|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Ifosfamide, Carboplatin, and Etoposide: A Highly Effective Cytoreduction and Peripheral-Blood Progenitor-Cell Mobilization Regimen for Transplant-Eligible Patients With Non-Hodgkin's LymphomaFrom the Lymphoma and Hematology Services, Department of Medicine, and Departments of Radiotherapy, Pathology, and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Craig H. Moskowitz, MD, Memorial Sloan-Kettering Cancer Center, Box 350, 1275 York Ave, New York, NY 10021; email amoskowiz{at}mskcc.org
PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granuloctye colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34+ cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P = .003). The median number of CD34+ cells/kg collected was 8.4 x 106. The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.
THE INCIDENCE OF non-Hodgkin's lymphoma (NHL) has increased in recent years at a rate faster than any noncutaneous malignancy, with 56,800 cases expected in 1998. Despite advances in therapy, approximately 26,000 people died from NHL in 1998.1 Results indicate that 40% to 60% of patients with NHL either fail to achieve a complete remission or relapse after receiving standard front-line therapy. High-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT) has been the most successful therapeutic approach for patients with relapsed intermediate-grade NHL with chemosensitive disease, and multiple studies have defined chemosensitivity as the most important predictor of long-term event-free survival (EFS).2-5 Mobilized peripheral-blood progenitor cells (PBPCs) have largely replaced stem cells collected from the bone marrow as the stem-cell source for high-dose therapy. Initially, high-dose cyclophosphamide at varying doses followed by granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor was the most common method of PBPC mobilization.6 However, more recently, PBPC mobilization has also used specific, second-line, antilymphoma chemotherapy regimens such as etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHAP; mesna, ifosfamide, mitoxantrone, and etoposide–ESHAP) or dexamethasone, cisplatin, and cytarabine (DHAP) in combination with hematopoietic growth factors.7,8 These regimens have major response rates of 45% to 65% when administered for up to six cycles (or for approximately 18 weeks). Some second-line regimens, such as those containing high-dose cytarabine, are associated with poor mobilization of CD34+ cells.9 Other regimens, eg, those containing cisplatin, may have significant nonhematologic toxicity, making subsequent transplantation more difficult.10 Cytoreductive regimens such as mini–carmustine, etoposide, cytarabine, and melphalan (BEAM) (or dexa-BEAM) have a similar response rate (40% to 55%), but these regimens contain both carmustine and melphalan, which are known stem-cell—toxic chemotherapeutic agents.11,12 Because of this significant hematologic toxicity, several groups have demonstrated an inability to collect an adequate number of PBPCs after administration of these regimens.13-15 In 1993, we developed a regimen of infusional ifosfamide with bolus carboplatin and etoposide (ICE) plus G-CSF for cytoreduction and PBPC mobilization in patients with primary refractory or relapsed NHL. The goals of this pretransplant cytoreductive regimen were to attain a significant response (complete response [CR] and partial response [PR]) in at least 50% of patients, with limited nonhematologic side effects, and to allow collection of at least 2.0 x 106 CD34+ cells/kg. We treated 163 patients with NHL with ICE chemotherapy from October 1993 to December 1997, and report that the ICE regimen has a high response rate in patients with either relapsed or primary refractory NHL. Furthermore, ICE chemotherapy followed by G-CSF at 10 µg/kg is an excellent PBPC-mobilizing regimen with minimal toxicity in patients with pretreated lymphoma.
Patients One hundred sixty-three consecutive transplant-eligible patients with relapsed or primary refractory NHL at Memorial Sloan-Kettering Cancer Center were treated from October 1993 to December 1997 with ICE chemotherapy. The first 36 patients were treated on an institutional review board—approved protocol for relapsed and refractory intermediate-grade NHL or immunoblastic lymphoma after informed consent was obtained. The response data on these patients were previously reported as part of a prognostic model for transplantation.16 The remaining 127 consecutive patients received ICE chemotherapy on protocol or as standard of care.
