57 results on '"Appelbaum F"'
Search Results
2. Low platelet count reduces subsequent complete remission rate despite marrow with <5% blasts after AML induction therapy.
- Author
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Chen X, Newell LF, Xie H, Walter RB, Pagel JM, Sandhu VK, Becker PS, Hendrie PC, Abkowitz JL, Appelbaum FR, and Estey EH
- Subjects
- Female, Humans, Induction Chemotherapy, Male, Middle Aged, Neoplasm Staging, Platelet Count, Prognosis, Remission Induction, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blast Crisis drug therapy, Blast Crisis pathology, Bone Marrow Cells cytology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology
- Published
- 2015
- Full Text
- View/download PDF
Catalog
3. Declining rates of treatment-related mortality in patients with newly diagnosed AML given 'intense' induction regimens: a report from SWOG and MD Anderson.
- Author
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Othus M, Kantarjian H, Petersdorf S, Ravandi F, Godwin J, Cortes J, Pierce S, Erba H, Faderl S, Appelbaum FR, and Estey E
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- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Induction Chemotherapy adverse effects, Middle Aged, Retrospective Studies, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality
- Abstract
Less-intense remission induction regimens for adults with newly diagnosed acute myeloid leukemia (AML) aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15-20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG (Southwest Oncology Group) trials and 1942 patients treated at MD Anderson (MDA) from 1991 to 2009. Eighty-eight percent of SWOG patients received '3+7' or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5-2.0 g/m(2) daily × 3-5 days+other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18-3% in SWOG and 16-4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (P=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status or a lower white blood cell count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy. more...
- Published
- 2014
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4. Mutations in the DNMT3A exon 23 independently predict poor outcome in older patients with acute myeloid leukemia: a SWOG report.
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Ostronoff F, Othus M, Ho PA, Kutny M, Geraghty DE, Petersdorf SH, Godwin JE, Willman CL, Radich JP, Appelbaum FR, Stirewalt DL, and Meshinchi S
- Subjects
- Aged, Aged, 80 and over, Cytarabine administration & dosage, DNA Methyltransferase 3A, Daunorubicin administration & dosage, Etoposide administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Mitoxantrone administration & dosage, Neoplasm Staging, Prognosis, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, DNA (Cytosine-5-)-Methyltransferases genetics, Exons genetics, Leukemia, Myeloid, Acute mortality, Mutation genetics
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- 2013
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5. Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706.
- Author
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Hussein MA, Gundacker H, Head DR, Elias L, Foon KA, Boldt DH, Dobin SM, Dakhil SR, Budd GT, and Appelbaum FR
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Humans, Male, Middle Aged, Treatment Outcome, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR. more...
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- 2005
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6. Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen.
- Author
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Gutierrez-Delgado F, Holmberg L, Hooper H, Petersdorf S, Press O, Maziarz R, Maloney D, Chauncey T, Appelbaum F, and Bensinger W
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols toxicity, Busulfan administration & dosage, Female, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Hodgkin Disease complications, Hodgkin Disease mortality, Humans, Male, Melphalan administration & dosage, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Salvage Therapy methods, Survival Analysis, Thiotepa administration & dosage, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation methods, Hodgkin Disease therapy, Whole-Body Irradiation
- Abstract
We evaluated prognostic factors and treatment outcome of patients with relapsed/refractory Hodgkin's disease (HD) receiving autologous stem cell transplantation (ASCT). In total, 92 patients received total body irradiation, cyclophosphamide and etoposide (TBI/CY/E) (n=42) or busulfan, melphalan and thiotepa (Bu/Mel/T) (n=50) supported with ASCT. A total of 33 (66%) patients receiving the Bu/Mel/T regimen had a prior history of dose-limiting irradiation. Mucositis, hepatic and pulmonary toxicities were the main causes of morbidity and mortality, irrespective of the conditioning regimen. The transplant-related mortality was 15%. With a median follow-up of 6 years (range 2.5-11), the cumulative probabilities of survival, event-free survival (EFS) and relapse at 6 years were 55, 51 and 32%. The 6-year Kaplan-Meier (KM) probabilities of EFS for patients with less advanced disease (patients in first chemotherapy-responsive relapse or second remission (n=42)) and more advanced disease (all other patients (n=50)) were 60 and 44%. No differences in toxicities and efficacy between the conditioning regimens were found. ASCT is an effective treatment for patients with refractory/relapsed HD. Female patients and patients with less advanced disease at transplant had a better outcome. Patients with prior irradiation benefited from the Bu/Mel/T regimen. more...
