Hematopoietic growth factors like G-CSF or GM-CSF have been shown to shorten the period of severe neutropenia after HD chemotherapy and autologous BMT, and are now widely used to mobilize hemopoietic stem cells into peripheral blood. In order to evaluate the possibility of delaying G-CSF administration after transplantation of G-CSF mobilized blood stem cells (BSC), we randomized 35 cancer patients to receive CSF at day 1 (group 1, n = 19) or at day 6 (group 2, n = 16) after transplantation and here we present their hematological reconstitution. BSC collection was performed by apheresis after G-CSF priming for 5 or 6 days (600 micrograms daily subcutaneously). Hematological recovery is comparable between the two groups: a median of 10 (range 7-16) vs 11 (range 9-18) days to reach an ANC > 0.5 x 10(9)/1 in group 1 (G-CSF day 1 after transplant) vs group 2 (G-CSF day 6 after transplant, P = NS). Median time to reach an unsupported platelet count of 25 x 10(9)/1 was 14 days in the two groups (range 8-110 and 10-40 respectively, P = NS); patients received less G-CSF after transplantation in group 2. No difference appeared in terms of transfusion support, number of days of fever of i.v. antibiotic treatment. Patients' hospital stay was the same in the two groups. Our data suggest that delaying G-CSF administration after infusion of mobilized blood cells is not detrimental to hematological recovery, while it lowers the overall cost of the procedure.

The aim of this study, carried out at the Institut Paoli-Calmettes (Marseille-France), was to compare, in terms of monetary and non monetary costs, alternate procedures for hematopoietic stem cells collection i.e. peripheral blood stem cells collection (PBSCC) and bone marrow collection (BMC) used in cancer therapies. Monetary costs have been evaluated by calculating the direct costs of the two types of procedures and non monetary costs by comparing anxiety, discomfort and pain of cancer patients submitted to PBSCC or BMC. Patients, randomized (7/1993-2/1994), in view of autologous transplantation, to receive the first procedure or the second one received three self-administered questionnaires to complete before, during and after the procedure. Pain was assessed using visual analogical scale and McGill Pain questionnaire. Anxiety was evaluated by means of State-Trait Anxiety Inventory. Results showed that, under some conditions, presently realized in the current practice, direct costs of PBSCC (10,140 to 13,780 FF) were lower than BMC ones (16,509 FF) and that anxiety and pain experienced by patients submitted to PBSCC, with or without femoral catheter, were significantly less severe than in other group patients (State anxiety, before procedure : p < 0.01 ; pain related to the procedure assessed on VAS : p < 0.001 and total McGill score : p < 0.00001). These findings justify the substitution of bone marrow transplantation by peripheral blood stem cells transplantation, provided there is a demonstration of similar medical efficacy for cancer therapy.

These studies investigated the effectiveness of in vivo administration of cytokines in ameliorating potential marrow damage induced by chemotherapy. Breast cancer patients received 5-fluorouracil, leucovorin, doxorubicin and cyclophosphamide (FLAC) followed by either GM-CSF, PIXY321, or no cytokine. Marrow was obtained before and after one or two cycles of FLAC once blood cell counts had recovered. Colony-forming units for granulocytes and macrophages (CFU-GM) were used to indicate the effect of therapy on recovery of committed progenitor cells responsible for early blood cell recovery. The frequency and number of CFU-GM in marrow obtained after FLAC + PIXY321 were significantly lower than in marrow obtained after FLAC+GM-CSF or FLAC without cytokine. CD34+ cell numbers were also reduced after FLAC + PIXY321. CFU-GM production in marrow long-term cultures (LTC) was used to assess the effect of therapy on primitive progenitors. After 5 weeks the number of CFU-GM in LTC of post-therapy marrow from all three treatment arms was < 15% of the number in pre-therapy LTC. Suppressive effects of FLAC on primitive progenitors were observed even when committed progenitors and CD34+ cells had recovered to pre-therapy levels. These results demonstrate that cytokine treatment did not ameliorate suppressive or toxic effects of FLAC on the functional integrity of the marrow.

