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PubMed1998

Mobilized CD34+ cells selected as autografts in patients with primary light-chain amyloidosis: rationale and application.

BACKGROUND: Concern about tumor cell contamination in stem cell preparations has led to the use of CD34+ cell selection as a means of purging. Increasing the number of CD34+ cells per leukapheresis may help to provide an adequate dose of CD34+ cells. STUDY DESIGN AND METHODS: The reverse transcriptase polymerase chain reaction (RT-PCR) was employed to clone overexpressed clonotypic immunoglobulin light-chain variable region genes (Ig VL) from bone marrows of patients with primary light-chain amyloidosis (AL). Patient-specific primers were designed to evaluate stem cell collections for contamination. CD34+ cell selection was performed on components from AL patients who underwent mobilization with granulocyte-colony-stimulating factor (G-CSF) (filgrastim; 16 microg/kg/d for 4 days) and collection by large-volume leukapheresis (LVL;25L) on Days 4 and 5. The selected cells alone were transfused after patients received mephalan (200 mg/m2). RESULTS: Contamination was found in collections from 4 to 7 patients, which provided the rationale for a subsequent trial of CD34+ cell selection. The median number of CD34+ cells per kg collected on Days 4 and 5, and in toto, was 4.0 x 10(6)(1.1-12.7), 7.9 x 10(6)(1.8-12.7), and 10.7 x 10(6)(2.9-25.4), respectively (n = 9 patients). The median yield per selection was 38 percent, with a purity of 85 percent (45-97%), and the viability of CD34+ cells averaged 96.4 +/- 3.6 percent (n = 18 selections). The median number of CD34+ cells infused was 5.9 x 10(6) per kg (2.1-10.1). In comparison with AL patients given unselected autografts, patients receiving selected CD34+ cells experienced similar reconstitution of neutrophils and platelets but slower lymphocyte recovery. CONCLUSION: Patients with AL often have contamination with clonotypic cells in their blood autografts. G-CSF mobilization and LVL provide components that allow the selection of adequate doses of CD34+ cells. The use of CD34+ cells in patients with AL achieves rapid neutrophil and platelet recovery but delayed lymphocyte recovery. CD34+ cell selection is feasible in the treatment of AL, but its effectiveness in purging clonotypic cells remains to be ascertained.

Adult↗
PubMed2004

Adoptive immunotherapy with antigen-specific T cells in myeloma: a model of tumor-specific donor lymphocyte infusion.

Although partial remissions rates of up to 60% are obtained with conventional therapeutic regimens, multiple myeloma is essentially an incurable disease with a median survival of approximately 30 months. Allogeneic stem cell transplantation (SCT) results in a high percentage of complete remissions (CRs), but it can be associated with significant treatment-related mortality. Recent clinical studies have shown that highly immunosuppressive, yet nonmyeloablative, doses of fludarabine-based chemotherapy can result in alloengraftment. However, even with a reduction in treatment-related mortality, success with allogeneic SCT is limited by the significant risk of relapse. The goal of the strategy described is to transfer tumor antigen-specific immunity induced in the stem cell donor to the allogeneic SCT recipient to reduce relapse. Donors are immunized with a well-defined vaccine, specific for the patient's tumor. The allogeneic SCT is performed with a conditioning regimen consisting of cyclophosphamide and fludarabine, and the stem cell source is blood mobilized with filgrastim, which could potentially enhance the transfer of a larger number of tumor-specific T cells in the allograft, as compared to bone marrow. Donor immunization with myeloma idiotype protein in the setting of a nonmyeloablative SCT may represent a novel strategy for the treatment of myeloma.

Animals↗
PubMed1995

[Agranulocytosis caused by infectious-toxic bone marrow damage after Borrelia infection].

A 19-year-old girl developed a fever of up to 40 degrees C and, during an episode of high fever, generalized seizures. Physical examination on admission was unremarkable, except for several small lymph nodes. Differential blood count showed a leukopenia (1700/microliters) with 14% stab and 7% segmented neutrophils. After initial clinical improvement she again became feverish and the differential count now showed agranulocytosis with a total white cell count of 1400/microliters. Because of the time of year and the geographic location borreliosis was now considered in the differential diagnosis. The antibody titre against Borrelia was raised to 1:64 (IgM) and 1:256 (IgG). Her condition and the differential blood count rapidly improved on intravenous antibiotic treatment with cefotiam (2 g two times daily) and gentamicin (120 mg two times daily), as well as filgrastim (granulocyte-colony stimulating factor) subcutaneously. Antibiotic treatment was continued after 6 days with oral ampicillin (1 g three times daily) for 3 weeks. Follow-up examination six weeks later found the patient to be symptom-free.

