High-dose cyclophosphamide + carboplatin and interleukin-2 (IL-2) activated autologous stem cell transplantation followed by maintenance IL-2 therapy in metastatic breast carcinoma – a phase II study

Summary:The purpose of this study was to evaluate pre-transplant T-cell status in autologous hematopoietic progenitor-cell transplantation (HPCT) recipients. Between 1999 and 2002 we prospectively enrolled 85 autologous HPCT recipients with solid tumors (N ¼ 50) or hematologicaland amyloidosis (N ¼ 1). Levels of CD3, CD4, CD8, memory and naı¨ve CD4, and CD8 T-cell subsets were analyzed before autologous HPCT. Autologous HPCT recipients presented with lower pretransplant counts of CD3, CD4, but not CD8 T cells, as compared to healthy controls. Pre-transplant CD4 T-cell levels correlated with progression-free survival (PFS) (P ¼ 0.002) and overall survival (OS) (P ¼ 0.05), in patients with hematologic malignancies (P ¼ 0.02) and breast cancer (P ¼ 0.04). Specifically, pre-transplant memory CD4 þ CD45RAÀCD62LÀ T-cell levels correlated with PFS (P ¼ 0.01). The prognostic effects of pretransplant CD4 and CD4 þ CD45RAÀCD62LÀ T cells were independent of tumor diagnosis, tumor stage, tumor sensitivity, and, for breast cancer patients, Her2/neu status. Our results suggest that pre-transplant CD4 T-cell status, specifically CD4 þ CD45RAÀCD62LÀ memory T cells, correlates with the outcome of autologous HPCT recipients. These observations suggest the feasibility of prospective identification of those patients at higher risk of relapse, based on their immune status.

Section: Discussionmentioning

confidence: 99%

Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant

Rosinski

McNiece

Shpall

et al. 2005

“…6,[9][10][11] The relatively simple pharmacokinetics of carboplatin suggest that drug exposure measured by the area under the plasma concentration vs time curve (AUC) correlates closely with renal function, 8,[12][13][14] and that toxicities may be more accurately predicted when the dose is determined not on the patient's body surface area (BSA), but by achieving a specific carboplatin AUC. 5,8,15,16 A dosing equation based on pre-treatment renal function as assessed by glomerular filtration rate (GFR) has been designed by Calvert and colleagues13 where the carboplatin dose (mg) = AUC (mg/ml Ϫ1 min) ϫ (GFR (ml/min) + 25).…”

mentioning

confidence: 99%

High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

Colby

Koziol

McAfee

et al. 2002

Self Cite

Summary:Pharmacokinetic analysis of carboplatin dosing suggests a more accurate prediction of toxicity when the dose is based on the area under the plasma concentration vs time curve (AUC) instead of body surface area (BSA). We retrospectively calculated the carboplatin AUC of 117 patients who received an autologous stem cell transplant following a conditioning regimen consisting of carboplatin 1800 mg/m 2 and cyclophosphamide 6000 mg/m 2 to identify whether higher carboplatin exposure resulted in an increase in regimen-related non-hematologic toxicities. The most common non-hematologic toxicities were gastrointestinal and hepatic. Twenty (17%) patients experienced additional уgrade 2 toxicity, specifically, renal toxicity significantly associated with a higher median AUC of 10.2 mg/ml ؊1 min (P = 0.001). Prior platinum therapy was also significantly associated with toxicity (P = 0.052). While carboplatin dose based on BSA varied minimally (median 990 (range 450-1340) mg, the calculated AUC showed a near four-fold range of exposure (median 7.8 (range 3.6 to 13.8) mg/ml ؊1 min). These data suggest a relationship between nonhematologic adverse events and the estimated AUC. Prospective trials will be necessary to identify the target carboplatin AUC which optimizes outcome and minimizes toxicity in the autologous transplant setting.

