Randomized clinical trials for hematopoietic stem cell transplantation: lessons to be learned from the European experience.

We evaluated the number and characteristics of randomized controlled trials (RCTs) addressing hematopoietic stem cell transplantation (HSCT) for patients with hematological malignancies, comparing the productivity of US and Europe. A MEDLINE search was conducted to identify all published RCTs for the management of adult patients with hematological malignancies from January 1992 to December 2003. Eighty-three of the 306 trials identified included HSCT as one of the treatment arms. The US produced 25, Europe 54, and all other countries four. Four European countries, France, Italy, Germany, and UK (FIGU), produced 32 out of the 54 European studies. Significant differences emerged when focus of the study and accrual numbers were analyzed. Trials comparing HSCT to standard dose therapy represented 34.9% of the 83 trials and 59.4% of FIGU trials, but only 4% of US studies (P = 0.001). US trials accrued a mean of 110.2 patients per study, as compared to 222.6 in FIGU studies (P = 0.006) and 205.3 when all non-US countries are considered (P = 0.01). Our conclusions are that US transplant RCT have focused on issues other than the comparison of HSCT to standard therapies. There is serious paucity of US trials defining the role of HSCT in the management of hematological malignancies.

Adoptive immunotherapy with donor lymphocyte infusions and interleukin-2 after high-dose therapy and autologous stem cell rescue for multiple myeloma.

In an attempt to induce a graft-versus-myeloma effect, we administered donor lymphocyte infusions (DLI) after high-dose therapy with autologous stem cell transplant rescue to seven patients with refractory or relapsed multiple myeloma. High-dose therapy consisted of melphalan, idarubicin and etoposide (days -9 to -6) followed by autologous stem cell infusion on day 0. DLI (five of seven donors with two or three HLA antigens mismatched) were administered on days +1, +5 and +10 along with IL-2 (from day +1 through +12). Six of the seven patients developed acute graft-versus-host disease (GVHD), which resolved spontaneously, coincidentally with autologous hematopoietic reconstitution. One patient failed to engraft and received a second autologous graft. One patient died from complications of a pulmonary hemorrhage after experiencing GVHD. With a minimum follow-up of 38 months, five patients remain without disease progression in complete remission or with minimal residual disease. In this setting, DLI/IL-2 is biologically active resulting in GVHD. A graft-versus-myeloma effect is suggested by the improved outcome of our small cohort of high-risk patients. The use of partially mismatched related donors makes this approach potentially available to nearly all patients.

Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (P = 0.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, P = 0.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153-160.

Collection of peripheral blood progenitor cells (PBPC) based on a rising WBC and platelet count significantly increases the number of CD34+ cells.

The kinetics of mobilization and optimal timing of peripheral blood progenitor cell (PBPC) collection were evaluated in 190 patients with multiple myeloma undergoing stem cell harvest after mobilization with cyclophosphamide, prednisone and G-CSF. There was a strong correlation between the WBC count and the number of CD34+ cells circulating in peripheral blood (r = 0.875). Initiating leukapheresis based on rising WBC and platelet counts rather than on a fixed day increased the mean number of CD34+ cells 115% (9.7 to 20.9 x 10(6) CD34+ cells/kg; P = 0.010) for the total of all leukaphereses and 59% for the total of all CD34-selected products (5.1 to 8.1 x 10(6) CD34+ cells/kg; P = 0.011). Although the yield and purity of the CD34-selected product were not significantly affected (P > or = 0.071), the percentage of patients with concentrations of CD34+ cells in the initial leukapheresis of > 1% increased from 47% to 70% (P = 0.004). The mean purity of the selected product was related to the starting percentage: 48.9% if < 1% and 81.5% if > or = 1% (P < 0.001). Collection of stem cells based on rising WBC and platelet counts significantly increased the number of CD34+ cells in leukaphereses and CD34-selected products in comparison with collection on a fixed day.

Multicenter phase III trial to evaluate CD34(+) selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma.

