Autologous stem cell transplantation: exogenous granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor modulate the endogenous cytokine levels.
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Adult↗
Biomedical subjects
G Menichella
Publications and source records attributed to G Menichella.
Evaluation of a new protocol for peripheral blood stem cell collection with the Fresenius AS 104 cell separator.
In this report we analyzed sixty leukapheresis procedures on 35 patients with a new protocol for the Fresenius AS 104. Yields and efficiencies for MNC, CD 34+ cells, and CFU-GM indicate that the new protocol is able to collect large quantities of hemopoietic progenitors. Procedures were performed processing 8.69 +/- 2.8 liters of whole blood per apheresis and modifying 3 parameters: spillover-volume 7 ml, buffy-coat volume 11.5 ml, centrifuge speed 1,500 rpm; blood flow rate was 50 ml/min and the anticoagulant ratio was 1:12. No side effects were observed during apheresis procedures except for transient paresthesia episodes promptly resolved with the administration of calcium gluconate. Yields show a high capacity of the new program to collect on average MNC 17.28 +/- 10.85 x 10(9), CD 34+ 471 +/- 553.5 x 10(6) and CFU-GM 1278.7 +/- 1346.3 x 10(4) per procedure. Separator collection efficiency on average was 49.91 +/- 23.28% for MNC, 55.1 +/- 35.66% for CFU-GM, and 62.97 +/- 23.09% for CD 34+ cells. Particularly interesting are results for MNC yields and CD 34+ efficiency; these results make the new program advantageous or similar to the most progressive blood cell separators and capable to collect a sufficient number of progenitor cells for a graft with a mean of 1.80 +/- 0.98 procedures per patient.
Adolescent↗
High-dose carboplatin, etoposide and melphalan (CEM) with peripheral blood progenitor cell support as late intensification for high-risk cancer: non-haematological, haematological toxicities and role of growth factor administration.
The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.
Adult↗
Generation of multinuclear tartrate-resistant acid phosphatase positive osteoclasts in liquid culture of purified human peripheral blood CD34+ progenitors.
Circulating CD34+ cells were isolated from leukapheresis products collected from patients with ovarian cancer. CD34 contaminating cells, identified immediately after immunoselection, ranged from 5% to 25% in five different experiments and were predominantly CD3+ T-lymphocytes (range 2-12%), CD3+/CD16+/CD56+ natural killer cells (range 2-11%) and rare mature CD15+/ CD11b+ granulocytes (range 1-2%). CD34+ cells were cultured in liquid medium in the presence of interleukin-3, granulocyte-macrophage colony stimulating factor. stem cell factor, granulocyte colony stimulating factor and a powerful proliferation with prevalent differentiation along the granulocytic/monocytic lineage was obtained. After 10 d of culture a small but consistent number of early multinucleated osteoclasts were identified with a frequency of one cell per 700 granulocytic/monocytic cells, as revealed by cytologic examination. This observation was confirmed by staining for tartrate-resistant acid phosphatase activity which revealed red multinucleated elements with a frequency comparable to that reported above. Conversely, no osteoclasts were observed in those cultures in which macrophage overgrowth was obtained by culturing CD34+ cells until day 35. These observations suggest that circulating progenitors have a multilineage potential in vitro and contribute to the clarification of osteoclast development in humans: additionally, they provide the basis for the future development of optimized osteoclast culture techniques in liquid medium and the basic culture system, to test the distinct activity of 1,25(OH)2D3. parathyroid hormone interleukin-11 and of other cytokines on osteoclast development in humans.
Acid Phosphatase↗
Purified unfractionated G-CSF/chemotherapy mobilized CD34+ peripheral blood progenitors and not bone marrow CD34+ progenitors undergo selective erythroid differentiation in liquid culture in the presence of erythropoietin and stem cell factor.