Eligibility for ICE Chemotherapy
Eligibility for High-Dose Therapy and ASCT
ICE Second-Line Chemotherapy Treatment Program
Stem-Cell Collection (PBPC) Mobilization For each apheresis, 10 L of blood was processed over a 2.5- to 3-hour time period (median number of blood volumes processed per collection, 1.9; range, 1.4 to 3.4). Bone marrow collections were performed for all patients who mobilized less than 4 x 106 CD34+ cells/kg. If less than 2 x 106 CD34+ cells/kg were obtained, both PBPCs and bone marrow cells were reinfused. In patients who mobilized more than 6 x 106 CD34+ cells/kg, a minimum of 2 x 106 CD34+ cells/kg was stored for future use, if necessary. Before cryopreservation, mononuclear cells in each leukapheresis collection were analyzed for CD34 expression using flow cytometry as previously described.16 All hematopoietic progenitor cell components (bone marrow, buffy coat, or leukapheresis product) were frozen within 24 hours of collection using 5% DMSO (Cryoserv; Research Industries Corporation, Salt Lake City, UT), 6% hydroxyethyl starch (Pentastarch; McGaw Inc, Irvine, CA), and 4% serum albumin (Albuminar-25; Armour Pharmaceutical Co, Kankakee, IL) as the cryopreservation solution (final concentrations). Components were placed in a -90°C electrical freezer overnight and then transferred to a -135°C electrical freezer for storage.
Patients Treated With Investigational Cytokines
Patients Who Received Allotransplant
Statistical Methodology The outcome variables examined were as follows: (1) overall survival, defined from the time of initiation of ICE chemotherapy to date of last follow-up evaluation or death; (2) EFS, defined from the time of initiation of ICE chemotherapy until treatment failure (including < 50% response to ICE, ICE-related toxicity, and subsequent inability to be re-treated with ICE), failure after transplant or death from another event; (3) ICE response (CR or PR v failure); and (4) number of CD34+ cells collected after ICE treatment. Survival curves were estimated using the method of Kaplan and Meier and were compared across ICE response groups using the log-rank test.21
Prognostic variable analyses for ICE response.
Univariate analyses were performed using All prognostic factors associated with ICE response based on a univariate (P < .10) criterion were entered into a multivariate logistic regression model. A stepwise elimination procedure was used to restrict further the subset of variables associated with ICE response. One hundred sixty-three patients were available for this analysis.22,23 Prognostic variable analyses for CD34+ cells collected (mobilization). Univariate analyses were performed using the Pearson correlation coefficient and t test to examine the association between the number of CD34+ cells collected after ICE therapy and the following five potentially prognostic variables: age, WBC count at time of first collection, platelet count at time of first collection, bone marrow involvement (yes v no), and previous treatment regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or CHOP-like v NHL-15 [a chemotherapy regimen developed at Memorial Sloan-Kettering Cancer Center]).24,25 One hundred patients were available for this analysis.
Patient Characteristics One hundred sixty-three consecutive patients with primary refractory NHL and NHL in first relapse were evaluated for ICE response, toxicity, PBPC mobilization, EFS, and overall survival. The intent was that all patients would undergo potentially curative high-dose chemoradiotherapy and transplantation; however, only patients who achieved a CR or PR to ICE were eligible for the transplant phase of the program. All patients are included in the EFS and overall survival analyses.
Patient characteristics before the initiation of ICE chemotherapy are listed in Table 1. There were 109 men and 54 women. The median age was 46 years; 13% of patients were older than 60 years. A poor KPS (
EFS and Overall Survival Analyses
ICE Response
Transplant Data
PBPC Analysis Potential variables affecting mobilization included age, WBC count at initiation of apheresis, platelet count at the initiation of apheresis, bone marrow involvement with NHL, and type of initial chemotherapy (CHOP v NHL-15). In univariate analyses, none of these factors reached statistical significance.
ICE Toxicity
Hematologic Toxicity
Grade 4 neutropenia with hospitalization occurred in 12.9% of the 381 cycles of ICE administered. The source of infection was identified for only 14% of the hospitalizations (one case of pneumonia and six cases of bacteremia). Twenty-five patients had their treatment delayed because of grade 4 neutropenia. The pattern of neutropenia produced by ICE was brief (2 to 4 days), with nadirs occurring 7 to 9 days after the beginning of a cycle. Anemia was common, and RBC transfusions were administered to 98 of 163 patients. In cycle one, 43 of 163 patients received an RBC transfusion; the median number of RBC transfusions was two (range, one to nine). In cycle two, 47 of 127 patients received a median of two RBC transfusions (range, one to 10). In cycle three, 43 of 119 patients received a median of two RBC transfusions (range, one to 11). Seven patients required RBC transfusions after each cycle of ICE.