High-dose chemotherapy followed by autologous transplantation has been shown to improve response rates and survival in multiple myeloma and other malignancies. However, autografts frequently contain detectable tumor cells. Enrichment for stem cells using anti-CD34 antibodies has been shown to reduce autograft tumor contamination in phase I/II studies. To more definitively assess the safety and efficacy of CD34 selection, a phase III study was completed in 131 multiple myeloma patients randomized to receive an autologous transplant with either CD34-selected or unselected peripheral blood progenitor cells after myeloablative therapy. Tumor contamination in the autografts was assessed by a quantitative polymerase chain reaction detection assay using patient-specific, complementarity-determining region (CDR) Ig gene primers before and after CD34 selection. A median 3.1 log reduction in contaminating tumor cells was achieved in the CD34 selected product using the CEPRATE SC System (CellPro, Inc, Bothell, WA). Successful neutrophil engraftment was achieved in all patients by day 15 and no significant between-arm difference for time to platelet engraftment occurred in patients who received an infused dose of at least 2.0 x 10(6) CD34(+) cells/kg. In conclusion, this phase III trial demonstrates that CD34-selection of peripheral blood progenitor cells significantly reduces tumor cell contamination yet provides safe and rapid hematologic recovery for patients receiving myeloablative therapy.

Broadened clinical utility of gene gun-mediated, granulocyte-macrophage colony-stimulating factor cDNA-based tumor cell vaccines as demonstrated with a mouse myeloma model.

Effective immunization against the murine B16 melanoma by a nonviral approach in which a gene gun is used to transfer GM-CSF cDNA into tumor cells has been described. We have extended this nonviral approach by using the poorly immunogenic murine myeloma MPC11 model. Vaccination with the transfected, GM-CSF-expressing MPC11 cells induced a potent antitumor cytotoxic T lymphocyte response associated with tumor rejection in the majority of the test mice. Furthermore, nearly 100% (27 of 28) of the tumor-free mice were able to reject a tumor rechallenge. While this approach is clinically attractive because of minimal tissue manipulation/culturing and the absence of infectious agents, a number of tested human primary tumors, including myeloma cells, have failed to produce high levels of GM-CSF after gene gun transfection. To circumvent the low transfection efficiency in certain human tumor cells, we showed that combining irradiated tumor cells to provide tumor antigens together with gene gun-transfected fibroblasts to provide GM-CSF induced effective tumor rejection. We also report that normal human skin fibroblasts transfected by the gene gun produce high levels of human GM-CSF (250 ng/10(6) cells/24 hr). These results suggest that combining irradiated tumor cells with gene gun-transfected fibroblasts results in antitumor immune responses and may allow for a wider application of this approach to cancer immunotherapy.

Defining the role of novel high-dose chemotherapy regimens for the treatment of high-risk breast cancer.

We have explored several novel high-dose combinations in an attempt to increase antitumor activity while decreasing treatment-related toxicity. From October 1989 through June 1997, we performed phase I/II dose-escalation trials exploring novel high-dose regimens including ifosfamide/carboplatin/etoposide, mitoxantrone/thiotepa, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/mitoxantrone/thiotepa. We have also evaluated busulfan/cyclophosphamide and cyclophosphamide/thiotepa/carboplatin in phase II trials. Three hundred ninety-three patients have been treated in these trials and followed for a minimum of 3 months. Event-free survival (including relapses and treatment-related mortality; +/-SE) at 3 years by stage and chemosensitivity is as follows: stage II, four to nine positive nodes (n=16), 52%+/-17%; stage II, greater than nine nodes (n=30), 46%+/-11%; stage III (n=59), 50%+/-8%; inflammatory stage III (n=15), 27%+/-17%; stage IV, anthracycline responsive (n=69), 19%+/-5%; stage IV, anthracycline refractory but responsive to salvage therapy with ifosfamide, carboplatin, and etoposide or paclitaxel (n=53), 12%+/-6%; stage IV, refractory (n=128), 5%+/-2%; and stage IV, not evaluable for response (n=23), 10%+/-8%. Treatment-related mortality was 4% for both phase I and II studies involving stage II breast cancer patients, 5% for stage III breast cancer, 15% for inflammatory breast cancer, and 18% for all stage IV breast cancers, responsive and refractory. We conclude that high-dose therapy for the treatment of high-risk early stage breast cancer or metastatic breast cancer results in durable remissions. Chemosensitivity to induction regimens remains the most important prognostic indicator, although long-term survival has been seen even in patients with highly refractory disease. Further studies are necessary to define optimal high-dose strategies based on stage and chemosensitivity of disease.