Improved methods for mobilization may reduce the number of aphereses required to collect adequate numbers of peripheral blood stem cells (PBSC) and hasten engraftment following high-dose therapy. Mobilization with cytokines alone enables engraftment after myeloablative therapy. The optimal cytokine regimen for mobilization has not been established. The study evaluated the effects of four interleukin-3-containing cytokine regimens administered during steady state hematopoiesis on PBSC mobilization in 30 patients with breast cancer or lymphoid malignancies. These regimens included IL-3 alone (Arm 1), sequential IL-3 --> G-GSF (Arm 2), sequential IL-3 --> GM-CSF (Arm 3) and combined IL-3 + G-CSF (Arm 4). Consecutive days of apheresis were performed until a target of 4-6 x 10(8) mononuclear cells/kg were collected. All patients received intravenous GM-CSF after PBSC infusion. Median days to an ANC > or = 500/ microliters in Arm 3(22 days) was significantly slower than for patients in Arm 2 (13 days) but not significantly different from patients in Arm 1 or Arm 4. There was no significant difference in platelet engraftment or days of hospitalization between the study arms. Addition of GM-CSF to IL-3-containing mobilization regimens results in collection of PBSC that lead to delayed engraftment. Further development of Arms 1, 2, and 4 appear warranted.

In June 1992, we started a dose-escalated cytotoxic therapy with peripheral blood progenitor cell (PBPC) transplantation in patients with chemosensitive multiple myeloma (MM). At the time of best response to conventional treatment, 70 patients received high-dose cyclophosphamide (HD-CY) or, in case of pre-existing heart disease, dose-escalated ifosfamide/mitoxantrone followed by filgrastim (R-metHuG-CSF, 300 micrograms/day). PBPC collection was commenced when CD34+ cells were detectable using direct immunofluorescence analysis. Fifty-four out of 70 patients were successfully harvested (> or = 2.5 x 10(6) CD34+ cells/kg body weight [BW]) after the first cycle of HD chemotherapy. Conditioning therapy consisted of 140 mg/m2 melphalan plus TBI (14.4 Gy hyper-fractionated) or 200 mg/m2 melphalan in patients not eligible for TBI because of previous radiotherapy. To date, 56 patients have been transplanted. Autografts contained a median of 3.4 x 10(6) CD34+ cells/kg BW. Following reinfusion of PBPC, rapid engraftment was achieved in 54 out of 56 patients with a median of 14 days (range 9-23) to reach 0.5 x 10(9)/l neutrophils and 10 days (range 5-22) for an unsubstituted platelet count of > 20 x 10(9)/l. One patient died of transplantation-related complications. Sequential HD treatment improved the remission status (European Bone Marrow Transplantation criteria) in 19 out of 46 patients (9 patients too early). Of note, in 11 patients the immunofixation became negative and a polyclonal immunoglobulin reconstitution was achieved. Our protocol provides an effective treatment strategy for patients with advanced MM combined with low treatment-related toxicity.

The more mature erythroid progenitor assayable in vitro, the colony-forming unit-erythroid (CFU-E), is normally found in the bone marrow (BM) but is virtually absent from peripheral blood (PB), unlike the more immature progenitor, the burst-forming unit-erythroid (BFU-E). We report on the detection of CFU-E in the PB of six of 18 patients during hematopoietic recovery following allogeneic bone marrow transplantation (BMT); three of six patients with PB CFU-E were under treatment with recombinant human erythropoietin (rhEpo) as well as six of 12 who did not present with PB CFU-E. PB CFU-E were found as early as day 14 following BMT, reached a peak on day 28, and were still detectable on day 60. The presence of PB CFU-E was associated with signs of stimulated erythroid engraftment--an accelerated reticulocyte recovery, an increased number of reticulocytes, higher levels of serum transferrin receptor, and a reduction in transfusional requirements were found in these patients compared to those without PB CFU-E. The numbers of PB and BM BFU-E were similar in the two groups, as well as the numbers of PB and BM CFU-granulocyte/macrophage (CFU-GM) and multipotential CFU (CFU-GEMM); on the other hand, the percentage of BM BFU-E in S phase of the cell cycle was higher in the group of patients with PB CFU-E. While there was no difference between the two groups in serum Epo levels assayed on days 14 and 28 after BMT, patients with PB CFU-E had higher Epo levels in serum samples collected before starting the BMT procedure. These data suggest that the appearance of circulating CFU-E early after BMT is characteristic of a group of patients with an accelerated erythroid engraftment, although the mechanisms leading to the circulation of CFU-E after BMT remain unclear.

