G-CSF dosage and scheduling following autologous PBSC transplantation.
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Drug Administration Schedule↗
Biomedical subjects
N H Russell
Publications and source records attributed to N H Russell.
Blast maturity and CD34 expression determine the effects of the differentiating agents KH1060 and 9-cis-retinoic acid on the differentiation and clonogenicity of non-M3 acute myeloid leukaemia cells.
The vitamin D analogue KH1060 and the retinoids all-trans retinoic acid (ATRA), 9-cis-retinoic acid (9-cRA) and 4-hydroxyphenyl retinamide (4-HPR) induce differentiation and/or apoptosis and inhibit clonal growth of acute promyelocytic leukaemia cells. We have studied the effects of these agents in vitro on cells from 12 patients with other forms of acute myeloblastic leukaemia (AML). Treatment with KH1060 (10(-6) M) caused decreases in cell viability in suspension culture to a median of 44% of control values (P=0.02). However, retinoids had little effect. Subsequent clonal growth in semi-solid medium was inhibited to 5% (median) of control with 10(-6) M KH 1060 (P=0.03) and to 73% with 10(-6) M 9-cRA (P=0.01). Further inhibition of clonal growth by the combination of 5 x 10(-7) M 9-cRA and 5 x 10(-7) M KH1060 was only noted in one case. Following the primary suspension culture, cells from 6/6 CD34 positive samples grew in semi-solid cultures without analogues, whereas cells from 3/6 CD34 negative cultures grew. 10(-6) M KH1060 completely abolished colony growth in all three CD34 negative samples and 10(-6) M 9-cRA inhibited the number of colonies to a median of 11% of control values. In the six CD34 positive samples median colony growth was inhibited to 36% of control values by KH1060 and to 83% of control values by 9-cRA. CD11b expression was increased by 210% (median) with 9-cRA and by 90% (median) with KH1060 in early to intermediate myeloblast (M0, M1, M2) clones. A different pattern was noted in more mature (M4, M5, M6) clones: here there was little or no increase in CD11b expression induced by retinoids or KH1060, but the ratio of apoptotic to viable CD11b+ cells, measured by CD11b/7-AAD double staining, was increased in 6/6 cases treated with KH1060 or the combination of 9-cRA and KH 1060, and in 5/6 cases treated with 9-cRA. No overall significant change in bcl-2 or bax expression on G0/G1 cells was found after 3 days' suspension culture with the analogues. However bcl-x was downregulated in G0/G1 cells treated with KH1060 (median bcl-x relative fluorescence intensity = 45.3 in cells treated with KH1060, compared with 65.7 in control wells, P=0.028). We conclude that CD34+ samples are relatively resistant to the growth inhibition induced by KH1060 and 9-cRA. However, downregulation of bcl-x in cells which have survived treatment with KH1060 may increase the susceptibility of the remaining leukaemic cells to cytotoxic drugs.
Alitretinoin↗
Allogeneic bone marrow transplantation for systemic AL amyloidosis.
Low-intensity chemotherapy is ineffective in most patients with AL amyloidosis, probably because clinical benefit requires regression of the amyloid deposits, and this occurs only very gradually after the underlying plasma cell dyscrasia has been suppressed. We report the first successful allogeneic bone marrow transplant (allo-BMT) for AL amyloidosis, which after 3 years was associated with complete clinical recovery. This supports the idea that there may be a brief window of opportunity in patients with AL amyloidosis during which dose-intensive chemotherapy is feasible and most likely to produce clinical benefit.
Amyloidosis↗
Functional multidrug resistance in acute myeloblastic leukaemia: a standardized flow cytometric assay for intracellular daunorubicin accumulation.
We have developed a standardized flow cytometric method for the measurement of in vitro multidrug resistance in acute myeloblastic leukaemia (AML) blasts, using carboxylate microspheres which bind the fluorescent drug daunorubicin. Cells and beads were incubated concurrently with the drug. Fluorescence was expressed as a cell:bead ratio. Bead fluorescence at a fixed cytometer voltage was consistent over at least a 3-month period (CV 5.47%), and repeat assays up to 8 months later correlated well (R = 0.86). Bead to drug binding provides a valuable measure of quality assurance as well as a standard for cellular drug accumulation assays and would therefore be suitable for reproducibly reporting the results of multidrug resistance analysis in a clinical setting.