A combination of erythropoietin (EPO) plus stem cell factor (SCF) drove purified unfractionated granulocyte colony stimulating factor (G-CSF)/chemotherapy mobilized peripheral blood CD34+ cells to selective erythroid differentiation in liquid culture with an average 28-fold increase in the total cell number after 21 d. From day 6 of culture cytologic and cytofluorimetric characterization revealed that cultured cells belonged to the erythroid lineage with a gradual wave of maturation along the erythroid pathway to terminal cells. A similar pattern of erythroid differentiation was observed when the same peripheral blood CD34+ cells were culture with EPO plus SCF in serum-free medium. This cytokine combination produced selective erythroid differentiation with the complete exhaustion of the clonogenic potential on day 21. In parallel experiments the same circulating CD34+ cells underwent granulocytic/ monocytic differentiation in liquid culture in response to granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and SCF, demonstrating that these CD34+ progenitors had intact pluripotent differentiating potential. Conversely, bone marrow CD34+ cells isolated from bone marrow allografts were unable to selectively differentiate along the erythroid pathway when they were exposed to EPO plus SCF combination. However, these cells maintained a greater number of colony forming cells on day 21 of culture compared to mobilized peripheral blood CD34+ cells. This model is a simple and reliable way to obtain selective erythroid differentiation of peripheral blood G-CSF/ chemotherapy mobilized CD34+ progenitor cells in liquid culture. The absence of cytokines such as GM-CSF and IL-3 in the culture medium permits studies on in vitro erythropoiesis without disturbance of prevalent myelopoiesis.
Antigens, CD34↗
Autologous stem cell transplantation: evaluation of erythropoietic reconstitution by highly fluorescent reticulocyte counts, erythropoietin, soluble transferrin receptors, ferritin, TIBC and iron dosages.
The plasma concentrations of erythropoietin (Ep), soluble transferrin receptors (sTfRs), iron, total iron binding capacity (TIBC) and ferritin were monitored in five leukaemia patients undergoing autologous bone marrow stem cell transplantation (BMSCT) and in 10 lymphoma and 21 ovarian cancer patients undergoing autologous peripheral blood SCT (PBSCT); 9/21 ovarian cancer patients received recombinant human G-CSF and Ep and six recombinant human GM-CSF and Ep following SCT. All parameters were evaluated in relation to the kinetics of erythroid reconstitution as evaluated by haemoglobin (Hb) and reticulocyte levels [including the fraction of immature reticulocytes, also called highly fluorescent reticulocytes (HFR)]. Leukaemia patients undergoing BMSCT showed only a delayed (occurring at days 35-50 after SCT) and partial RBC, neutrophil and platelet recovery, whereas all patients undergoing PBSCT exhibited a rapid (occurring at days 10-15 after SCT) and sustained haemopoietic recovery. The various levels of erythroid rescue observed among these patients markedly influenced the kinetics of the different parameters investigated: (i) in leukaemia BMSCT patients sTfRs declined following SCT and remained at low levels thereafter, whereas Ep, iron. TIBC and ferritin showed a progressive and significant increase; (ii) in the different groups of patients undergoing PBSCT: (a) sTfR levels first declined following SCT and then returned to pre-therapy values at days 12-16, this response preceded erythropoietic recovery; (b) Ep, total iron, TIBC and ferritin showed an initial increase in the first days following SCT and then returned to pre-therapy values. Altogether, these observations indicate that: (i) both sTfR levels and reticulocyte counts are predictive parameters of erythropoietic recovery; (ii) coordinated changes of biochemical parameters underlying iron metabolism (iron, TIBC and ferritin) accompany erythroid rescue following SCT.
Adolescent↗
Evaluation of two different protocols for peripheral blood stem cell collection with the Fresenius AS 104 blood cell separator.