The aim of this study was to evaluate the efficacy, safety and toxicity of short-term priming with recombinant human granulocyte colony-stimulating factor (rhG-CSF) immediately after diagnosis but before combination chemotherapy (CHOP) for non-Hodgkin's lymphomas. Of fourteen patients entering the study, seven received five days subcutaneous injection of rhG-CSF (5 micrograms/kg/day) before CHOP (CSF-group), and seven were treated with CHOP alone (control group). Blood samples were studied before and on days 1-5 during rhG-CSF priming as well as twice weekly after treatment. The number of blood and bone marrow progenitors was identified by clonogenic growth day 7, 14 and 21 of GM-CFU in semisolid medium. Blood absolute neutrophil counts increased in all rhG-CSF primed patients. The expansion of marrow myelopoiesis resulted in increased myeloid:erythroid ratios, increased bone marrow cellularity and increased numbers of myeloid progenitors both in the blood as well as the marrow. Chemotherapy induced neutropenia developed on day 9-12 in all patients independent of myeloid growth factor priming. However, neutropenia appeared earlier in the cytokine primed group (P = .0038). Five patients in the CSF-group and three patients in the control group were hospitalized with neutropenic fever, and septicemia was documented in three patients in the CSF-group. RhG-CSF induced expansion of myelopoiesis immediately before combination chemotherapy mobilized sufficient number of blood progenitors for apheresis but did not result in reduction of duration and degree of neutropenia in patients with newly diagnosed non-Hodgkin's lymphoma. Although the small number of patients prevents drawing definite conclusions, this time schedule for priming should be used with caution in the future due to an increased risk of hematologic toxicity.

The aim of this study was to compare anxiety, pain and discomfort of cancer patients submitted to either peripheral blood progenitor cell collection (PBPCC) or bone marrow harvest (BMH). Patients, randomized (7/1993-2/1994), in view of autograft, to receive the first procedure or the second one, completed self-administered questionnaires. Anxiety was assessed by the State Trait Anxiety Inventory and pain using visual analogical scale (VAS) and McGill Pain questionnaire. Before the procedure, BMH patients (n = 25) experienced more anxiety (P < 0.01) and more trouble or inconvenience for having to come and stay at the hospital (P < 0.0001) than PBPCC patients (n = 40). Pain due to BMH is significantly higher than pain induced by PBPCC (P < 0.001 for VAS and total McGill score). However, patients submitted to PBPCC with a femoral catheter (n = 19) had significantly higher total McGill scores and sensory sub-scores than patients without it (n = 21). At discharge from the hospital, PBPCC patients expressed more positive judgements towards the collection procedure than BMH patients. These results suggest that a better patient acceptability of high-dose chemotherapy followed by autograft may be obtained by substituting PBPCC for BMH for stem cell collection.

Eighty-four patients with locally advanced, non metastatic squamous cell carcinoma of head and neck or esophagus, were included in a multicentric double-blind randomized trial, comparing goralatide (12.5 or 62.5 micrograms/kg/day, d1-d4) to placebo, associated with carboplatin (400 mg/m2, d1) and 5-fluorouracile (1 g/m2/d continuous IV over 96 hours). Haematological toxicity was analysed on 221 cycles of chemotherapy. All but one patient were evaluable because of early death without haematological toxicity. No significant difference was observed for mean nadir of leukocytes, granulocytes, platelets counts and hemoglobin level. Duration of haematological toxicity was no significantly different for the two groups of patients. Anemia and lymphopenia were more frequent in the goralatide treated patients. Clinical and biological tolerability of goralatide was excellent.