Antibiotics, Antineoplastic↗
Dendritic cells cultured from mononuclear cells and CD34 cells in myeloma do not harbour human herpesvirus 8.
Dendritic cells (DC) are antigen-presenting cells with the potential to be a powerful adjuvant in the immunotherapy of haematological malignancy, including myeloma. Recently, human herpesvirus 8 (HHV-8) infection of dendritic cells in the long-term bone marrow stromal cultures of patients with myeloma has been reported. This finding is of great potential importance regarding oncogenesis in myeloma in addition to having significant implications for the use of DC in the immunotherapy of this disease. Therefore DC generated from mobilized blood mononuclear cells (MO-DC) and purified CD34+ cells (CD34-DC) of myeloma patients were examined for the presence of HHV-8 using a sensitive PCR technique. HHV-8 was not demonstrated in MO-DC or CD34-DC and we conclude that these cells remain a suitable vehicle for investigation in the immunotherapy of myeloma.
Antigens, CD34↗
Developments in allogeneic peripheral blood progenitor cell transplantation.
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Antigens, CD34↗
A novel BCR-ABL fusion gene (e2/1a) in a patient with Philadelphia-positive chronic myelogenous leukaemia and an aggressive clinical course.
A novel variant BCR-ABL mRNA transcript was detected by reverse transcription polymerase chain reaction (RT-PCR) in a patient with Philadelphia positive (Ph+ve) chronic myelogenous leukaemia (CML) who had an aggressive clinical course. Sequence analysis of the amplified cDNA fragment revealed an in-frame fusion with part of BCR exon e2 joined to part of ABL exon 1a. PCR of genomic DNA from this patient demonstrated that this unusual chimaeric mRNA resulted from breakpoints that fell within each of these exons. This is the first report of breakpoints occurring within both ABL and BCR exons and the first fusion to involve ABL exon 1a.
Base Sequence↗
A comparison of two different systems for CD34+ selection of autologous or allogeneic PBSC collections.
This study compared CD34 selection procedures using the CellPro CEPRATE and the Baxter Isolex 300 systems. Thirty-two procedures were performed, 19 CEPRATE and 13 Isolex. Median starting CD34 percentages were (CEPRATE/Isolex) 0.80% (range 0.24%-7.73%) and 0.85% (range 0.27%-10.17%), respectively (p = 0.788). After selection, there was a highly significant difference in purity of the product (CEPRATE/Isolex), 54% and 82% respectively (p < 0.0001). There was no significant difference in median recovery (CEPRATE/Isolex), 43% and 50%, respectively (p = 0.383). The starting CD34 percentage influenced the purity of the final product, and at high and low starting percentages, the Isolex produced superior purity. Improved efficacy of T cell depletion was observed with the Isolex, a median log depletion of 3.4 compared with 2.9 for the CEPRATE system (p = 0.012). In conclusion, the Isolex 300i produced a significantly higher purity CD34+ fraction, even at starting CD34+ levels of <0.5%, with no significant difference in recovery when compared with the CEPRATE system. The associated log T cell depletion is significantly improved with the Isolex system, with possible implications for use in CD34-selected allogeneic transplants.
Hematologic Neoplasms↗
Peripheral blood stem cell transplants.
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Bone Marrow Transplantation↗
Allogeneic bone marrow transplant for multiple myeloma.
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Adult↗
Biology of acute leukaemia.
The leukaemias vary in their response to therapy. In acute myeloid leukaemia, for instance, response to therapy is poorer in older than in younger patients. One explanation for this is that in older patients the acute myeloid leukaemia is more likely to have arisen from a pluripotent stem cell than from a lineage-restricted progenitor cell; the former has a high self-renewal capacity, an active drug-efflux pump, and high content of anti-apoptotic proteins, all of which contribute to chemoresistance. Unravelling the biology of the leukaemias should help in the development of novel therapies.