Administration, Oral↗
PubMed2002

Regression of a plasmablastic lymphoma in a patient with HIV on highly active antiretroviral therapy.

We describe an HIV-infected 44-year-old man who presented 1 month after discontinuation of HAART therapy with a large mass extending from the mediastinum, enclosing the heart and extending through the diaphragm to the epigastric region. Biopsies subsequently revealed a highly aggressive non-Hodgkin's lymphoma (NHL) producing sheets of cells with an organoid distribution. The cells had abundant basophilic cytoplasm and a plasmacytic appearance. Although immunohistochemistry failed to show either B- or T-cell markers, antigens consistent with plasma cells were found. An immunoglobulin heavy chain clonal rearrangement was identified by PCR analysis. These studies were supportive of a diagnosis of a plasmablastic lymphoma. While awaiting the results of these tests, the patient was reinitiated on his HAART regimen. He was found on follow-up a month later to have complete resolution of his bulky mediastinal mass. He remained free of disease for 3 months with subsequent rectal and abdominal recurrence. Treatment with CHOP chemotherapy with filgrastim support was begun which resulted in another remission. Plasmablastic lymphoma is now reported in some studies to account for 2.6% of all HIV-related NHL. Originally described in 1997 in a series of 16 patients, this entity is highly associated with HIV infection in its later stages. Often, patients present with oral or jaw lesions with a rapidly progressive course. The tumors have the morphologic appearance of a plasmacytoid tumor with high proliferative index. Markers are positive mainly for LCA, CD79a, VS38C, and CD138. Co-infection with HHV-8 and EBV has not been consistently reported. Therapy with standard regimens has variable response. One case has been reported with a 3.5 year disease free survival. The regression of disease after resumption of HAART therapy alone in this patient suggests that HAART has an important role in the treatment of lymphoma in the HIV infected patient.

Adult↗
PubMed2005

R-CHOP-14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy.

Treatment of diffuse large B-cell lymphoma (DLBCL) with CHOP-21 (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg for 5 days every 21 days) results in long-term remission in approximately 45% of patients. Recent phase III trials have demonstrated improved survival by modifying CHOP either through adding rituximab or shortening the time between cycles to 14 days. These studies prompted our institution to treat newly diagnosed patients with DLBCL refusing or not eligible for protocol-based therapy with R-CHOP-14. In this single-institution retrospective analysis, we report our results with this regimen. Forty-nine patients with newly diagnosed DLBCL and ineligible or refusing protocol-based therapy were retrospectively identified. Patients were treated with 6-8 cycles of R-CHOP-14 given with filgrastim and prophylactic antibiotics. The main toxicities with R-CHOP-14 were hematological and neurological and were not unexpected. There were no treatment-related deaths. Patients received 90% of planned cytotoxic drug density. The complete remission/complete remission uncertain (CR/CRu) rate was 82.2%. At a median follow-up of 24 months, the event-free survival was 80% and overall survival 90%. These results demonstrate R-CHOP-14 can be given to patients safely and short-term results regarding survival are promising. Whether adding rituximab and increasing dose intensity improves survival over either alone will require randomized studies.

Antibodies, Monoclonal↗
PubMed2001

Allogeneic hematopoietic cell transplantation without myeloablative conditioning for patients with advanced hematologic malignancies.