Since 1986, we have treated young patients with aggressive multiple myeloma (MM) by high-dose chemotherapy (HDC) and total body irradiation (TBI) followed with autologous blood stem cell transplantation (ABSCT). To evaluate this strategy: 1) We conducted a phase II trial that included 63 patients. Within a median follow-up of five years after transplantation, overall survival was 60% and median event-free survival was four years, and 2) In the early 1990s, we initiated a prospective trial where, after collection of chemotherapy-mobilized ABSC, patients under 55 years of age with newly diagnosed MM were randomly assigned either to HDC and TBI supported with ABSCT (high-dose therapy [HDT] arm) or to a conventional vincristine, melphalan, cyclophosphamide and prednisone (VMCP) regimen (VMCP arm). In the latter, HDT with ABSCT was performed as a rescue therapy, in case of primary resistance to VMCP or at relapse in responders. As of June 1994, 167 patients have been enrolled since a median time of 26 months. Fourteen (8%) could not be randomized. Among the randomized patients (n = 153), 30 deaths were observed, 13 in the HDT group and 17 in the VMCP group (p = 0.28, two-sided log rank test). Overall survival rates at two years were estimated at 78% for all 167 patients, at 82% in the HDT group and at 67% in the VMCP group. ABSC, provided they are collected early in the disease course, allow a great majority of myeloma patients to receive HDT.(ABSTRACT TRUNCATED AT 250 WORDS)

Eighty-four patients with myeloma were randomized to receive maintenance Intron A (Schering-Plough, Suffolk, UK), 3 mega units/m2 s.c. three times weekly or no treatment following induction therapy with cyclophosphomide, vincristine, doxorubicin, methyl prednisolone (C-VAMP), consolidated with high-dose melphalan (HDM) 200 mg/m2 + autologous bone marrow transplantation (ABMT). The patients have been followed up for a median of 52 months. Overall, median progression-free survival (PFS) from HDM was 27 months in the control group and 46 months in the Intron A group (< 0.025). For the 65 patients who achieved complete remission (CR) with HDM, there was a significant prolongation of remission (p = 0.02) for those who received Intron A and 49% of these patients remained in remission four years after high-dose treatment. However, for partial responders (PR) and nonresponders to HDM there was no significant prolongation of PFS. Overall, survival was also significantly better for the Intron A group, with 5 deaths versus 14 deaths in the control group (p = 0.006). Subsequently, 54 consecutive patients received the same HDM followed by rescue with peripheral blood stem cells after induction chemotherapy which included C-VAMP. Intron A was started in 45 of these patients at a median of 62 days which was comparable to the ABMT arm. The overall response rate in these patients was 79.62% (43/54-CR+PR) and the probability of survival at 18 months was 74.2% by the Kaplan Meier method.(ABSTRACT TRUNCATED AT 250 WORDS)

The positive role of G-CSF in hastening the myeloid recovery of patients undergoing allogeneic bone marrow transplantation (ALLO-BMT) or autologous bone marrow transplantation (ABMT) has recently been established. Considerable knowledge about adequate doses and route of administration has been accumulated in the past few years. Nonetheless, the optimal time to start growth-factor administration remains undetermined. We have performed a stratified study according to the source of hematopoietic progenitors (ALLO-BMT or ABMT), underlying disease and its stage, and acute graft-versus-host disease (GVHD) prophylaxis regimen and randomized patients in two arms: group A, which started G-CSF on day 0 (36 patients), and group B, which started on day +7 post-BMT (39 patients). The same dose (5 micrograms/kg/day) and route of administration were employed in both groups. We found no significant differences in the time to reach an absolute neutrophil count (ANC) of 0.1, 0.5, and 1 x 10(9)/l and 50 x 10(9) platelets/l (medians: 10 and 11, 14.5 and 14, 17 and 16, 23 and 24 days, respectively, in groups A and B). We did not find differences in the days of fever or days on antibiotic treatment with less than 1 x 10(9)/l ANC, rate of bacteriemia, or days of hospitalization in both groups. In contrast, a considerable saving of G-CSF in B group was found (mean days of infusion in group A, 18, versus 11 in group B) (p < 0.0001). This is equivalent to a saving of 1120 $US per patient.(ABSTRACT TRUNCATED AT 250 WORDS)