OBJECTIVES: Reconstitution of hematopoiesis by means of peripheral blood stem cells is a valid alternative to autologous bone marrow transplantation. The aim of this investigation was to increase the efficiency of collection of circulating blood progenitor cells and to obtain a purer product for transplant. METHODS: We carried out leukapheresis procedures with the Fresenius AS 104 blood cell separator, using two different protocols, the previously used PBSC-LYM and a new mononuclear cell collection program. RESULTS: Both programs were highly effective in collecting mononuclear cells (MNC) and CD34+ cells. Some differences were found, especially regarding MNC yield and efficiencies. There are remarkable differences in the efficiency of collection of CD34+ cells (62.38% with the new program as opposed to 31.69% with the older one). Linear regression analysis showed a negative correlation between blood volume processed and MNC efficiency only for the PBSC-LYM program. Differences were also observed in the degree of inverse correlation existing in both programs between patients' white blood cell precount and MNC collection efficiency. The inverse correlation was stronger for the PBSC-LYM program. Seven patients with solid tumors and hematologic malignancies received high dose chemotherapy and were subsequently transplanted with peripheral blood stem cells collected using the new protocol. All patients obtained a complete and stable engraftment with the reinfusion product collected with one or two leukapheresis procedures. CONCLUSIONS: High efficiencies and yields were observed in the new protocol for MNC and CD34+ cells. These were able to effect rapid and complete bone marrow recovery after myeloablative chemotherapy.
Adolescent↗
Growth factor administration following autologous peripheral blood progenitor cell transplantation.
Hematopoietic growth factor (HGF) administration following autologous peripheral blood progenitor cell transplantation (APBPCT) is a current approach for shortening the duration of high-dose chemotherapy-induced transient peripheral pancytopenia. Several published clinical experiences and a retrospective study reported here show that recombinant human granulocyte colony stimulating factor (rhG-CSF) or recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) administration potentiates polymorphonuclear leukocyte (PMN) and white blood cell (WBC) recovery with some clinical benefits mainly related to the reduction of infectious complications during the shortened period of neutropenia. However, this therapeutic strategy does not produce any enhancement of platelet (PLT) recovery or potentiation of red cell production. Conversely, a recent phase I/II study carried out in our institution showed that the combined administration of rhG-CSF and recombinant human erythropoietin (rhEPO) is able to potentiate trilineage hematopoietic recovery with a reduction of PLT transfusions and to considerably simplify the clinical management of patients as compared to patients treated with APBPCT alone. The post-APBPCT administration of rhEPO with rhGM-CSF decreased the number of days with WBC < 1 x 10(9)/L but failed to produce any appreciable effect on PLT recovery. Both combined treatments significantly reduced the patients' hospital stay and allowed the abrogation of systemic antibiotic administration following APBPCT. A further group of patients were treated with the combined administration of rhEPO, rhG-CSF and rhGM-CSF; they did not show a faster hematopoietic recovery than rhG-CSF plus EPO treated patients and a consistent hyperthermia was observed in most patients as a prominent side effect. Future prospective randomized studies will clarify the efficacy of HGF administration following APBPCT. Moreover, further improvements in the hematopoietic support of transplanted patients may be obtained when stem cell factor, flt3/flk2 tyrosine kinase ligands or megakaryocyte growth and development factor will become clinically available.
Erythropoietin↗
Secondary leukemia after autologous peripheral blood progenitor cell transplantation for breast cancer.
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Adult↗
The combination of erythropoietin and granulocyte colony-stimulating factor increases the rate of haemopoietic recovery with clinical benefit after peripheral blood progenitor cell transplantation.