- Published
- 2003
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7. Mevastatin can increase toxicity in primary AMLs exposed to standard therapeutic agents, but statin efficacy is not simply associated with ras hotspot mutations or overexpression.
- Author
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Stirewalt DL, Appelbaum FR, Willman CL, Zager RA, and Banker DE
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- Acute Disease, Bone Marrow Cells drug effects, Bone Marrow Cells pathology, Case-Control Studies, Cell Survival drug effects, Drug Synergism, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Leukemia, Myeloid drug therapy, Mutation, Myeloid Cells drug effects, Tumor Cells, Cultured, ras Proteins genetics, ras Proteins metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Leukemia, Myeloid pathology, Lovastatin analogs & derivatives, Lovastatin pharmacology
- Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate biochemical pathway and HMG-CoA reductase inhibitors (statins) show toxicity for certain tumors, including acute myeloid leukemia (AML). This toxicity has been attributed to statin inhibition of Ras isoprenylation in tumors like AML where oncogenic ras mutations and/or overexpression are common. We show that mevastatin kills certain AML cell lines and is more toxic to a majority of primary AML cell samples than to myeloid cells in bone marrow (BM) samples from normal donors, and that mevastatin can produce more than additive kill with standard chemotherapeutics. Mevastatin reduces Ras membrane localization, but statin sensitivity in primary AML cells is not consistently associated with ras mutations nor with Ras overexpression, suggesting that another mevalonate pathway by-product(s) is the statin target in at least some AMLs. more...
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- 2003
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8. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study.
- Author
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List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, Dorr R, Karanes C, Hynes HE, Doroshow JH, Shurafa M, and Appelbaum FR
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 analysis, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclosporine administration & dosage, Cyclosporine adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Cytarabine therapeutic use, Cytogenetic Analysis, Daunorubicin administration & dosage, Daunorubicin adverse effects, Daunorubicin therapeutic use, Disease-Free Survival, Drug Interactions, Gene Expression, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Remission Induction, Risk Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclosporine therapeutic use, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute drug therapy
- Abstract
Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P =.0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P =.14), relapse-free survival (34% versus 9% at 2 years, P =.031) and overall survival (22% versus 12%, P =.046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P =.0089) and daunorubicinol (P <.0001) were significantly higher in CsA-treated patients. Survival (P =.0003) and induction response (P =.028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML. more...
- Published
- 2001
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9. Autologous stem cell transplantation for non-Hodgkin's lymphoma: comparison of radiation-based and chemotherapy-only preparative regimens.
- Author
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Gutierrez-Delgado F, Maloney DG, Press OW, Golden J, Holmberg LA, Maziarz RT, Hooper H, Buckner CD, Appelbaum FR, and Bensinger WI
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy adverse effects, Combined Modality Therapy methods, Female, Humans, Lymphoma, Non-Hodgkin mortality, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Prognosis, Radiotherapy Dosage, Survival Rate, Transplantation Conditioning methods, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Lymphoma, Non-Hodgkin therapy, Whole-Body Irradiation adverse effects, Whole-Body Irradiation methods
- Abstract
The aim of this study was to compare toxicity and efficacy of total body irradiation (TBI), cyclophosphamide (CY) and etoposide (E) (TBI/CY/E) vs busulfan, melphalan and thiotepa (Bu/Mel/T) in patients receiving autologous stem cell infusion (ASCI) for malignant lymphoma (NHL). Between September 1990 and July 1998, 351 patients with NHL were treated with TBI/CY/E (n = 221) or Bu/Mel/T (n = 130) followed by ASCI. Patients in first, or second remission, first responding or untreated relapse were defined as having less advanced disease before transplantation. The median follow-up was 5 years (range 1-9) and 3.5 years (1-6) for patients receiving TBI/CY/E and Bu/Mel/T, respectively. The cumulative probabilities of survival, event-free survival (EFS) and relapse at 5 years were 44%, 32%, 49% following TBI/CY/E and 42%, 34% and 42% following Bu/Mel/T. The probability of EFS at 5 years for patients who had prior dose-limiting radiation (n = 59) was 32% after Bu/Mel/T therapy. Transplant-related mortality was 16% for TBI/CY/E and 21% for Bu/Mel/T. In univariate and multivariate analyses, more advanced disease status was associated with poor outcome (TBI/CY/E: RR 0.70, CI 0.50 to 0.97 P = 0.04; Bu/Mel/T: RR 0.61, CI 0.39 to 0.97 P = 0.03). No significant differences in toxicities and outcomes were observed between these two regimens despite the inclusion of patients who had received dose-limiting irradiation in the Bu/Mel/T regimen. more...