Nonhematologic Toxicity Cardiac toxicity was rare, with one case each of congestive heart failure and supraventricular tachycardia. Neither patient was re-treated with ICE, and both are included as treatment failures. Neurologic toxicity was evident in five patients. There was one case of self-limited peripheral neuropathy, and four patients developed confusion. Each patient with confusion underwent a formal neurology consultation and a computed tomography scan of the brain. The diagnosis in each case was chemotherapy-induced encephalopathy secondary to ifosfamide. Although these symptoms resolved without intervention, no patient was re-treated with ICE. These four patients are included as treatment failures.
A
Prognostic Factor Analyses for ICE Response
Univariate analysis determined that histology may be an important prognostic factor before second-line chemotherapy; however, the multivariate logistic regression model showed no significant association between histology and ICE response. This may be because of the fact that 118 of 163 patients (72.3%) had diffuse large-cell lymphoma, B-cell phenotype. Among the 17 patients with follicular center cell lymphoma, 16 had either a CR or PR to ICE. Furthermore, 11 of these 17 patients are event-free at 40 months. This is in contradistinction to the 19 patients with peripheral T-cell lymphoma: 11 patients responded to ICE but only one patient is event-free (Table 5). Further studies are needed to address the specific role of ICE in patients with these two histologies.
Multiple phase II studies have demonstrated that high-dose therapy with ASCT can cure a subset of patients with chemoresponsive intermediate-grade NHL.3-5 The Parma study, a randomized trial that compared six cycles DHAP chemotherapy with two cycles of DHAP followed by high-dose therapy and autologous bone marrow transplant (ABMT), clearly demonstrated that high-dose therapy and ABMT improves EFS and overall survival in patients with chemotherapy-sensitive relapsed intermediate-grade NHL.2 Although patients who underwent ABMT in the Parma trial had improved EFS, the patient population was atypical in that two groups were excluded: those with primary refractory intermediate-grade NHL and those with bone marrow involvement. Many reported studies have determined that these two groups of patients comprise up to 50% and 25%, respectively, of patients entering a second-line treatment program using cytoreductive chemotherapy with PBPC mobilization followed by high-dose chemoradiotherapy and ASCT.4,5,26,27 In the current study, 48% of patients had primary refractory NHL, and 33% had bone marrow involvement. The Parma trial confirmed the efficacy of the DHAP regimen in patients with relapsed NHL with a 58% overall response rate after two courses of therapy, although, as with other second-line regimens, hematologic toxicity was common. Unfortunately, renal insufficiency was observed in 20% of patients, defined as a doubling of the patient's serum creatinine level. Investigators at the Fred Hutchinson Cancer Center gave one to six cycles of the DHAP regimen before planned bone marrow transplantation to 39 refractory NHL patients and confirmed a response rate of 67%; however, only 17 patients were able to receive high-dose therapy and ABMT.10 The "second-generation" treatment program of ESHAP has an equivalent CR rate with less myelotoxicity than DHAP, but the incidence of renal insufficiency was unchanged. In addition, both treatment programs had toxic death rates of more than 5%, and neither is a particularly effective PBPC-mobilizing regimen.7-9 We and other investigators have shown that patients who have received more than 7.5 g cytarabine before PBPC mobilization commonly have inadequate numbers of CD34+ cells/kg collected.9,20,28 Mini-BEAM (or dexa-BEAM) has been used extensively as a salvage regimen before ASCT, with response rates of 40% to 55%; a higher response rate was observed in patients who had experienced treatment failure with only one prior chemotherapy regimen. Unfortunately, the stem-cell toxic drugs carmustine and melphalan are part of this treatment program, and it is difficult to collect sufficient numbers of PBPCs after therapy, especially when more than one cycle of therapy is administered. For example, after one cycle of dexa-BEAM, a median of 5.1 x 106 CD34+ cells/kg are collected, but yields after subsequent cycles are poor (median, 1.6 x 106 CD34+ cells/kg).13-15 Furthermore, prior therapy with mini-BEAM compromises any future attempts at PBPC mobilization with other standard regimens such as ICE.28 Therefore, as a pretransplant cytoreductive/mobilization regimen, the toxicity of this regimen may be prohibitive. Common practice in the United States is to use chemosensitivity as a prerequisite for transplant eligibility in patients with relapsed lymphoma. Therefore, it is critical that a cytoreductive regimen has a high response rate with limited nonhematologic toxicity while at the same time providing an adequate PBPC collection. The ICE combination has been evaluated by a number of groups in the treatment of