Cell Lineage↗
Use of haemopoietic growth factors: commentary on the ASCO/ECOG guidelines. American Society of Clinical Oncology/Eastern Co-operative Oncology Group.
In the past two to three years, a number of clinical guidelines have been issued that have attempted to recommend specific indications for the use of haemopoietic colony-stimulating factors. Some of which have recently been updated. These guidelines are, for the most part, a welcome initiative to guide clinicians as to the most appropriate use of these powerful and expensive drugs. Here, we have attempted to offer a perspective on these guidelines based upon both a review of the literature and our own clinical experience, concentrating primarily on their use following conventional and high-dose therapy and for the purpose of peripheral blood stem cell mobilization. For the latter, it is worth remembering that a product licence for this indication was only obtained in Europe in 1995 and that this only covers autologous mobilization and not the mobilization of normal donors. Both the American Society of Clinical Oncology and the Eastern Co-operative Oncology Group guidelines rightly confine their comments to best practice. However, certainly in the United Kingdom and probably elsewhere, it is impossible to divorce this entirely from the economic realities involved in the widespread use of colony-stimulating factors, hence the increasing number of research papers in which the authors emphasize not only the clinical but also the financial implications of their findings. Here, we have taken note of both clinical and economic considerations in framing our comments.
Hematopoietic Cell Growth Factors↗
Allogeneic peripheral blood stem cell transplantation for haematological malignancies--an analysis of kinetics of engraftment and GVHD risk.
We have carried out an analysis of 44 patients undergoing allogeneic PBSC transplants from fully HLA-matched related donors with particular emphasis on engraftment kinetics and the incidence and severity of GVHD. The recipients had a median age of 37 years (range 5-56 years), 16 patients had standard-risk disease and 28 had poor-risk disease. GVHD prophylaxis was with cyclosporin A and methotrexate (n = 41), cyclosporin A alone (n = 2) or cyclosporin A and methyl-prednisolone (n = 1). Stem cells were mobilised using G-CSF, collecting a median of 5.75 x 10(6) CD34+ cells/kg recipient weight (range 0.94-35 x 10(6) CD34+ cells/kg). Engraftment times to a neutrophil count > 0.5 x 10(9)/1 and platelets > 20 x 10(9)/1 were achieved at a median of day +14 (range 10-25) and day +14 (range 9-130) respectively. Patients receiving > or = 4 x 10(6) CD34+ cells/kg had significantly accelerated neutrophil and platelet engraftment and this number of CD34+ cells would appear to be a prerequisite for maximum engraftment using PBSC. Acute GVHD occurred in 25 of 43 evaluable patients although in only 12 was this clinically significant (grades II-IV). Chronic GVHD has occurred in 17 out of 36 evaluable patients, there was no significant difference between the standard- and poor-risk groups in incidence of either acute or chronic GVHD. In conclusion, these results confirm the feasibility of using PBSC for allogeneic transplantation without evidence for increased risk of either acute or chronic GVHD and provide further evidence supporting the potential of PBSC to replace bone marrow as the major source of haemopoietic cells for allogeneic transplantation.
Adolescent↗
Autologous GVHD following PBSCT, with evidence for a graft-versus-myeloma effect.
The development of GVHD following allogeneic BMT is known to be closely associated with significant antileukaemic activity. Immunological graft-versus-leukaemia (GVL) effects are now well established and are commonly exploited in the treatment of leukaemic relapse following allogeneic transplantation by the use of donor lymphocyte infusions. More recently a graft-versus-myeloma (GVM) effect following allogeneic transplantation has been documented, suggesting that eradication of haematological malignancies following allogeneic transplantation is achieved at least in part by immunological mechanisms. It is now also established that spontaneous GVHD can occur following autologous transplantation and can be induced by cyclosporin A administration. However, there is only limited evidence that the development of autologous GVHD has an antitumour effect. We report for the first time the development of autologous GVHD following PBSC transplantation for myeloma apparently resulting in a GVM effect.