- Published
- 2001
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10. Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.
- Author
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Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Martell RE, Larson RA, and Schiffer CA
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Chlorambucil administration & dosage, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Leukemia, Lymphocytic, Chronic, B-Cell complications, Male, Middle Aged, Ontario, Respiratory Tract Infections complications, Skin Diseases, Infectious complications, Treatment Outcome, United States, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Respiratory Tract Infections mortality, Skin Diseases, Infectious mortality
- Abstract
Purpose: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL)., Patients and Methods: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests., Results: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004)., Conclusion: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients. more...
- Published
- 2001
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11. Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.
- Author
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Witherspoon RP, Deeg HJ, Storer B, Anasetti C, Storb R, and Appelbaum FR
- Subjects
- Adult, Busulfan administration & dosage, Cyclophosphamide administration & dosage, Disease-Free Survival, Follow-Up Studies, Hematopoietic Stem Cell Mobilization, Humans, Leukemia, Myeloid, Acute etiology, Mortality, Myelodysplastic Syndromes etiology, Neoplasms, Second Primary etiology, Prognosis, Retrospective Studies, Transplantation, Autologous, Transplantation, Homologous, Whole-Body Irradiation, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary therapy
- Abstract
Purpose: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse., Patients and Methods: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients., Results: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02)., Conclusion: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality. more...
- Published
- 2001
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12. Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in adults 60 years of age and older.
- Author
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Gopal AK, Gooley TA, Golden JB, Maloney DG, Bensinger WI, Petersdorf SH, Appelbaum FR, and Press OW
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols standards, Antineoplastic Combined Chemotherapy Protocols toxicity, Cause of Death, Databases, Factual, Female, Humans, Infections etiology, Infections mortality, Lymphoma, Non-Hodgkin complications, Male, Middle Aged, Survival Rate, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Lymphoma, Non-Hodgkin therapy
- Abstract
High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the optimal treatment for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). HDT, however, is often reserved for relatively younger patients due to limited data in older adults. We treated 53 patients aged 60 years and older (median age 62 years, range 60.3-67.7 years) with HDT and ASCT for NHL at our centers. Forty-four patients (83%) had aggressive histology, 75% had chemosensitive disease and all had failed anthracycline therapy. Conditioning regimens included busulfan, melphalan, and thiotepa (45%); cyclophosphamide (CY), etoposide (VP-16), and total body irradiation (TBI) (30%); CY and TBI (15%); and other regimens (10%). Estimated 4-year overall survival (OS), progression-free survival, and treatment-related mortality (TRM) were 33%, 24% and 22%, respectively. A multivariable analysis demonstrated that patients with chemosensitive disease (P = 0.03) and < or =3 prior regimens (P = 0.03) had superior survival. Four-year OS in patients with chemosensitive disease was 39% vs 15% in patients with chemoresistant disease. Reduced TRM was associated with the CY, VP-16 and TBI regimen (P = 0.02). HDT therapy with ASCT may result in prolonged survival and potential cure for about a quarter of elderly patients, and for almost 40% with chemosensitive disease. Optimal conditioning regimen selection may further improve outcome by reducing TRM. Age alone should not be used to exclude patients from receiving myeloablative therapy with ASCT. more...
- Published
- 2001
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13. Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study.
- Author
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Petersdorf SH, Kopecky KJ, Head DR, Boldt DH, Balcerzak SP, Wun T, Roy V, Veith RW, and Appelbaum FR
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asparaginase administration & dosage, Disease-Free Survival, Dose-Response Relationship, Drug, Humans, Methotrexate administration & dosage, Remission Induction, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen. more...