“…Two clinical studies in women with poor risk breast cancer demonstrated the cytotoxic activity of mobilised PBSC. [7][8][9] The prognosis of stage 4 neuroblastoma has improved significantly with high-dose chemotherapy combined or not with TBI and ASCT as consolidation therapy 1,2 but remains poor. The respective role of autograft contamination by tumour cells and of persistent minimal residual disease is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…6 The early administration of low-dose IL-2 after transplantation of IL-2-activated PBSC was then demonstrated to be feasible in women with poor risk breast cancer. [7][8][9] In the light of these preliminary results we felt that children with solid tumours could benefit from HDC combined with immune modulation. The occurrence of spontaneous regressions, 10 intratumour lymphocyte infiltrates with T cell clonal expansion, 11 and the potential efficacy of immunotherapy 12 all argue in favour of a possible role of the immune system in the fight against neuroblastoma (NB), the most common paediatric tumour.…”

mentioning

confidence: 99%

In vitro generation of cytotoxic effectors activated by interleukin 2 (IL-2): comparison of autologous peripheral blood stem cells (PBSC) from adults and children

Valteau‐Couanet

Angevin

Leboulaire

et al. 2001

Summary:Previous studies demonstrated that ex vivo IL-2-activated PBSC could generate cytotoxic effectors without impairing haematopoietic reconstitution. Clinical experience and previous studies indicated that children with solid tumours could benefit from high-dose chemotherapy with immune modulation. We studied the generation of cytotoxic effectors from growth-factor ؎ chemotherapy-mobilised PBSC from 10 patients (five adults and five children) with different solid tumours. Cells were placed in culture in serum-free culture medium supplemented with IL-2 1000 U/ml ؎ IL-12 for 1, 2, 4 or 7 days. Anti-tumour cytotoxicity was tested against K562, Daudi and two neuroblastoma cell lines (Gau, NB91). Cultured adult PBSC in the presence of IL-2 (1000 U/ml) showed marked cytotoxicity against all the cell lines tested from day 1. At day 2, with an E:T ratio of 25:1, cytotoxicity was 53% ؎ 10.4, 63.2% ؎ 23.8, 38% ؎ 9.1, and 39% ؎ 15.7 against K562, Daudi, Gau and NB91, respectively. Cytotoxic activity of child PBSC was significantly lower (P Ͻ 0.05) and was displayed after longer culture times (day 4). No difference was found in the phenotype analysis of lymphoid subsets before and after IL-2 activation between adult and child PBSC. Haematological properties of the graft were not significantly impaired by IL-2 activation. Bone Marrow Transplantation (2001) 27, 869-875. Keywords: PBSC; interleukin 2; neuroblastoma; children High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) has been demonstrated to improve the prognosis of various solid tumours in children. 1,2 However, the risk of relapse remains high. Relapses may be attributed in part to residual disease in the patient and/or in the graft 3 and to the lack of a 'graft-versus-tumour effect' (GVT). 4 As the escalation of HDC is hampered by excessive visceral toxicity, other strategies must be devised to eradicate residual disease.Post-transplant immunotherapy using ex vivo-activated PBSC in combination with HDC may constitute an effective strategy for improving clinical outcome without the drawback of overlapping toxicities. Interleukin-2 (IL-2) therapy instituted immediately after IL-2-activated autologous stem cell transplantation (ASCT) proved effective in inducing graft-versus-leukaemia (GVL) effects in an acute myeloid leukaemia (AML) murine model. 5 This therapeutic approach was attempted in autologous bone marrow (ABM) and then in PBSC collected from cancer patients. The latter study demonstrated that ex vivo IL-2-activated PBSC could generate cytotoxic effectors without impairing haematopoietic reconstitution. 6 The early administration of low-dose IL-2 after transplantation of IL-2-activated PBSC was then demonstrated to be feasible in women with poor risk breast cancer. [7][8][9] In the light of these preliminary results we felt that children with solid tumours could benefit from HDC combined with immune modulation. The occurrence of spontaneous regressions, 10 intratumour lymphocyte infiltrates with T cell clonal expansion, 1...