In order to investigate the effects of erythropoietin (EPO) plus granulocyte colony-stimulating factor (G-CSF) administration after peripheral blood progenitor cell transplantation (PBPCT) we performed a phase I/II study in patients with high-risk cancer. 15 consecutive patients were treated wit recombinant human G-CSF (rhG-CSF) at the dose of 5 micrograms/kg subcutaneously (s.c.) every 24 h until day + 12 and with recombinant human EPO (rhEPO) at the dose of 150 IU/kg s.c. every 48 h until day + 11 following PBPCT. Their haemopoietic recovery was compared to that obtained in eight historic and control patients who did not receive any cytokines after PBPCT. No side-effects were observed during EPO plus G-CSF treatment and the treatment was not discontinued in any of the patients before completion of the treatment plan. The administration of EPO plus G-CSF after PBPCT produced a significant increase in the rate of white blood cell (WBC) (P = 0.0005), polymorphonuclear leucocyte (PMN) (P = 0.0005) and platelet (PLT) (P = 0.0105) recovery compared to the control group. The acceleration in haemopoietic recovery observed in the EPO plus G-CSF-treated patients produced a significant reduction of the days with WBC < 1 x 10(9)/l (P = 0.0009), PMN < 0.2 x 10(9)/l (P = 0.0030) and PMN < 0.5 x 10(9)/l (P = 0.0006). EPO plus G-CSF-treated patients required a significantly lower number of single donor PLT transfusions (P = 0.0142) and did not experience neutropenic fever, but historic control patients experienced fever > 38 degrees C for a median period of 4 d (0-12) with a medial period of parenteral antibiotic administration of 7.5 d (0-17). The length of the hospital stay was significantly shorter in the study group than in the historic control group (P = 0.0264). In conclusion, we can confirm that EPO plus G-CSF treatment is feasible and potentiates the haemopoietic recovery after PBPCT, thus simplifying the clinical management of cancer patients who undergo high-dose chemotherapy.
Adult↗
rhG-CSF in healthy donors: mobilization of peripheral hemopoietic progenitors and effect on peripheral blood leukocytes.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16 micrograms/kg/day was given to 9 healthy donors to recruit hemopoietic progenitors (HP) for allogeneic transplantation or donor leukocyte infusion. rhG-CSF was administered s.c. for 5 days. No side effects were encountered except for moderate bone pain and lumbago. Mobilization was effective, reaching a peak median value of 187 x 10(3) CD34+ cells/ml (range 51.2-1127) and 2170 x 10(3) colony-forming units-granulocyte macrophage (CFU-GM)/ml (range 1138-4190). Peak values were obtained at a median of 4 days of rhG-CSF and represented, respectively, a 13-fold and a 37-fold increase from baseline values (p = 0.0007 and p = 0.006). White blood cell (WBC) counts increased 6-fold from baseline values (p < 0.0007) and reached a median peak of 34 x 10(6)/ml (23.5-59). Polymorphonuclear (PMN), and mononuclear (MNC) cells increased 10-fold and 2-fold, respectively (p = 0.0039 and p = 0.0026) and reached a median peak of 32.1 x 10(6)/ml (18.2-52) and 4.42 x 10(6)/ml (3.14-12.42). Absolute lymphocyte and monocyte counts increased at peak day in all donors 1.5-fold and 5.7-fold from baseline values (p = 0.0017 and p = 0.0018). In 7 of 9 donors, lymphocyte subsets were analyzed in detail. CD3+ and CD19+ lymphocytes increased 1.5-fold and 3-fold, respectively (p = 0.032 for both). NK and activated T lymphocytes doubled at a median of 4 days of rhG-CSF (p = 0.032 and p = NS, respectively). Similar changes were observed in lymphocytes collected in leukapheresis product. T helper and T suppressor subsets displayed a similar increase. Thus, besides the anticipated priming effect on HP and PMN, rhG-CSF in healthy donors produced an unexpected and still unexplained modification of lymphocyte subsets in peripheral blood.
Adolescent↗
Endogenous cytokine levels after immunoselected CD34+ peripheral blood progenitor cell transplantation.
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Antigens, CD34↗
The administration of growth factors post-PBPC transplantation abrogates the dose-effect of CFU-GM on the rate of PMN recovery.
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Adult↗
Separation of chemotherapy plus G-CSF-mobilized peripheral blood mononuclear cells by counterflow centrifugal elutriation: in vitro characterization of two different CD34+ cell populations.