lymphoma. Phase I data from the National Cancer Institute has determined that the maximally tolerated dose of these agents when given with bone marrow support is 16 g/m2 for ifosfamide, 1.8 g/m2 for carboplatin, and 1.5 g/m2 for etoposide.29 When administered in nonmyeloablative doses, a variety of doses and schedules has been used with response rates in small studies ranging from 50% to 68%.30,31 The current study represents a large experience with a fixed regimen. The ICE regimen was designed as a short-course, dose-intensive, cytoreductive/mobilization regimen for patients with NHL. The goal was to reduce tumor burden, demonstrate chemosensitivity, and collect an adequate number of CD34+ cells/kg for a potentially curative transplant. We hoped to minimize nonhematologic toxicity to permit all responding patients to enter the transplant part of the treatment program. To minimize nephrotoxicity, we used carboplatin rather than cisplatin, which is included in a similar regimen (decadron, bolus ifosfamide, cisplatin, and etoposide).32 With this similar regimen, the incidence of renal insufficiency was 18%. In addition, we administered ifosfamide as a 24-hour infusion with the hope of decreasing the incidence of ifosfamide-induced encephalopathy, which has been reported to occur in up to 17.8% of patients who receive bolus administration.33-35 The response rate to ICE was 66.3%, with 24% of the patients achieving a CR and 42.3% achieving a PR, which compares favorably to results with other second-line regimens. The median time to deliver these three cycles was 5.5 weeks, compared with up to 18 weeks for other second-line regimens. In fact, the entire program, consisting of three cycles of ICE, PBPC collection, boost radiation therapy to bulky sites of disease, high-dose chemoradiotherapy, stem-cell infusion, and hematopoietic recovery, took a median of 12 weeks to complete. As expected, patients who did not respond to ICE fared poorly and had a median survival duration of only 5 months. The ability to mobilize PBPCs is a critical requirement for a second-line chemotherapy regimen. Although the optimal number of CD34+ cells/kg needed for marrow reconstitution is unclear, most studies demonstrate that at least 2 x 106 CD34+ cells/kg are needed for consistent early platelet engraftment, fewer platelet transfusions, and shorter hospitalizations.36 In addition, for patients whose transplant conditioning regimen uses total-body irradiation, 4 to 6 x 106 CD34+ cells/kg may be a more optimal number.28 The median number of CD34+ cells/kg collected after ICE and G-CSF was 8.4 x 106, and 86% of patients mobilized more than 2 x 106 CD34+ cells/kg. In addition, 61% of patients mobilized more than 6 x 106 CD34+ cells/kg. This compares favorably to either the DHAP (ESHAP) or dexa-BEAM (mini-BEAM) regimens, where the median number of CD34+ cells/kg collected was 3.6 and 1.6, respectively.9,13 In addition, because purging the PBPC product results in loss of up to 50% of the CD34+ cells, most centers recommend that at least 6 x 106 CD34+ cells/kg be placed on a CD34+ selection device to get an adequate yield after purging.37 Sixty-one percent of patients who received ICE plus G-CSF achieved that target with only one to three apheresis procedures. Therefore, the ICE regimen may be the regimen of choice, if antilymphoma cytoreductive therapy is coupled with mobilization and purging. Nonhematologic toxicity of the ICE regimen was minor, and no toxic deaths occurred in 163 patients. There was one case of reversible and mild renal insufficiency, and only four patients experienced encephalopathy (2.5%). Trials have been conducted with investigational cytokines in an attempt to reduce the incidence and magnitude of thrombocytopenia.38 Patients with primary refractory disease, multiple extranodal sites of disease and a poor KPS faired less well with this treatment program. Prognostic factors associated with a poor outcome in other reports include some measure of tumor burden (lactate dehydrogenase, disease stage, or extranodal sites) and/or primary refractory disease.5,16,26,27 Predictors of poor response seem to be consistent in multipletrials; thus, therapy for these high-risk patients requires new strategies. In conclusion, our data suggest that three cycles of ICE, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects and with carboplatin rather than cisplatin to minimize nephrotoxicity, for cytoreduction and mobilization of PBPCs, provides effective and clearly less toxic therapy than other reported regimens. ICE has excellent antitumor activity against NHL in both the relapsed and primary refractory setting, with minimal nonhematologic side effects. The timing of PBPC mobilization is predictable with the ICE regimen. Because the yield of CD34+ cells/kg is superior than with other antilymphoma chemotherapy/cytokine regimens, the ICE/G-CSF regimen will allow us to evaluate the potential role of purging PBPCs in NHL in the context of an intent-to-treat program encompassing ICE second-line chemotherapy followed by high-dose chemoradiotherapy and purged PBPCs.
