized PBSC was 75.3% +/- 6.0%, which is similar to the concentration of donor CFU-S seen after bone marrow transplantation. Similarly, there was no difference in the concentration of CFU-S in mice reconstituted with transduced mobilized PBSC or bone marrow cells. However, in both cases the CFU-S content in the bone marrow was reduced fivefold to 10-fold compared with the concentration of CFU-S in mice transplanted with nontransduced bone marrow. The SRA of CFU-S in mice reconstituted with peripheral blood and bone marrow cells was the same 1.5 months posttransplantation, but after an additional 4 months, SRA of mice reconstituted with bone marrow cells was fivefold higher as compared with those engrafted by PBSC. The integration of the human ADA gene was observed during 9 months in about 60% of studied CFU-S. The proportion of marked colonies sharply decreased 1 year following reconstitution. One to 9 individually labeled clones could be shown simultaneously by Southern blot hybridization in the same reconstituted mice during the whole period of observation. The time of clone existence was about 3 months. We conclude that long-term marrow repopulating cells mobilized into circulation by treatment with granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are capable of maintaining lifelong polyclonal hematopoiesis in reconstituted mice.

Adenosine Deaminase↗
PubMed1997

Inverse correlation of interleukin-6 with soluble interleukin-6 receptor after transplantation of bone marrow or peripheral blood stem cells.

The relationship between interleukin-6 (IL-6) and the soluble interleukin-6 receptor (sIL-6R) was analyzed in 1481 serum samples of 82 patients after bone marrow or peripheral blood cell transplantation. The cytokine and its soluble receptor were measured on a daily basis starting at day -3 before and ending at day 21 after transplantation. IL-6 serum levels increased after transplantation, were at a maximum at day 6 and returned to the baseline level thereafter. The levels of sIL-6R showed an inverse course with a minimum at day 6. Statistical analysis revealed a strong inverse correlation between IL-6 and sIL-6R with a weighted Spearman rank correlation coefficient of -0.53 (P < 0.001). IL-6 may play a role in the decrease of sIL-6R either by the direct inhibitory effect on the expression of the IL-6R gene or by formation of IL-6/sIL-6R complexes followed by their internalization in target cells.

Bone Marrow Transplantation↗
PubMed1997

Long-term follow-up of leukaemia patients after related cryopreserved allogeneic bone marrow transplantation.

We have previously shown that allogeneic bone marrow transplantation (BMT) with cryopreserved donor marrow cells can be used without prolonging the engraftment time or interfering with the reconstitution of haemopoiesis. In this report we extend our initial observations of the first 40 patients who underwent allogeneic bone marrow transplantation from related donors with cryopreserved donor bone marrow for haematological malignancies, including the long-term follow-up data of the previously reported patients. The outcome of these patients was compared with that of 40 related BMT recipients receiving fresh donor bone marrow (historic control group). Time until engraftment of all patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0.5 x 10(9)/l 17d (range 11-24 d) versus 17.5 d (range 10-28 d): platelets > 20 x 10(9)/l 21 d (range 11-85 d) versus 22 d (range 13-69 d), respectively). There was the same incidence of acute and chronic GvHD in patients receiving either cryopreserved bone marrow or fresh bone marrow (acute GvHD > or = II 61% v 60% and chronic GvHD 56% v 52%, respectively). Chimaerism studies showed no difference between the patient groups. Furthermore, the two groups did not differ in day 100 survival (82% v 72%). With a median follow-up of 520 d (range 47-1365 d) and 1289 d (range 48-1849 d), 60% of the patients receiving cryopreserved and 53% of the patients receiving fresh allogeneic donor bone marrow, respectively, are alive. We conclude that cryopreservation of allogeneic related donor bone marrow does not adversely affect engraftment, does not decrease the incidence of severe acute GvHD, and does not seem to affect the day 100 survival or long-term haemopoiesis.

Adolescent↗
PubMed1997

Economic analysis of a randomized clinical trial to compare filgrastim-mobilized peripheral-blood progenitor-cell transplantation and autologous bone marrow transplantation in patients with Hodgkin's and non-Hodgkin's lymphoma.