BACKGROUND: The effect of allogeneic hematopoietic cell transplantation (alloHCT) on hematologic malignancies is based on the graft-versus-malignancy effect. Obtaining this effect with reduced toxicity has been possible by non-myeloablative (NMA) alloHCT. Once mixed chimeric status, and host versus graft with graft versus host tolerance are achieved, further strengthening of chimerism and graft-versus-malignancy effect can be obtained by donor lymphocyte infusions (DLIs) when needed. METHODS: The patient group consisted of 13 patients with advanced hematological malignancies: seven had CML, four of them in blastic-, two in chronic- and the remainder in accelerated-phase; four patients with AML, refractory or in second remission state; one patient with primary refractory secondary AML; and one patient with ALL relapsed after alloHCT. Conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days and anti-T-lymphocyte globulin (ATG) 10 mg/kg/day for 4 days as immunosuppressive. Ara-C or Bu or melphalan were used as the cytoreductive component. All transplants were performed using HLA-identical sibling donors' peripheral blood hematopoietic cells, after priming with filgrastim. Post-transplant GvHD prophylaxis was achieved with CsA alone in 10 patients, and with CsA plus mycophenolate mofetil in the last three patients. RESULTS: Median follow-up is 3 months (range, 0-20) for all the patients and 6 months (range, 2-15) for the live patients. Donor chimerism was shown in 10 patients, not regarding any pretransplant feature. DLIs were performed in seven patients after transplantation and two of them achieved complete chimeric status and molecular remission. Two CML patients in blastic phase (CML-BP), and the primary refractory secondary AML patient did not respond to procedure. In four patients, drug therapy in conventional doses was added to post-transplant DLIs for their relapsed or refractory diseases. Two patients with AML in second CR, and another CML-BP patient, relapsed or progressed after transplantation. A patient with CML-BP achieved CR and full donor chimerism after transplantation, but developed refractory post-transplant lymphoproliferative disease in the 19th month. Two patients with refractory AML, one patient with relapsed ALL and two patients with CML in chronic phase were in complete chimeric status and free of disease signs. Acute GvHD, Grade II-III, was observed in five patients, and two of them developed secondary progressive chronic GvHD subsequently. We observed one early death in a platelet transfusion refractory blastic phase CML patient due to intracranial hemorrhage. Procedure-related severe toxicity was not observed, either in standard-risk patients or stem-cell donors. DISCUSSION: Establishing engraftment with donor chimerism was the first successful step in this approach. The second step, which was the result of the graft-versus-malignancy effect, could be seen in most of the patients, but was not sustained in all of them because of the aggressiveness of their malignancy. It can be suggested that the immunotherapeutic efficacy of this approach could be more successful, and with acceptable toxicity, when performed in patients with minimal residual disease. The role of NMA conditioning, and of the treatment in standard disease indications, remains to be determined in further studies.

Adult↗
PubMed2003

Collection of autologous PBSC in patients with polycythemia vera.

BACKGROUND: Allogeneic stem-cell transplantation (SCT) can eradicate myelofibrosis (MF), but is limited by donor availability and toxicity. We previously reported normalization of counts and resolution of MF after ablative, syngeneic SCT in spent phase polycythemia vera (PV). Hence, GvL is not required to eradicate MF. Autologous SCT may advance treatment for spent phase PV by restoring effective hematopoiesis. The influence of organomegaly, myelosuppression and MF on PBSC collection has not been studied in the setting of PV. METHODS: Sixteen patients with PV underwent PBSC collection. Mobilization was with filgrastim alone, with a target cell content of 2.5 x 10(6) CD34(+)/kg. All myelosuppression was discontinued 2 weeks prior to collection. RESULTS: Median ages at diagnosis and collection were 47 and 57 years, respectively. Organomegaly, MF and use of myelosuppressive therapies were present in 10 (63%), 4 (25%) and 7 (44%) patients. Median total nucleated cells (TNC) and CD34(+) counts were 8.3 x 10(8)/kg and 4.98 x 10(8)/kg. MF had an adverse effect on TNC (p=0.05) but not on the CD34(+) content. Time from diagnosis and the use of myelosuppresion had no influence on TNC and CD34(+) contents. Four patients had CD34(+) contents <2.5 x 10(6)/kg. Complete blood count (CBC) parameters were not predictive of CD34(+) content. DISCUSSION: Autologous PBSC collection is feasible in PV several years after diagnosis. Organomegaly and MF are not absolute contraindications for collection. Discontinuing myelosuppresion for 2 weeks before mobilization appears sufficient to collect adequate numbers of CD34(+) progenitors.

Adult↗
PubMed2003

Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas.

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction. This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m2 over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m2 bolus, followed by cisplatin 50-75 mg/m2 over 30 minutes and then infusional 5-FU 600 mg/m2 over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m2 inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.

Adenocarcinoma↗
PubMed1994

Characterization of peripheral blood progenitor cells mobilized by cytotoxic chemotherapy and recombinant human granulocyte colony-stimulating factor.