Counterflow centrifugal elutriation (CCE) has been extensively employed in T cell depletion of bone marrow cells for allografting. Nevertheless very little is known about CCE properties of mobilized hematopoietic progenitors. In this study five leukapheresis products collected after chemotherapy and G-CSF from patients with non-Hodgkin's lymphoma were elutriated. Two mononuclear cell fractions were obtained containing smaller and less dense cells (lymphocyte fraction) and larger and denser cells (monocyte fraction), respectively. The presence of immature CD34+ progenitor cells, not co-expressing CD33, CD38 and HLA-DR antigens, was demonstrated in both cell fractions. CD34+ cells were isolated from each fraction and grown in various culture conditions (CFU-GM and BFU-E assay, blast cell colony assay, cytokine supplemented liquid culture). CD34+ cells isolated from the monocyte fraction showed a longer lasting expansion in liquid culture and a higher number of blast cell colonies than CD34+ cells selected from the lymphocyte fraction. Moreover a significant reduction of T cell number was obtained in the monocyte fraction. These data suggest that chemotherapy plus G-CSF-mobilized progenitor cells show a characteristic behavior when subjected to CCE, allowing an efficient T cell depletion without losing more immature progenitors.
Adult↗
Very high-dose chemotherapy with autologous peripheral stem cell support in advanced ovarian cancer.
20 patients with stage III-IV ovarian cancer were submitted to induction chemotherapy (ICT) (40 mg/m2 cisplatin, days 1-4; 1.5 g/m2 cyclophosphamide, day 4; every 4 weeks for 2 cycles) followed by intensified CT (100 mg/m2 cisplatin, day 1; 650 mg/m2 etoposide, day 2; 1.8 g/m2 carboplatin by 24 h infusion, day 3). Haematological support consisted of autologous peripheral stem cells (APSC) and bone marrow (ABM) transplant (T) in 16 and 4 patients, respectively. All patients were evaluable for toxicity and 19 for pathological response (PR), one patient dying of systemic mycosis after ABMT. Severe (grade 3-4) non-haematological toxic effects were gastrointestinal (100%), neurological (10%) and hepatic (10%). PR was observed in 84% of patients (complete response 37%, partial response with microscopic residual disease 26%, partial response with macroscopic residual disease 21%). Five year overall survival was 60% and progression-free survival was 51% with 9 patients still disease-free (DFS). APSCT significantly reduced the duration of aplasia compared with ABMT, and toxicity was acceptable in those patients undergoing APSCT. The prolonged DFS in patients showing PCR suggests that this new approach may have a therapeutic impact.
Adenocarcinoma↗
High-dose chemotherapy with autologous peripheral stem cell support in advanced ovarian cancer.
Twenty patients with advanced (stage III-IV), previously untreated ovarian carcinoma were treated by: (a) induction chemotherapy (40 mg/m2 cisplatin, days 1-4; 1.5 g/m2 cyclophosphamide, day 4; every 4 weeks for two cycles) followed by (b) intensification chemotherapy (100 mg/m2 cisplatin, day 1; 650 mg/m2 etoposide, day 2; 1.8 g/m2 carboplatin, day 3). Eligibility criteria further included: age less than 55 years, moderately good to poor tumour grade, macroscopic (> 0.5 cm) residual tumour. Autologous peripheral stem cells were recruited after the induction cycles and, to ensure haematological support, autologous bone marrow harvesting was routinely performed in the first 14 cases. Haematological support consisted of autologous peripheral stem cells and autologous bone marrow transplant in 16 and four patients, respectively. All patients are evaluable for toxicity and 19 for pathological response, one being dead of systemic mycosis 35 days after the autologous bone marrow transplant. Severe extra-haematological toxicities were the following: gastrointestinal (100%), neurological (10%), hepatic (10%). Pathological response was detected in 84% of cases (CR 37%, microscopic PR 26%, macroscopic PR 21%). Median follow-up times of 48 and 41 months have been reached respectively from enrolment and second-look. Four-year 62% overall and 57% progression-free survivals have been reached. Ten patients are still alive with NED (six of seven with CR, three of five with microscopic PR, and one of four with macroscopic PR). Autologous peripheral stem cell transplant significantly reduced the duration of aplasia compared with autologous bone marrow transplant, and toxicity was proved to be manageable in those patients undergoing autologous peripheral stem cell transplant. The prolonged disease-free survival in patients showing CR and microscopic PR suggests that further investigation on this new approach is worthwhile.