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.

PURPOSE: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS: Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Nephrotoxicity of high-dose ifosfamide/carboplatin/etoposide in adults undergoing autologous stem cell transplantation.

The objective of this study was to evaluate nephrotoxicity in adult patients treated with high-dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation. We conducted a retrospective analysis of clinical and laboratory data from 131 patients with various malignancies who received treatment with escalating doses of ifosfamide, carboplatin, and etoposide followed by autologous stem cell transplantation as part of a phase I/II therapeutic trial. Abnormalities in glomerular filtration were evaluated by measuring peak creatinine levels and tubular dysfunction by the lowest recorded serum levels of potassium, magnesium, and bicarbonate, at different time periods after administration of ifosfamide, carboplatin, and etoposide, and after autologous stem cell transplantation. For the entire group of 131 patients, peak creatinine levels were > 1.5 mg/dL but < 3.0 mg/dL in 37% and levels were > 3.0 mg/dL in 11% at some time during their hospital stay. At the time of discharge, creatinine levels were 1.6 mg/dL to 3.0 mg/dL in 25% of patients and were > 3 mg/dL in 5%. Immediately after high-dose therapy, peak creatinine levels were significantly higher in patients receiving higher doses of ifosfamide compared to those receiving lower doses (P < 0.00001) and those receiving intermediate doses (P < 0.005). There was a dramatic decrease in serum bicarbonate, potassium, and magnesium levels immediately after chemotherapy, and they remained significantly decreased throughout the patient's hospital stay, despite massive replacement efforts (P ranging between < 0.008 and < 0.001). This is the largest adult population study documenting the incidence and severity of ifosfamide/carboplatin/etoposide-associated acute nephrotoxicity. Renal dysfunction was dose related and reversible in the majority of patients.

Assessment of intracellular TAP-1 and TAP-2 in conjunction with surface MHC class I in plasma cells from patients with multiple myeloma.

Immunotherapy involving cytotoxic T lymphocytes (CTLs) is an attractive alternative for treatment of various malignancies, including multiple myeloma. For tumour cells to be recognized and killed by CTLs they must express cell surface major histocompatibility complex (MHC) class I molecules and the transporter associated with antigen processing (TAP). However, loss of MHC class I and the TAP protein are common among several types of solid tumours. This study assessed the expression of TAP protein (by intracellular flow cytometry) and cell surface MHC class I molecules in three human myeloma cell lines as well as the plasma cell population (CD38+ bright) in bone marrow specimens from 13 multiple myeloma patients. In all of the patients, 100% of the plasma cell population expressed both the TAP subunits and cell surface MHC class I molecules, but at varying intensities. Both TAP and MHC class I were also expressed in the three myeloma lines. Additionally, the function of the antigen transport machinery was evaluated by a peptide transporter assay in the three myeloma lines. TAP transporter activity was readily detectable in two out of three myeloma lines, whereas the diminished activity in the third cell line was completely restored by co-culturing with recombinant interferon-gamma (rIFN-gamma).

Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC-IE): a novel, intensive induction chemotherapy regimen for patients with high-risk multiple myeloma.