Supported in part by Paul Singer Lymphoma Research Fund, The DeWitt Wallace Fund, and grant no. 5P01CA05826-34 from the National Institutes of Health, Bethesda, MD.
1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1998. CA Cancer J Clin48:6-29, 1998[Abstract]
2.
Philip T, Guglielmi C, Hagenbeek A, et al: ABMT as compared with salvage chemotherapy in relapses of chemotherapy sensitive NHL. N Engl J Med333:1540-1545, 1995 3. Philip T, Armitage JO, Spitzer G, et al: High dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate or high grade NHL. N Engl J Med316:1493-1498, 1987[Abstract] 4. Gulati S, Yahalom J, Acaba L, et al: Treatment of patients with relapsed and resistant NHL using total body irradiation, etoposide, and cyclophosphamide and ABMT. J Clin Oncol10:936-943, 1992[Abstract]
5.
Vose JM, Anderson JR, Kessinger A, et al: High dose chemotherapy and ASCT for aggressive NHL. J Clin Oncol11:1846-1853, 1993 6. Gianni AM, Siena S, Bregni M, et al: GM-CSF to harvest circulating hematopoietic stem cells for autotransplantation. Lancet334:580-584, 1989
7.
Velasquez WS, Cabanillas F, Salavador P, et al: Effective salvage therapy for lymphoma with cisplatin in combination with high dose Ara-C and dexamethasone (DHAP). Blood71:117-122, 1988
8.
Velasquez WS, McLaughlin P, Tucker W, et al: ESHAP: An effective chemotherapy regimen in refractory and relapsing lymphoma. J Clin Oncol12:1169-1176, 1994 9. Oliveri A, Offidani M, Ciniero L, et al: DHAP regimen plus G-CSF as salvage therapy and priming for blood progenitor cell collection in patients with poor prognosis lymphoma. Bone Marrow Transplant16:85-93, 1995[Medline] 10. Press OW, Livingston R, Mortimer J, et al: Treatment of relapsed NHL with dexamethasone, high dose cytarabine and cisplatin before BMT. J Clin Oncol9:423-431, 1991[Abstract]
11.
Girouard C, Dufresne J, Imrie K, et al: Salvage chemotherapy with mini-BEAM for relapsed or refractory NHL prior to ABMT. Ann Oncol8:675-681, 1997 12. Reiser M, Josting A, Dias P, et al: Dexa-BEAM is not effective in patients with relapsed or resistant aggressive NHL. Leukemia Lymphoma33:305-312, 1999 13. Kroger N, Zeller W, Fehse N, et al: Mobilizing peripheral blood stem cells with high dose G-CSF alone is as effective as with Dexa-BEAM plus G- CSF in lymphoma patients. Br J Hematol102:1101-1106, 1998[Medline]
14.
Dreger P, Kloss M, Peterson B, et al: Autologous progenitor cell transplantation: Prior exposure to stem cell toxic drugs determines yield and engraftment of PBPCs but not of bone marrow grafts. Blood86:3970-3978, 1995 15. Dreger P, Marquardt P, Haferlach T, et al: Effective mobilization of PBPCs with Dexa-BEAM and G-CSF: Timing of harvesting and composition of the leukapheresis product. Br J Cancer68:950-957, 1993[Medline] 16. Moskowitz CH, Nimer SD, Glassman JR, et al: The International Prognostic Index predicts for outcome following ASCT in relapsed and primary refractory NHL. Bone Marrow Transplant23:561-567, 1999[Medline] 17. The National Cancer Institute sponsored study of classification of NHL: Summary and description of a working formulation for clinical usage—The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer49:2112-2122, 1982[Medline]
18.