PURPOSE: High-dose chemotherapy (HDC) with peripheral-blood progenitor cell (PBPC) and autologous bone marrow (ABM) transplant (T) has documented survival benefits for relapsed Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Treatment costs associated with HDC and its supportive care have restricted its use both on and off clinical trial. In a prospective randomized clinical trial, filgrastim-mobilized PBPCT resulted in faster recovery of bone marrow function, with less hospitalization and supportive care than ABMT. This study was undertaken to analyze the costs of the two strategies using prospectively collected data from a randomized clinical trial that compared filgrastim-mobilized PBPCT versus ABMT. PATIENTS AND METHODS: Clinical results and resource utilization from a randomized clinical trial that compared filgrastim-mobilized PBPCT versus ABMT following carmustine, etoposide, cytarabine, and melphalan (BEAM) HDC for HD and NHL are presented. The trial was performed in six centers in Germany, the United Kingdom, and Belgium. Resource utilization data were used to project costs and Massay Cancer Center (MCC) in the United States incurred the cost of treating the cohort. Costs were projected to the United States, because the economic implications to United States centers are significant, costs of care vary markedly among countries but resource utilization on this trial did not, and a randomized trial is unlikely to be performed in the United States. RESULTS: Fifty-eight patients with relapsed HD or NHL underwent HDC with BEAM. The PBPCT and ABMT groups had similar short-term survival after BEAM. PBPCT patients had a shorter hospitalization (median, 17 v 23 days; P = .002), neutrophil recovery (11 v 14 days; P = .005), platelet recovery to > or = 20 x 10(9)/L (16 v 23 days; P = .02), and days of platelet transfusions (6 v 10; P < .001). Estimated costs were $8,531 for ABM harvest and $5,760 for PBPC collection, including filgrastim mobilization. The total estimated average cost was $59,314 for each ABMT patient versus $45,792 for each PBPCT patient. Cost savings of $13,521 (23%) were due to shorter hospitalizations with less supportive care. CONCLUSION: PBPCT is as safe and more effective than ABMT for HD and NHL in the short term. PBPCT represents a significant cost savings due to lower autograft collection costs, shorter hospital stays, and less supportive care. The savings exceed the costs for filgrastim mobilization and PBPC collection. Actual savings will vary depending on local practice patterns, charges, and costs.

Adolescent↗
PubMed1997

Allogeneic transplantation with CD34+-selected cells.

We report the outcome of eight patients with different hematological malignancies who were transplanted with allogeneic CD34-selected mononuclear cells following myeloablative therapy. Four patients received G-CSF mobilized CD34-enriched peripheral blood progenitor cells (PBPC) together with CD34-enriched bone marrow (BM), two patients were transplanted with allogeneic G-CSF mobilized CD34-enriched PBPC alone, and two patients received only allogeneic CD34-enriched BM cells. On average, patients received 2.66 x 10(6) CD34+-cells/kg BW (range: 0.53-8.40 x 10(6) CD34+-cells/kg body weight) and 0.57 x 10(6) CD3+-cells/kg BW (range: 0.20-1.10 x 10(6) CD3+-cells/kg BW), respectively. Seven of the eight patients engrafted (ANC > 0.5 x 10(9)/L median: day +19 (range: 16-23 days); platelets > 20 x 10(9)/L median: day +34 (range: 21-47 days); one patient died on day +16 after transplantation and was not evaluable for engraftment. Three of seven patients evaluable for acute graft-versus-host disease (GvHD) developed acute GvHD grade II which resolved upon steroid treatment. Five of the eight patients are still alive and in remission with a median follow-up of 215 days (range: 80-420 days). Causes of death included fungal infection, cerebral bleeding and sepsis. These preliminary data suggest that CD34-enriched cells can be successfully given during for allogenic transplantation following myeloablative therapy in hematological malignancies. The impact of T-cell depletion by enrichment for CD34+-cells in an attempt to reducing the incidence and/or severity of acute and/or chronic GvHD still remains to be determined.

Adult↗
PubMed1996

High-dose multidrug resistance in primary human hematopoietic progenitor cells transduced with optimized retroviral vectors.

Retroviral transfer of the multidrug-resistance 1 (mdr1) cDNA into primary human hematopoietic progenitor cells (HPC) of cancer patients undergoing high-dose chemotherapy has been proposed to protect the bone marrow from the dose-limiting cytotoxicity of cytostatic agents. Preclinical studies performed with vectors derived from the Moloney murine leukemia virus (MoMuLV) or the related Harvey murine sarcoma virus have established that chemoprotection of HPC is feasible. The efficacy of vector-mediated multidrug-resistance under high doses of cytostatic agents, however, remained unclear. We report here that this goal can only be achieved with improved vector design. Novel vectors termed SF-MDR and MP-MDR, which are based on the spleen focus-forming virus or the myeloproliferative sarcoma virus for the enhancer and the murine embryonic stem cell virus for the leader, significantly elevate survival of transduced primary human HPC under moderate doses of colchicine and paclitaxel in vitro when compared with a conventional MoMuLV-based vector. Importantly, SF-MDR and also MP-MDR confer an absolute advantage at high doses of paclitaxel in vitro corresponding to peak plasma levels achieved in patients during chemotherapy. This observation has important consequences for a variety of ongoing and planned gene therapy trials.

Animals↗
PubMed1996

Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients.