Antigens, CD34↗
Bcl-x(L) is heterogenously expressed by acute myeloblastic leukaemia cells and is associated with autonomous growth in vitro and with P-glycoprotein expression.
The cells from approximately 70% patients with acute myeloblastic leukaemia exhibit autonomous growth characteristics in vitro, which have been associated with a poor response to therapy. We have previously shown that leukaemic cells with autonomous growth characteristics express high levels of bcl-2 and are relatively resistant to apoptosis. As bcl-x(L) is a bcl-2-related gene with anti-apoptotic activity which also confers resistance to cytotoxic drugs we have studied its expression in AML in relation to cellular growth characteristics and to the expression of P-glycoprotein. Cells from 15 patients were studied. Immunoblotting demonstrated bands at 31 kDa corresponding to bcl-x(L) from the cells of all patients. Bcl-x(S) was not detected in any sample. Using standardised, quantitative flow cytometry, bcl-x(L) expression ranged from 0.25 x 10(5) to 4.24 x 10(5) bound FITC molecules, (median 1.35 x 10[5]). AML blasts with autonomous growth in vitro expressed more bcl-x(L) (median 1.76 x 10[5]) than those which did not (median 0.86 x 10(5), P=0.01). Quantitative bcl-x(L) expression strongly correlated with that of P-glycoprotein, also measured by quantitative flow cytometry using the MRK16 antibody (r=0.95, P < 0.001), but not with MRPr1. These results provide a further explanation for the poor prognosis associated with autonomous in vitro growth of AML blasts and illustrate that these cells may coexpress different modalities of resistance to cytotoxic drug therapy involving both anti-apoptotic pathways (bcl-x(L), bcl-2) and classic multidrug resistance (MDR1). The implication of these findings is that the use of agents to reverse MDR1 function in AML may be unsuccessful in the absence of strategies to reduce resistance to apoptosis.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide.
We analysed the factors influencing the efficacy of peripheral blood stem cell (PBSC) collection in patients with lymphoma. Sixty-six patients underwent initial PBSC collection following mobilization with chemotherapy plus recombinant granulocyte colony-stimulating factor (300 microg/d). Patients were mobilized with one of two chemotherapy regimens, either cyclophophamide (3 g/m2 or 4 g/m2) (n = 50) or ifosphamide, etoposide and epirubicin (IVE; n = 16). The target of collecting > 2.0 x 10(6) CD34+ cells/kg was achieved in 43/66 (65%) patients with a median of two apheresis procedures. The IVE plus G-CSF mobilization regimen gave a significantly higher median yield of CD34+ cells (8.62 x 10(6)/kg) compared with cyclophosphamide plus G-CSF (3.59 x 10(6)/kg) (P = 0.045). The median yield of CD34+ cells per leukapheresis was almost twice as high in patients receiving IVE (1.94 x 10(6)/kg) compared to cyclophosphamide (1.03 x 10(6)/kg) (P = 0.035). In a univariate analysis of the factors affecting mobilization, the subtype of lymphoma (high-grade NHL) and the mobilization regimen were the only factors associated with high CD34+ cell yield. However, in a multivariate analysis of factors affecting mobilization including age, lymphoma subtype, previous chemotherapy and radiotherapy, only the use of the IVE protocol was predictive of a high yield of CD34+ cells. In 13 patients undergoing a second mobilization procedure the use of IVE was associated with a significantly higher yield of CD34+ cells compared to cyclophosphamide; three patients who failed cyclophosphamide plus G-CSF mobilization were able to proceed to transplantation following successful mobilization with IVE + G-CSF. These results demonstrate that IVE is a highly effective mobilization regimen which is superior to cyclophophamide and has the benefit of being effective salvage therapy for lymphoma patients.
Adult↗
Low-dose filgrastim significantly enhances neutrophil recovery following autologous peripheral-blood stem-cell transplantation in patients with lymphoproliferative disorders: evidence for clinical and economic benefit.
