Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization

Vela‐Ojeda, Jorge; Tripp-Villanueva, F; Montiel‐Cervantes, Laura; Sánchez-Cortés, Evelia; Ayala-Sánchez, Manuel; Guevara-Moreno, M E; García-León, L. D.; Rosas-Cabral, Alejandro; Esparza, M A; González-Llaven, J

doi:10.1038/sj.bmt.1702426

Cited by 21 publications

(16 citation statements)

References 16 publications

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“…As an alternative to cyclophosphamide, it seems to offer some benefits in terms of antitumour effect, but only at the expense of a wider spectrum of toxicity (Vela-Ojeda et al, 2000). While a great deal of research has focused on the metabolism of IFO in relation to side effects such as nephrotoxicity (Boddy et al, 1996) and neurotoxicity (Wainer et al, 1994), relatively little is known concerning the relationship between systemic pharmacology and the drug interaction with its target, that is, DNA.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

et al. 2005

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The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r 2 ¼ 0.554, P ¼ 0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean7s.d., 27367597) than those patients in whom IFO was administered by continuous infusion (14537730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

et al. 2005

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“…13,16,17,33 Little data concerning prospective randomized trials describe the mobilizing and collecting potential of different regimens such as ESHAP or ifosfamide vs CPM. [18][19][20] Since we use DHAP to treat NHL, we decided to compare high-dose CPM and DHAP in a random fashion in an attempt to demonstrate some kind of prognostic significance in terms of mobilization potential or toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Few randomised studies report a comparison of mobilizing capacity of two different chemotherapeutic regimens such as ESHAP or ifosfamide vs CPM in lymphoproliferative disorders. [18][19][20] In our study 72 NHL patients undergoing PBSC transplantation were prospectively randomized to mobilize PBSC with the DHAP regimen or with high-dose CPM in order to evaluate whether there were any differences in the number of mononuclear cells harvested (× 10 8 /kg), CD34 + cells (×10 6 /kg), colony-forming units granulocyte-macrophage (CFU-GM) (×10 4 /kg) obtained or engraftment speed. …”

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confidence: 99%

Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma

Pavone

Gaudio

Guarini

et al. 2002

Bone Marrow Transplant

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Summary:Our study analyzes the mobilization of hematopoietic stem cells after two chemotherapeutic regimens in nonHodgkin's lymphoma (NHL) patients. The study included 72 patients with NHL (42 follicular and 30 large cells). The mean age was 37 years (range 17-60). Sixty-four patients (88.9%) had stage III-IV disease. Forty-eight patients (66.7%) had bone marrow involvement. Systemic B symptoms were present in 42 patients (58.3%). Mobilization chemotherapy regimens were randomly assigned as DHAP in 38 patients (52.7%) or cyclophosphamide (CPM) (5 g/m 2 ) in 34 (47.2%) and the results of 132 procedures were analyzed. At the time of PBSC mobilization, 46 patients (63.9%) were considered to be responsive (complete remission, partial remission or sensitive relapse) and 26 (36.1%) not responsive (refractory relapse or refractory to therapy). Pre-apheresis CD34 + blood cell count and number of previous chemotherapy treatments were used to predict the total number of CD34 + cells in the apheresis product. The mobilizing regimens (CPM or DHAP) were similar in achieving the threshold CD34 + cell yield, for optimal engraftment. Since DHAP was very effective as salvage treatment, we suggest using DHAP as a mobilizing regimen in patients with active residual lymphoma at the time of stem cell collection. ( toxicity. [5][6][7][8] In the literature, high-dose cyclophosphamide (CPM) seems to be the gold standard for mobilizing hematopoietic progenitor cells in lymphoproliferative disorders. 9,10 Single high doses of alkylating agents (high-dose CPM or melphalan) have been used as mobilizing chemotherapy in NHL and other malignancies. [9][10][11][12] Combination chemotherapy regimens such as DHAP or MAD or ESHAP have also been used for stem cell harvesting. [13][14][15] In a previous study the DHAP protocol has already shown real efficacy in debulking and in vivo purging in refractory or in partial remission NHL. 16,17 The DHAP regimen was thus integrated into various treatment plans tailored for NHL patients as a second-line therapy and salvage chemotherapy for PR patients, or as an intensification and mobilizing regimen in CR high risk patients. 16,17 In our previous experience, we used the DHAP protocol as salvage treatment in patients in PR or with refractory NHL. Few randomised studies report a comparison of mobilizing capacity of two different chemotherapeutic regimens such as ESHAP or ifosfamide vs CPM in lymphoproliferative disorders. [18][19][20] In our study 72 NHL patients undergoing PBSC transplantation were prospectively randomized to mobilize PBSC with the DHAP regimen or with high-dose CPM in order to evaluate whether there were any differences in the number of mononuclear cells harvested (× 10 8 /kg), CD34 + cells (×10 6 /kg), colony-forming units granulocyte-macrophage (CFU-GM) (×10 4 /kg) obtained or engraftment speed. Bone Marrow Transplantation Patients and methodsThe following parameters were examined in the two different mobilized groups: (1) Clinical: (i) type of mobilizing regimen (DHAP (cisplatin 100 mg/...