BACKGROUND: A randomised trial comparing filgrastim-mobilised peripheral blood progenitor cell (PBPC) transplants with autologous bone marrow transplantation (ABMT) for haematopoietic stem cell support has not been done. We compared the effects of filgrastim-mobilised PBPC or autologous bone marrow reinfused to lymphoma patients after high-dose chemotherapy in a prospective randomised multicentre trial. METHODS: The trial was done at six centres in three European countries. After high-dose chemotherapy (carmustine, etoposide, cytarabine, and melphalan [BEAM protocol]) 58 patients with advanced Hodgkin's disease or high-grade non-Hodgkin lymphoma received either filgrastim-mobilised PBPC (n = 27) or bone marrow (n = 31) for haemopoietic reconstitution. FINDINGS: The median number of days with platelet transfusions after grafting was 6 in the PBPC transplantation group and 10 in the ABMT group (estimate of treatment difference 5 days, 95% CI 3-7 days). Time to platelet recovery above 20 x 10(9)/L was 16 days in the PBPC transplantation group and 23 days in the ABMT group (p = 0.02). Time to neutrophil recovery above 0.5 x 10(9)/L was also reduced in the PBPC transplantation group (11 vs 14 days, p = 0.005). Patients randomised to PBPC transplantation needed fewer red blood cell transfusions (two vs three, p = 0.002) and spent less time in hospital (17 vs 23 days, p = 0.002). Early post-transplant morbidity and mortality as well as overall survival (median follow-up 311 days) were similar in both groups. There was no notable toxicity ascribed to filgrastim administration or the leucapheresis procedures. INTERPRETATION: In patients with lymphoma treated with high-dose chemotherapy, reinfusing filgrastim-mobilised PBPC instead of autologous bone marrow significantly reduced the number of platelet transfusions, the time to platelet and neutrophil recovery, and led to earlier discharge from hospital.

Adult↗
PubMed1996

Geoanalysis using plasma spectrochemistry - milestones and future prospects.

Highlights of plasma spectrochemistry in geoanalysis are reviewed. The techniques are evaluated in terms of recent instrumental developments, calibration strategies, spectral and matrix interferences and analytical performance. While acid decomposition results in solutions containing low salt contents, this decomposition strategy is inappropriate for numerous sample types due to poor recoveries. On the other hand, alkali fusions result in total decomposition, but solutions containing high salt contents constrain the accuracy due to interference effects in the inductively coupled plasma (ICP), the sample introduction system, and in the quadrupole mass spectrometer interface. Therefore, practical limits of determination are evaluated in terms of salt tolerances. It is concluded that ICP-atomic emission spectrometry (AES) is employed mainly for the accurate determination of the major and minor elements and the more abundant trace elements. On the other hand, ICP-mass spectrometry (MS) is used mainly for the determination of trace elements and together with the possibility of obtaining some isotopic information, it profoundly enhances the capability for solving geochemical problems. Several methods of direct solid sample introduction are described. These include direct current (DC) arc emission spectroscopy (DC-AES), slurry nebulization (SN), spark ablation (SA), laser ablation (LA) and glow discharges (GD). These devices allow direct solid analysis of bulk samples, single minerals and inclusions.

Journal Article↗
PubMed1996

Philadelphia chromosome-positive secondary acute myeloid leukemia following high-dose chemotherapy with peripheral blood progenitor cell support for relapsed low-grade non-Hodgkin's lymphoma.

We report the case of a 47-year-old patient who developed acute myelogenous leukemia (AML) 18 months after receiving high-dose chemotherapy with peripheral blood progenitor cell support (PBPCT) for relapsed low-grade follicular non-Hodgkin's lymphoma (NHL). Cytogenetic analysis of the leukemic cells showed the translocation (9;22)(q34;q11). In three mitoses, an additional Philadelphia chromosome (Ph1) was present. In the literature, Philadelphia chromosome-positive secondary AML has been described only once before in a patient with multiple myeloma.

Acute Disease↗
PubMed1996

The pharmacokinetics and toxicity of two application schedules with high-dose VP-16 in patients receiving an allogeneic bone marrow transplantation.

BACKGROUND: Etoposide is one of the few drugs being used in conditioning regimens because of the ease with which its dosage can be escalated by a factor of 6 compared to the normal dose. The best schedule in high-dose chemotherapy is not known. PATIENTS AND METHODS: We evaluated the pharmacokinetics (PK) of high-dose VP-16 during two different schedules (6-hour and 3 x 1-hour infusions) and the toxicity of the two application modes in patients with leukemia who underwent allogeneic bone marrow transplantation. RESULTS: A significant difference (p = 0.008) in the volume of distribution at steady state was observed. The mean Vss was 0.21 L/kg in the 6-hour group and 0.36 in the 3 x 1-hour group. The total drug exposure time with plasma levels > 100 ng/ml is significantly longer in the 'split' group (74 vs. 143 h). Other PK parameters such as plasma clearance and area under the curve were not significantly different. Leukocyte recovery to WBC levels > 0.2 and > 0.5/nl as well as platelet recovery to stable counts > 50/nl was significantly (p = 0.002, 0.009 and 0.04) prolonged in the 'split' group (3.7 vs. 12.3, 8.3 vs. 14.3 and 25 vs. 35 d). The liver toxicity as indicated by bilirubin peak levels was significantly (p = 0.02) more severe in the 'split' group (1.7 vs. 5.4 mg/dl). CONCLUSION: The area under the curve as a measure of total drug exposure cannot be correlated to the observed higher toxicity in the patient group with the 'split' application mode. The drug exposure time as well as the three high peak plasma levels may be more important.

Antineoplastic Agents, Phytogenic↗