With the increasing concern over the high cost of health care, policy makers have incorporated economic analyses into phase III clinical trials as the randomized clinical trials can provide important information on the efficacy and potential cost-effectiveness of new pharmaceutical agents. Economic analyses of single-hospital experience during phase III trials of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy for high dose chemotherapy with autologous stem cell support found significant shortening of neutropenia with GM-CSF at each hospital, but shortened hospitalization (and lower costs) at only two of three hospitals. In this study, we added data from three additional hospitals and found that the 103 patients who received GM-CSF had, on average, 5.7 days shorter durations of severe neutropenia than the 95 patients who received placebo (p < 0.0001) and 3.4 days shorter in hospitalization (p = 0.06). However, the duration of hospitalization, the primary determinant of health care costs, was shorter for GM-CSF patients in only four of the six centers and the duration of hospitalization of placebo patients was shorter at the other two centers. Careful analyses must be carried out when phase III clinical trial results are used to derive estimates of cost-effectiveness of new pharmaceutical agents. The interpretation of economic analyses of phase III clinical trials raises issues related to the perspective of the investigators, study design, collection of data on resource utilization, learning curve effects and generalizability of the results to other settings.

The aim of this study was to compare anxiety, pain and discomfort of cancer patients submitted to two procedures of hematopoietic stem cells collection: peripheral blood stem cells collection (PBSCC) or bone marrow collection (BMC). Patients, randomized (July 1993-February 1994), in view of autograft, to receive the first procedure or the second one, completed self-administered questionnaires before, during and after the procedure. Anxiety was evaluated by State-Trait Anxiety Inventory. Pain was assessed using visual analogical scale (VAS) and McGill Pain questionnaire. Before the procedure, in comparison with PBSCC patients (n = 40), BMC patients (n = 25) experienced more State-anxiety due to the procedure approach (p < 0.01) and more trouble or inconvenience for having to come and stay at the hospital (p < 0.0001). During the procedure, pain related to BMC, as assessed by VAS, is significatively higher than pain induced by PBSCC, whichever the access used (p < 0.001). The McGill total score is twice as high for BMC patients than for patients submitted to PBSCC with femoral catheter (n = 19). The latter patients significatively reported more pain than patients without femoral catheter (n = 21). At the discharge from hospital, 32% of BMC patients judged the procedure quite difficult vs 5% of PBSCC patients (p < 0.05). These results explain a higher acceptability of the peripheral blood stem cells collection.

Patients suffering from high-risk multiple myeloma (MM) were randomized to receive single high-dose cyclophosphamide followed by either rhGM-CSF or rhG-CSF in order to harvest circulating peripheral blood progenitor cells. The safety of the procedure, the mobilization kinetics, the relative efficacy of rhGM-CSF and rhG-CSF to mobilize progenitor cells and their relative toxicity were studied. Special attention was paid to the antigenic profile of CD34+ progenitor cells. Group I patients (n = 11) were treated with cyclophosphamide 4 g/m2 i.v. followed by rhGM-CSF at 10 micrograms/kg/d by subcutaneous administration. Group II (n = 11) patients received rhG-CSF s.c. at 10 micrograms/kg/d after the same dose cyclophosphamide. Both mobilization regimens appeared to be equally effective. No significant differences in absolute numbers of circulating progenitors, determined by CD34 expression or in yields of MNC, CFU-GM, BFU-E and CD34 subsets were observed. rhGM-CSF administration resulted however in delayed haemopoietic recovery and an increased complication rate. We conclude that rhG-CSF may be preferred because of its markedly lower toxicity and lower in-hospital costs.

To compare autologous bone marrow (BM) with peripheral-blood progenitor cells (PBPC) as hematopoietic rescue after high-dose chemotherapy (HDCT).

It is well-established that the infusion of hematopoietic growth factors (HGF) accelerates neutrophil recovery in patients undergoing high-dose therapy followed by autologous bone marrow infusion. In addition, there is evidence that the infusion of autologous peripheral-blood stem cells (PBSC) accelerates engraftment in comparison to patients who receive bone marrow alone. However, few data are available regarding the ability of HGF to accelerate engraftment further in patients who receive PBSC following high-dose therapy.