- Published
- 2001
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14. Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial.
- Author
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Bennett CL, Hynes D, Godwin J, Stinson TJ, Golub RM, and Appelbaum FR
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- Age Factors, Aged, Biopsy, Bone Marrow pathology, Costs and Cost Analysis, Cytarabine therapeutic use, Daunorubicin administration & dosage, Disease-Free Survival, Fever economics, Hospitalization economics, Humans, Infections economics, Leukemia, Myeloid, Acute economics, Leukemia, Myeloid, Acute pathology, Middle Aged, Placebos, Southwestern United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Granulocyte Colony-Stimulating Factor economics, Granulocyte Colony-Stimulating Factor therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients > 55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment. more...
- Published
- 2001
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15. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.
- Author
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Press OW, Eary JF, Gooley T, Gopal AK, Liu S, Rajendran JG, Maloney DG, Petersdorf S, Bush SA, Durack LD, Martin PJ, Fisher DR, Wood B, Borrow JW, Porter B, Smith JP, Matthews DC, Appelbaum FR, and Bernstein ID more...
- Subjects
- Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Cyclophosphamide administration & dosage, Etoposide administration & dosage, Humans, Iodine Radioisotopes adverse effects, Iodine Radioisotopes pharmacokinetics, Iodine Radioisotopes therapeutic use, Lymphoma, B-Cell mortality, Lymphoma, B-Cell pathology, Middle Aged, Neoplasm Staging, Recurrence, Survival Rate, Tissue Distribution, Transplantation, Autologous, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Lymphoma, B-Cell therapy, Radioimmunotherapy adverse effects
- Abstract
Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis. more...
- Published
- 2000
16. A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617.
- Author
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Chauncey TR, Rankin C, Anderson JE, Chen I, Kopecky KJ, Godwin JE, Kalaycio ME, Moore DF, Shurafa MS, Petersdorf SH, Kraut EH, Leith CP, Head DR, Luthardt FW, Willman CL, and Appelbaum FR
- Subjects
- Acute Disease, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Cyclosporins administration & dosage, Cyclosporins pharmacokinetics, Disease-Free Survival, Etoposide administration & dosage, Etoposide pharmacokinetics, Female, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid mortality, Male, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone pharmacokinetics, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy
- Abstract
Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity. more...
- Published
- 2000
- Full Text
- View/download PDF
17. High-dose busulfan, melphalan and thiotepa as consolidation for non-inflammatory high-risk breast cancer.
- Author
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Gutierrez-Delgado F, Holmberg LA, Hooper H, Appelbaum FR, Livingston RB, Maziarz RT, Weiden P, Rivkin S, Montgomery P, Kawahara K, and Bensinger W
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms mortality, Breast Neoplasms surgery, Busulfan administration & dosage, Chemotherapy, Adjuvant, Disease-Free Survival, Female, Follow-Up Studies, Humans, Inflammation, Melphalan administration & dosage, Middle Aged, Multivariate Analysis, Neoplasm Staging, Survival Rate, Thiotepa administration & dosage, Time Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms therapy, Hematopoietic Stem Cell Transplantation
- Abstract
The purpose of this study was to evaluate the toxicity and efficacy of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) in patients with high-risk non-inflammatory breast cancer defined as stage II disease > or =10 lymph nodes (n = 52) or stage III (n = 69), and prognostic factors for treatment outcome. One hundred and twenty-one patients (median age, 46 years) were treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) (HDC) followed by autologous stem cell infusion (ASCI). One hundred patients were initially treated with surgery followed by standard adjuvant chemotherapy prior to HDC/ASCI. Twenty-one patients with stage III disease had inoperable tumors at diagnosis and were treated with neoadjuvant chemotherapy and surgery before HDC/ASCI. Transplant-related mortality was 6%. The probabilities of event-free survival (EFS) at 3 and 5 years (median follow-up of 36 months) from transplant were, for all patients: 0.62-0.60; stage II: 0.71-0.67: stage III: 0.55-0.55 (for stage III adjuvant and neoadjuvant groups: 0.60-0.60 and 0.42-0.42, respectively). Multivariate analysis did not identify variables associated with poor outcome. The efficacy of Bu/Mel/TT is similar to other HDC regimens reported for patients with high-risk non-inflammatory breast cancer. Bu/Mel/TT has high activity in stage II disease and a moderate benefit in stage III operable tumors. more...