The purpose of this study was to evaluate the antigenic profile of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) in patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and multiple myeloma (MM). The mobilization regimens consisted of high-dose cytarabine/mitoxantrone for patients with NHL, DexaBEAM for patients with HD, and high-dose cyclophosphamide (4 or 7 g per m2) for patients with MM. Cytotoxic therapy was supported by recombinant human G-CSF (Filgrastim, 300 micrograms/day sc) to shorten the period of neutropenia and to increase the number of circulating hematopoietic progenitor cells. The mean numbers of circulating CD34+ cells/microliters during leukocyte recovery were different between patient groups, 80.5 +/- 9.8 (mean +/- SEM) in low-grade NHL and 51.2 +/- 9.7 in high-grade NHL compared with 31.3 +/- 6.9 in HD and 24.4 +/- 4.1 in patients with MM. As a result, the greatest numbers of CD34+ cells/kg collected per leukapheresis were observed in patients with NHL, whereas the collection efficiency was substantially lower in patients with HD or MM. Patients with MM had also the smallest proportion of CD34+ cells in the mononuclear cell fraction (mean 0.79 +/- 0.10% versus 2.15 +/- 0.19% in low-grade NHL) but the greatest proportion of early CD34+ HLA-DR- progenitor cells (mean 2.38 +/- 0.51 versus 0.84 +/- 14% in low-grade NHL). Patients with MM had a mean proportion of CD34/c-kit+ cells that was twofold greater than that observed in patients with high- or low-grade NHL.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1998

Analysis of engraftment kinetics in pediatric patients undergoing autologous PBPC transplantation.

We sought to analyze factors that affect the engraftment kinetics following autotransplantation with PBPC mobilized by filgrastim (G-CSF). Forty-six consecutive pediatric patients with hematologic malignancies (n = 23) or solid tumors (n = 23) underwent autologous PBPC transplantation after myeloablative therapy. PBPC were mobilized using G-CSF alone. All patients received G-CSF after PBPC infusion. Factors potentially influencing the neutrophil and platelet engraftment were examined using univariate and multivariate analysis. All patients experienced rapid hematopoietic recovery, with a median of 9 days (range 7-15) to achieve a neutrophil count of 0.5 x 10(9)/L and a median of 15 days (range 9-37) to achieve a platelet count of 20 x 10(9)/L. The most important predictive factor of both platelet (p = 0.002) and neutrophil (p = 0.0001) recovery was the number of CD34+ cells infused. Patients receiving > or =5 x 10(6)/kg CD34+ cells had a more rapid hematopoietic recovery (p < 0.001) than those receiving a lower cell dose. The CD34+ cell dose is the most important predictive factor for engraftment kinetics after PBPC transplantation. Although a minimal CD34+ cell dose could not be defined, a dose > or =5 x 10(6)/kg CD34+ cells may be optimal to ensure rapid neutrophil and platelet recovery.

Adolescent↗
PubMed1995

Treatment of Kaposi's sarcoma with liposomal doxorubicin.

The efficacy of liposomal doxorubicin for treating Kaposi's sarcoma (KS) in patients infected with human immunodeficiency virus (HIV) was studied. Eight men with HIV infection and KS were to be given liposomal doxorubicin 20 mg/sq m i.v. monthly for six months and 10 mg/sq m i.v. monthly thereafter, depending on the response. They were assessed for the onset, extent, and duration of clinical response; relapse; adverse effects; development of new opportunistic infections; quality of life; and survival. Five patients had a clinical complete response (i.e., complete resolution of the manifestations of KS, as determined by physical examination but not confirmed by biopsy) and three patients had a partial response to the induction regimen of liposomal doxorubicin. Relapse occurred in all patients in whom therapy was stopped; reinstatement of therapy elicited a partial response. Neutropenia occurred in two patients; filgrastim therapy enabled the liposomal doxorubicin therapy to continue uninterrupted. Thromboembolic events developed or were suspected in three patients, although they may not have been caused by liposomal doxorubicin. Monthly i.v. administration of liposomal doxorubicin partially or completely eliminated the clinical manifestations of Kaposi's sarcoma in eight men infected with HIV.

AIDS-Related Opportunistic Infections↗
PubMed1995

Potential strategies for improving the results of high-dose chemotherapy in patients with metastatic breast cancer.