We evaluated toxicities and responses to a novel, dose intensive and time sequenced, chemotherapy programme (DC-IE) in 45 patients with high-risk myeloma. DC-IE consisted of: dexamethasone (days 1-4); cyclophosphamide (day 5); idarubicin and etoposide (days 8-10). Complete response (CR) was achieved in four patients, six patients achieved near complete responses (nCR) and 21 patients achieved a partial remission (PR). Overall response rate was 76% (CI 56-94%) for newly diagnosed patients (n = 21) and 62% (CI 36-81%) for relapsed/refractory patients (n = 24). Toxicities were limited to myelosuppression; two patients died of sepsis during neutropenia (4%). DC-IE is active and tolerable for high-risk multiple myeloma, including patients with relapsed or refractory disease to anthracycline containing regimens.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group.

BACKGROUND: Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS: Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS: Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

Effect of haemoglobin and endogenous erythropoietin on hypothalamic-pituitary thyroidal and gonadal secretion: an analysis of anaemic (high EPO) and polycythaemic (low EPO) patients.

OBJECTIVE: Correction of anaemia with recombinant human erythropoietin (rHu-EPO) improves the responsiveness of thyroidal and gonadal axes to exogenous TRH and GnRH in chronic haemodialysis patients, but the mechanisms remain to be fully elucidated. In order to assess the influences of endogenous erythropoietin on the hypothalamo-hypophyseal thyroidal and gonadal axes, we studied the response of polycythaemic and anaemic patients, in comparison to normal controls, after the administration of exogenous TRH and GnRH. DESIGN: Exogenous hypothalamic factors, 500 micrograms TRH and 100 micrograms GnRH, were administered as a bolus and blood samples were obtained over a 3-hour period at 30, 60, 90, 120 and 180 minutes. PATIENTS: Five male polycythaemic patients (low EPO), three male anaemic patients (high EPO) and six normal age and sex matched controls were studied. MEASUREMENTS: Blood samples were centrifuged immediately and the serum was stored at -20 degrees C until assayed for total T4, free T4, free T3, TSH, prolactin, growth hormone (TRH test), and FSH, LH, testosterone (GnRH test). Haematological parameters and biochemical profiles were also measured. RESULTS: After TRH administration, both patient groups showed a normal TSH response; however, their free T4 and free T3 secretion was blunted compared to controls. Normal basal PRL levels increased in an exaggerated fashion, whereas, when compared to chronic renal failure patients on chronic haemodialysis, we did not see a paradoxical GH response or a basal GH increase in these 5 patients. GnRH administration in the study groups elicited a normalization in the LH response without an increase in testosterone levels; however, an exaggerated FSH response was found in the polycythaemic patients (low EPO). CONCLUSIONS: Thus by investigating the role of low endogenous EPO levels in non-anaemic and anaemic patients with high EPO levels, our study suggests that the underlying chronic disease state may be the major contributing factor in the regulation of the hypothalamo-hypophyseal thyroid and gonadal axes, rather than the EPO levels.

Maximum-tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem-cell rescue: toxicity profile.

PURPOSE: A phase I dose-escalation study of ifosfamide, carboplatin, and etoposide (ICE) with autologous stem-cell rescue (ASCR) was conducted to determine the maximum-tolerated dose (MTD) of ICE given over 6 days. PATIENTS AND METHODS: One hundred fifty-four patients with a variety of poor-prognosis malignancies received escalating doses of ifosfamide 6,000 to 24,000 mg/m2, carboplatin 1,200 to 2,100 mg/m2, and etoposide 1,800 to 3,000 mg/m2 divided over 6 days. Mesna was administered in a dose equal to ifosfamide. ASCR was performed 48 hours after the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cells (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy. RESULTS: The MTD of the ICE regimen is 20,100 mg/m2 of ifosfamide, 1,800 mg/m2 of carboplatin, and 3,000 mg/m2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine levels were noted in 29% of patients treated at the upper dose levels. Forty-six patients were treated at the MTD. Severe, reversible mucositis and enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absolute neutrophil count > or = 0.5 x 10(9)/L, to a platelet count > or = 20 x 10(9)/L, and to discharge were 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment. CONCLUSION: ICE is well tolerated, with acceptable hematopoietic side effects and predictable organ toxicity.