Adult↗
Chemotherapy and recombinant human granulocyte colony-stimulating factor primed donor leukocyte infusion for treatment of relapse after allogeneic bone marrow transplantation.
Two patients affected by acute leukemia relapsed 10 and 12 months respectively after allogeneic bone marrow transplantation. They were treated with aggressive chemotherapy and then infused with HLA-identical donor leukocytes (DLI) collected after recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration. A total of 5.6 and 6.3 x 10(6)/kg CD34+ cells, 2.7 and 3.0 x 10(4)/kg CFU-GM, 4.7 and 4.4 x 10(8)/kg MNC, 4.6 and 3.9 x 10(9)/kg PMN respectively were infused. Both patients achieved complete remission (CR) and complete chimerism was re-established. One patient developed grade IV acute graft-versus-host disease of the liver requiring immunosuppression and he died in CR from disseminated aspergillosis, 7 months after chemotherapy; one patient is alive in relapse 12 months after treatment.
Acute Disease↗
Autologous stem cell transplantation: release of early and late acting growth factors relates with hematopoietic ablation and recovery.
We have monitored the serum concentrations of hematopoietic growth factors (HGFs; ie, stem cell factor [SCF], leukemia inhibitory factor [LIF], interleukin-3 [IL-3], IL-6, IL-8, and granulocyte colony-stimulating factor [G-CSF]) in 15 lymphoma/leukemia and 6 ovarian cancer patients undergoing autologous bone marrow (BM) or peripheral blood (PB) stem cell transplantation (SCT). Thus, the analysis was performed during and after high-dose chemotherapy (from day -6 to day -1), at the time of SCT (day 0), and thereafter (through day +17). Despite the heterogeneity of these patients and their conditioning regimens, a consistent kinetic pattern was observed for all analyzed cytokines. Particularly, (1) SCF serum concentration did not significantly fluctuate. (2) High levels of LIF (approximately 250 to 450 pg/mL) before chemotherapy rapidly declined to markedly lower concentrations (approximately 10 ng/mL) starting from day -1 through day +17; (3) conversely, IL-3 level was low before treatment, sharply increased during chemotherapy, and rapidly returned to base-line level after SCT. Hypothetically, the sharp LIF decrease and IL-3 increase during chemotherapy may underlie the induction of stem cell cycling and differentiation caused by hematopoietic ablation. Furthermore, (4) IL-6 concentration was low before and immediately after chemotherapy, but increased starting from day +5, peaked at day +6 through 9 and then declined to baseline level from day +10 onward; (5) a strictly similar pattern was consistently observed for both G-CSF and IL-8 levels, in agreement with our previous studies. It is relevant that peak IL-6, G-CSF, and IL-8 concentrations were directly correlated to peak neutrophil numbers in the recovery phase, thus suggesting an important role for these cytokines in granulocyte rescue; in line with this interpretation, hematologic patients undergoing PBSCT (10 of 15) exhibited higher peaks of IL-6, G-CSF, and IL-8 and a more pronounced increase of neutrophil/platelet number than did hematologic cases undergoing BMSCT (5 of 15). Altogether, these studies indicate a coordinate pattern of cytokine release during hematopoietic ablation/recovery after chemotherapy and autologous SCT, the fluctuations of LIF and IL-3 levels during chemotherapy are seemingly related to stem cell recruitment, whereas the post-SCT increase of IL-6, G-CSF, and IL-8 may underlie the neutrophil recovery.
Adolescent↗