- Published
- 2000
- Full Text
- View/download PDF
18. Hemopoietic stem cell transplantation for myelodysplastic syndrome.
- Author
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Deeg HJ and Appelbaum FR
- Subjects
- Adult, Age Factors, Aged, Child, Dose-Response Relationship, Drug, Humans, Middle Aged, Prognosis, Transplantation, Autologous, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Myelodysplastic Syndromes therapy
- Abstract
The term myelodysplastic syndrome (MDS) describes a spectrum of disorders that are characterized by dysplastic marrow cell morphology, the development of peripheral blood cytopenias, and a tendency to evolve into acute myeloid leukemia. MDS has been recognized as a stem-cell disease, and hemopoietic stem-cell transplantation is currently the only potentially curative therapy. In patients with less advanced MDS (<5% blasts in the marrow), 3-year survival rates of 70% and 65% can be achieved with HLA-identical related and HLA-matched unrelated donors, respectively. The overall probability of disease recurrence in these patients is less than 5%. Of patients with advanced disease (5% marrow blasts or more), about 40% to 45% and 25% to 30% are surviving in remission after transplantation from a related or an unrelated donor, respectively. This inferior outcome is largely due to a higher incidence of post-transplantation relapse (20% to 30%). Inclusion of the International Prognostic Scoring System criteria into outcome analyses shows an inverse correlation between overall risk category and relapse-free survival after transplantation. Future trials should explore the usefulness of different transplantation regimens for different risk categories. Among patients with less advanced disease, use of a conditioning regimen that combines cyclophosphamide and busulfan, dose adjusted to reach target plasma levels, has been associated with improved survival in recipients of transplants from related and unrelated donors. It has also permitted successful hemopoietic stem-cell transplantation in patients as old as 66 years of age. Improved survival with transplants from unrelated volunteer donors has been achieved with selection of donors based on high-resolution HLA typing. Autologous stem-cell transplantation may provide excellent consolidation for selected patients who have obtained complete remission with conventional chemotherapy. High treatment-related morbidity and mortality rates, particularly after allogeneic transplantation, remain challenges that must be addressed with innovative approaches. more...
- Published
- 2000
- Full Text
- View/download PDF
19. A phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia.
- Author
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Rosen PJ, Rankin C, Head DR, Boldt DH, Luthardt FW, Norwood T, Pugh RP, Karanes C, and Appelbaum FR
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Recurrence, Remission Induction, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cytarabine administration & dosage, Mitoxantrone administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose: The Southwest Oncology Group performed a Phase II study to investigate the effectiveness of an induction regimen of high dose cytosine arabinoside (ara-C) with high dose mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia (ALL)., Patients and Methods: Patients at least 16-years-old with ALL that was in relapse after, or was refractory to, standard induction therapy including at least vincristine and prednisone were eligible, as long as they had no prior treatment with high dose ara-C. The induction regimen included high dose ara-C (3 g/m2 by 3-h i.v. days 1-5) and mitoxantrone (80 mg/m2 by 15-30 min i.v. 12-20 h after the first dose of ara-C). The study design called for a maximum of 55 patients, with early termination if less than nine of the first 30 achieved complete remission., Results: Thirty-three patients entered the study, and 31 were included in the analysis. All 31 completed one course of induction therapy. Four patients died of infection and a fifth of cardiomyopathy with possible sepsis. Seven patients achieved complete remission (23%; 95% confidence interval 10-41%). One of the seven received syngeneic bone marrow transplantation while in remission, and the other six all relapsed within 10 months. All 31 patients died within 25 months after entering the study., Conclusions: The regimen of high dose ara-C and mitoxantrone was found to be insufficiently effective to warrant further investigation. more...
- Published
- 2000
- Full Text
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20. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.