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“…A number of chemotherapy-based mobilizing regimens has been reported in lymphoma patients, [32][33][34][35] however, only one is a randomized comparison to cyclophosphamide alone. 32 That trial compared ifosfamide 10 g/m 2 and GM-CSF to cyclophosphamide 4 g/m 2 and GM-CSF and reported similar CD34 + yields, but improved neutrophil engraftment and less toxicity with cyclophosphamide. Only one randomized controlled trial has compared a chemotherapy-based regimen (cyclophosphamide 5g/m 2 + G-CSF) with a cytokine alone (G-CSF alone).…”

Section: C+e C (Matched Controls)mentioning

confidence: 99%

Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma

Mollee

Pereira

Nagy

et al. 2002

Bone Marrow Transplant

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Summary:We aimed to assess the effectiveness of cyclophosphamide, etoposide and G-CSF (C+E) to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma. A matched cohort study was performed comparing patients mobilized with C+E to patients mobilized with cyclophosphamide and G-CSF (C alone). Patients were matched for disease, prior radiotherapy and a chemotherapy score reflecting the amount and type of prior chemotherapy. Thirty-eight consecutive patients mobilized with C+E were compared with 38 matched controls. C+E was equivalent to C alone in terms of numbers of patients achieving a minimum threshold of у2 ؋ 10 6 /kg CD34 + cells (82% vs 79%, P = 0.74). C+E was superior, however, in terms of total CD34 + yield (6.35 vs 3.3 ؋ 10 6 /kg, P Ͻ 0.01), achieving a target graft of у5 ؋ 10 6 /kg (55% vs 34%, P = 0.04) and obtaining both a minimum (61% vs 32%, P Ͻ 0.01) and target (45% vs 13%, P Ͻ 0.01) graft in one apheresis. This superiority was largely confined to patients with lower chemotherapy scores. There was no difference in neutrophil and platelet recovery or transfusion requirements for those who subsequently received high-dose therapy and stem cell transplantation. Thus, C+E improves the efficiency of peripheral blood stem cell collection, but does not increase the number of patients who can proceed to transplantation. Most of the benefit of the regimen was confined to patients who had not received extensive prior therapy. Novel strategies are required to increase the collection efficiency of 'hard to mobilize' patients. in patients with lymphoma. Engraftment following transplantation of PBSCs is more rapid than with bone marrow 1 and has been demonstrated to correlate best with the number of CD34 + cells in the graft. With standardization of CD34 + enumeration, 2 у5 ϫ 10 6 /kg CD34 + cells has been suggested as a reasonable target for PBSC collection, as this allows optimal engraftment in nearly all patients. [3][4][5] Alternatively, transplantation of Ͻ1 to 2 ϫ 10 6 /kg CD34 + cells has been associated with delayed and failed engraftment, 6-10 leading to the concept of a minimum threshold CD34 + count in order to safely proceed with ASCT.Optimizing PBSC collection remains an important goal for several reasons: to increase the proportion of patients who can proceed to ASCT; to reduce the time to hematopoietic recovery post transplant; to maximize the efficiency of the PBSC collection process given the morbidity and costs of apheresis; and to reduce the need for second mobilizations and bone marrow harvests. Several studies 5,11-14 have described factors influencing the yield of PBSCs, including age, diagnosis, marrow involvement, prior radiation and time from prior chemotherapy therapy, but amount of previous chemotherapy seems to be the most consistent. The prior use of stem cell toxic regimens or agents such as nitrogen mustard, procarbazine, melphalan, carmustine, high-dose cytarabine, 15 Dexa-BEAM 16 and mini-BEAM 17,18 result in poor and unpredictable mob...

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Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization

Cited by 21 publications

References 16 publications

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma

Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma

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