High-dose chemotherapy (HDC) is the most effective approach for inducing complete remissions in patients with metastatic breast cancer, and although most patients will relapse, a small percentage (10%-15%) achieve durable remissions beyond five years. Additionally, HDC has produced five-year relapse-free survival rates in excess of 70% in patients with stage II breast cancer with > 10 nodes. The use of HDC in breast cancer remains controversial and randomised trials are required to assess the survival impact of this approach. The introduction of haematopoietic growth factors (HGF) and peripheral blood progenitor cells (PBPC) has advanced the use of HDC by reducing treatment-related mortality (from 20% to 5%) and by allowing the development of multiple cycles of intensive therapy. Based on tumour kinetic models we have hypothesised that multiple, rapidly cycled courses of high-dose therapy may improve the rate of durable remission in metastatic breast cancer. The feasibility of this approach has been shown in a series of pilot studies in which one or more courses of high-dose cyclophosphamide and recombinant granulocyte colony-stimulating factor (G-CSF) (filgrastim) were given to obtain PBPC which were then used to support one or more courses of HDC. In successive studies the HDC component consisted of: a single course of carboplatin, etoposide and cyclophosphamide; four courses of carboplatin; tandem courses of thiotepa; or a sequence of melphalan and thiotepa. Promising response rates have been produced in advanced breast and ovarian cancer with the later generation of regiments. These results justify the conduct of prospective randomised trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Haematological support of high-dose sequential chemotherapy: clinical evidence for reduction of toxicity and high response rates in poor risk lymphomas.

The toxicity and feasibility of a high-dose sequential (HDS) chemotherapy programme delivered with growth factor support were evaluated in patients with intermediate and high-grade non-Hodgkin's lymphoma (NHL) or with progressive Hodgkin's disease. The scheme includes the sequential administration of single cytotoxic drugs at very high doses followed by intensified treatment with circulating progenitor autograft. In some instances, the original HDS scheme, initially designed at the Milan Cancer Center, was partially modified and intensified with a preliminary debulking phase. The use of G-CSF (filgrastim) made toxicity in the high-dose phase acceptable and allowed good harvests of peripheral blood progenitor cells (PBPC); the use of PBPC in the final autografting phase resulted in low haematological toxicity. Of 71 patients with NHL treated at our institution with either the original or the intensified HDS version, the overall toxicity-related mortality was 5.6%, thus comparable to lethal toxicity commonly associated with conventional chemotherapy. Adequate PBPC harvests are crucial for good tolerability of the programme. Optimal harvests are generally obtained in patients without neoplastic marrow infiltration while patients with marrow disease often have a poorer mobilisation. However, an optimally time-spaced chemotherapy debulking might also restore sufficient mobilisation in these latter patients. In terms of therapeutic efficacy, HDS had produced promising results since the initial experience in relapsed patients. More recently, HDS was evaluated as first-line treatment in a series of 22 consecutive patients, presenting with advanced-stage, intermediate-grade NHL other than diffuse large cell subtype. A CR rate of 82% was obtained following HDS, with a projected survival of 86% at five years. Thus, delivery of an intensive high-dose chemotherapy programme with haematopoietic growth factor support was found to be feasible and reasonably safe. The high anti-tumour efficacy of such a scheme makes it suitable for wider applicability in all those chemosensitive tumours where a dose increase might enhance the chance of cure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Practical applications for peripheral blood progenitor cells in the treatment of lymphomas and solid tumours.

Autologous blood progenitor cell (BPC) support is used in conjunction with high-dose chemotherapy regimens and also permits the use of increasing dose-intensity schedules of conventional cytotoxic chemotherapy. However, our understanding of the optimal BPC support to be used in these different conditions is incomplete. These difficulties result from the use of different BPC collection procedures in different centres, to different patient populations and considerable variability between patients. For such treatment to be cost effective, greater knowledge is required about the best way of achieving mobilisation, collection, storage and engraftment of BPC. The use of G-CSF in combination with chemotherapy can yield sufficient BPC at a single apheresis to achieve haematopoietic reconstitution after high-dose therapy. This was partly achieved by accurate prediction of the optimum timing of cell collection, which coincided with the early exponential increase in white blood cells (WBC) after the chemotherapy induced nadir. BPC in apheresis product or whole blood from patients primed with chemotherapy and filgrastim (G-CSF) were found to be viable for 48 hours when stored at 4 degrees C. Patients receiving multicyclic ifosfamide, carboplatin and etoposide (ICE) chemotherapy received BPC in apheresis product or whole blood, which had been stored at 4 degrees C, on day 3 of each treatment cycle. Such an approach allowed a 200% increase in dose intensity without any increase in toxicity or the need for supportive care. Optimal use of BPC support may increase the effectiveness of chemotherapy for the common solid tumours.