Harris NL, Jaffee ES, Stein H, et al: A revised European-American classification for lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood84:1361-1392, 1994 19. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol7:1748-1754, 1989[Abstract]
20.
Moskowitz CH, Stiff PS, Gordon MS, et al: Recombinant methionyl stem cell factor and filgrastim for PBPC mobilization and transplantation in non-Hodgkin's lymphoma patients: Results of a phase I/II trial. Blood89:3136-3147, 1997 21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assos53:457-481, 1958 22. SAS Institute Inc: SAS/STAT User's Guide, Version 6, Volume 2. Cary, NC, SAS Institute, 1989, chapter 26 23. Hosmer DW Jr, Lemeshow S: Applied Logistic Regression. New York, NY, Wiley, 1989, pp 38-81 24. O'Brien JP O'Keefe P Alvarez A, et al: The NHL-15 protocol for diffuse aggressive lymphomas: Two year median follow-up on the first 100 patients. Proc Am Soc Clin Oncol14:1230, 1995 (abstr) 25. Collett D: Modelling Survival Data in Medical Research. London, United Kingdom, Chapman and Hall, 1994, chapter 3, pp 53-106 26. Prince HM, Imrie K, Crump M, et al: The role of intensive therapy and ASCT for chemotherapy sensitive relapsed and primary refractory NHL: Identification of major prognostic groups. Br J Hematol92:880-889, 1996[Medline] 27. Kreuk AM, Ossenkoppele GJ, Meijer CJLM, et al: Prognostic factors for survival of NHL patients treated with high dose therapy and ABMT. Bone Marrow Transplant17:963-970, 1996[Medline]
28.
Moskowitz CH, Glassman JR, Wuest D, et al: Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. Clin Cancer Res4:311-316, 1998
29.
Wilson WH, Jain V, Bryant G, et al: Phase I and phase II study of high-dose ifosfamide, carboplatin and etoposide with autologous bone marrow rescue in patients with lymphomas and solid tumors. J Clin Oncol10:1712-1722, 1992 30. Wheeler C, Shulman LN, Elias A, et al: Sequential ifosfamide, carboplatin and etoposide with steroids and cyclophosphamide/G-CSF mobilized PBPC support (SPICE) in relapsed lymphoma. Proc Am Soc Clin Oncol14:913, 1995 (abstr) 31. Vose JM: Dose-intensive ifosfamide for treatment of NHL. Semin Oncol23:33-37, 1996 (suppl 6) 32. Haim N, Ben Shahar M, Faraggi N, et al: DICE as second line therapy in patients with NHL. Cancer80:1989-1996, 1997[Medline] 33. Meanwell CA, Blake AE, Blackledge G, et al: Encephalopathy associated with ifosfamide/mesna therapy. Lancet1:406-407, 1985[Medline] 34. Antman KH, Elias A, Ryan L: Ifosfamide and mesna: Response and toxicity at standard and high dose schedules. Semin Oncol17:68-73, 1990 (suppl 4) 35. Cerny T, Castiglione M, Brunner K, et al: Ifosfamide by continuous infusion to prevent encephalopathy. Lancet335:175, 1989 (letter) 36. Schmitz N, Linch DC, Dreger P, et al: Randomized trial of filgrastim-mobilized PBPCT vs ABMT in lymphoma patients. Lancet347:353-357, 1996[Medline]
37.
Vescio R, Schiller G, Stewart AK, et al: Multicenter phase III trial to evaluate CD34+ selected vs. unselected PBPCT in multiple myeloma. Blood93:1858-1868, 1999 38. Moskowitz CH, Nimer SD, Gabrilove J, et al: A randomized, double blind placebo controlled trial of PEG-MGDF in NHL patients receiving ICE. Proc Am Soc Clin Oncol17:295, 1998 (abstr) Submitted May 5, 1999; accepted August 10, 1999. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
1.5 mg/dL (or creatinine clearance 
60 mL/min). Some patients with follicular center cell or mantle-cell lymphoma had received more than one prior chemotherapy regimen before the institution of ICE chemotherapy. Patients older than 60 years received ICE only if they had a Karnofsky performance status (KPS) of 
2 tests and t tests to examine the association between ICE response and the following eight potentially prognostic variables: disease stage (I/II v III/IV), number of extranodal sites (