PURPOSE: To assess the clinical and economic benefit of low-dose (50 microg/m2) filgrastim after peripheral blood stem-cell transplantation (PBSCT) in a randomized, placebo-controlled double-blinded study. PATIENTS AND METHODS: Thirty-eight patients with lymphoproliferative disorders were randomized to receive low-dose filgrastim (19 patients) or placebo (19 patients) beginning on the first day after stem-cell reinfusion and continuing until absolute neutrophil count (ANC) was greater than 0.5 x 10(9)/L. All patients received greater than 2.5 x 10(6) CD34+ cells/kg, which was mobilized with chemotherapy and filgrastim 300 microg from the fifth day. An economic analysis was performed based on the outcome in the two groups. RESULTS: Neutrophil engraftment was significantly more rapid in patients who received filgrastim with a median number of days until ANC was greater that 0.5 x 10(9)/L of 10 (9 to 13) versus 14 (9 to 19; P < .0001). The time to reach an ANC greater than 1 x 109/L was 12 (9 to 14) versus 16 days (10 to 25; P < .0001). The total number of patients who required intravenous antibiotic therapy was lower in the filgrastim-treated group (68%) compared with the placebo group (89%); also, the median number of days with fever and the duration of antibiotic therapy were shorter, although these differences did not reach statistical significance. However, although only three of 19 (16%) patients who received filgrastim required amphotericin, 11 of 19 (58%) who received placebo did require it, and amphotericin usage was significantly less in the filgrastim group (P = .029). Finally, in-patient stay was significantly shortened in those who received filgrastim from 16 (13 to 23) to 13 days (11 to 18; P = .0003). CONCLUSION: Low-dose filgrastim significantly reduces neutrophil engraftment time post-PBSCT and also reduces in-patient stay and costs, which makes it economically viable for patients who are undergoing high-dose chemotherapy.
Adult↗
Engraftment and molecular monitoring of CD34+ peripheral-blood stem-cell transplants for follicular lymphoma: a pilot study.
PURPOSE: A pilot study to validate the use of CD34+ selection (Ceprate SC) of blood stem-cell collection in patients with advanced follicular lymphoma receiving myeloablative chemoradiotherapy. PATIENTS AND METHODS: Seventeen patients were entered onto the protocol. Thirteen of 17 patients have undergone transplantation; the median age is 42.5 years (range, 33 to 51), seven of 13 are stage IVB, two stage IVA, three stage IIIB, and one stage IIB. All except two patients were treated after first or subsequent relapses after receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to achieve a good partial (six of 13) or complete (seven of 13) response before stem-cell mobilization with cyclophosphamide 3 g/m2 and filgrastim 300 microg once daily. RESULTS: Eleven of 13 patients had a detectable t(14;18) by nested polymerase chain reaction (PCR). Median CD34+ count before selection was 2.9 x 10(6)/kg (range, 1.17 to 11.3) and after CD34+ selection was 1.54 x 10(6)/kg (range, 0.88 to 7.6) with a median CD34+ yield of 62.4% (range, 17% to 95%) and purity of 60% (range, 39.3% to 73%). Of the 11 patients known to have t(14;18), 10 had PCR-detectable contamination of stem-cell harvests that became PCR negative in six of the 10 after CD34+ selection. Engraftment was rapid with a median day to absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L of 13 days (range, 11 to 21) and platelet count greater than 20 x 10(9)/L of 14 days (range, 10 to 44). With a median follow-up duration of 15 months, three patients have remained persistently PCR-positive, two of whom received PCR-positive stem cells. Two have relapsed. Of the seven patients who received PCR-negative stem cells, five have had no PCR-detectable disease in posttransplant bone marrow samples. CONCLUSION: Longer follow-up duration is required to determine the significance of these findings, but we have confirmed the feasibility of CD34+ selected cells to deplete peripheral-blood stem cells of tumor cells from patients undergoing high-dose therapy for follicular lymphoma.
Adult↗