Cell Separation↗
PubMed2003

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.

Adult↗
PubMed2006

Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma.

We have treated 75 transplant-eligible patients with relapsed or refractory lymphoma using an outpatient-based fractionated regimen of ifosfamide, carboplatin and etoposide (ICE) for both salvage and stem cell mobilisation. Patients included DLBC (n = 33), follicular (n = 23), NK/T-cell (n = 3), mantle cell (n = 3) and Hodgkin's lymphoma (n = 13). Cycles of outpatient ICE were given every 21 days and consisted of: ifosfamide 5000 mg/m(2) i.v. fractionated into three equally divided doses and infused over 2-3 h on days 1-3, carboplatin (mg dose = 5 x AUC) i.v. over 1 h on day 1; and etoposide 100 mg/m(2) i.v. daily on days 1-3, plus filgrastim 5 microg/kg/day. Most patients with indolent lymphoma also received rituximab. The median age of patients was 52 years (range 26-69 years). Patients received a mean of 2.8 cycles of ICE. Non-haematological toxicities included grade 1/2 CNS toxicity in four patients, cardiac toxicity in two, reversible renal impairment and haematuria in one each. Haematological toxicity included grades III/IV thrombocytopenia and neutropenia with at least one cycle of ICE in 71% and 72% of patients, respectively. The median time to PBSC harvest was 14 days (range 10-20 days), while the median CD34(+) cell yield was 4.8 x 10(6)/kg (range 2.3-37.8). Five patients (7%) failed to mobilise PBSCs. The overall response rate to ICE was 89%, comprising 29% who achieved a CR and 60% who achieved a PR; for DLBCL, the overall response rate was 85% including 36% who achieved a CR and 49% who exhibited a PR. At a median follow-up of 24 months, the Kaplan-Meier estimates of the overall and event-free survival for all patients were 65% and 42%, respectively. For patients with DLBCL overall and event-free survival figures were 51% and 35%, respectively, at a median follow-up of 14 months. These data confirm the efficacy and tolerability of outpatient fractionated ICE as both a salvage and mobilisation regimen in relapsed/refractory lymphoma.

Adolescent↗
PubMed2006

A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study.

BACKGROUND: Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 107 patients treated with rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas and identified cases with LON as defined by the neutrophil count of <or=1.0 x 10(9)/l without an apparent cause after the recovery of neutrophil count following completion of the intended chemotherapy. RESULTS: With a median follow-up of 411 days, 23 patients developed LON out of the 107 at a median of 106 days after the last chemotherapy. Cumulative incidence of LON among the total patients was 24.9%. The median neutrophil count nadir was 0.61 x 10(9)/l. The LON episodes were generally self-limited, and filgrastim was administered in one patient. Including this patient, there were no serious infectious episodes in the cases with LON. In multivariate analysis, intensive chemotherapy regimens including high-dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) and high-dose methotrexate-containing regimens without ASCT were a risk factor for LON. CONCLUSION: This study suggests that LON is a frequent complication of rituximab-containing intensive chemotherapy.

Adult↗
PubMed1996

Phase II study of vinorelbine/ifosfamide/cisplatin for the treatment of advanced non-small-cell lung cancer.

PURPOSE: To evaluate the combination of vinorelbine, ifosfamide and cisplatin (VIP) in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-six untreated patients with stages IIIB-IV NSCLC; the chemotherapy regimen consisted of vinorelbine (25 mg/sqm on days 1 and 8), ifosfamide (3 g/sqm on day 1 with uroprotective mesna), and cisplatin (80 mg/sqm on day 1). The cycles were administered on an outpatient basis every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity: grades 3-4 neutropenia was observed in 26% of the cycles and 19 episodes of febrile neutropenia were reported in 289 evaluable courses. Filgrastim 5 micrograms/kg was administered in 27% of the courses. Sixty-seven of 76 patients were evaluable for response: the overall response rate was 51% (95% confidence interval 35%-77%) with 2 complete responses (3%) and 32 (48%) partial responses. No significant differences in response rate were observed according to histology or stage of disease. The median time to progression was 6 months (range 1 to 29+) and the median overall survival 10 months (range 1-33+). CONCLUSION: The combination of vinorelbine, ifosfamide and cisplatin in the dose and schedule employed in this trial shows an interesting response rate with acceptable toxicities. This regimen should be tested in the multimodality therapy of stage IIIA/B NSCLC.

Adult↗