- Author
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Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Rowe JM, François C, Larson RS, and Wiernik PH
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Cytarabine administration & dosage, Daunorubicin administration & dosage, Dexamethasone therapeutic use, Female, Fever chemically induced, Glucocorticoids therapeutic use, Humans, Incidence, Infant, Lung drug effects, Lung pathology, Male, Middle Aged, Pericardial Effusion chemically induced, Pleural Effusion chemically induced, Remission Induction, Respiratory Distress Syndrome chemically induced, Syndrome, Weight Gain, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin adverse effects
- Abstract
We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95) more...
- Published
- 2000
21. Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogenic marrow transplants during chronic phase of chronic myeloid leukemia.
- Author
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Clift RA, Radich J, Appelbaum FR, Martin P, Flowers ME, Deeg HJ, Storb R, and Thomas ED
- Subjects
- Busulfan therapeutic use, Combined Modality Therapy, Cyclophosphamide therapeutic use, Follow-Up Studies, Humans, Survival Analysis, Time Factors, Transplantation, Homologous, Whole-Body Irradiation, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy
- Published
- 1999
22. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study.
- Author
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Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH, Vial RH, Lichtin A, Nand S, Samlowski WE, and Appelbaum FR
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Cytarabine administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Mitoxantrone administration & dosage, Prognosis, Recurrence, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy
- Abstract
The aim of this study is to determine whether the addition of mitoxantrone to high dose cytarabine improves the outcome of treatment in patients with relapsed or refractory acute myeloid leukemia (AML). One hundred and sixty-two eligible patients, 14-76 years of age, with AML either in first relapse or that failed to respond to initial remission induction therapy, with no CNS involvement were randomized to receive therapy with cytarabine 3 gm/M2 i.v. over 2 h every 12 h for 12 doses on days 1-6 (Arm I) (HIDAC); or HIDAC plus mitoxantrone 10 mg/M2 i.v. daily on days 7 9 (Arm II) (HIDAC + M). Patients achieving complete remission were treated with three courses of consolidation including HIDAC (Ara-C 3 gm/M2 i.v. 12 h days 1 3; 2 gm/M2 over age 50) alone (ARM I) or with mitoxantrone (10 mg/M2 i.v. day 1) (ARM II). Among 162 patients (81 HIDAC, 81 HIDAC + M) evaluated for induction toxicity, there were 10 (12%) induction deaths with HIDAC and 13 (17%) with HIDAC + M (2-tailed P = 0.65). Most early deaths were due to infection and/or hemorrhage. Among 162 patients evaluated for responses to induction therapy, 26/81 (32%) HIDAC and 36/81 (44%) HIDAC + M patients achieved complete remission (two-tailed P = 0.15). Although this difference was not statistically significant in univariate analysis, it was after adjusting for the effects of WBC and PMN percentage in multivariate analysis (P=0.013). Median survivals from study entry were 8 months (HIDAC) and 6 months (HIDAC + M); 2-tailed logrank P = 0.58. Among 48 patients registered for consolidation, the median disease-free survivals from that registration were 8 months with HIDAC and 11 months with HIDAC + M (P = 0.60). There were three treatment-related deaths during consolidation (1 HIDAC, 2 HIDAC + M), all due to infections. In this randomized trial, the addition of mitoxantrone to high-dose cytarabine was associated with a trend toward a higher CR rate. There was less evidence for an advantage in disease-free or overall survival, although any such conclusion is limited by the size of the study. more...
- Published
- 1999
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23. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology.
- Author
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Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, and Tura S
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Busulfan adverse effects, Busulfan therapeutic use, Combined Modality Therapy, Humans, Hydroxyurea adverse effects, Hydroxyurea therapeutic use, Interferon-alpha adverse effects, Interferon-alpha therapeutic use, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Evidence-Based Medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy
- Abstract
Because there are differing opinions regarding treatment of patients in the chronic phase of chronic myeloid leukemia (CML), the American Society of Hematology convened an expert panel to review and document evidence-based benefits and harms of treatment of CML with busulfan (BUS), hydroxyurea (HU), recombinant interferon-alpha (rIFN-alpha), and bone marrow transplantation (BMT). The primary measure for defining efficacy was survival. Analysis indicated a survival advantage for HU over BUS. Observational studies of rIFN-alpha suffer from numerous biases including sample size, variations in study populations, definitions of hematologic and cytogenetic remissions, and dose. That rIFN-alpha is more efficacious than chemotherapy is demonstrated by 6 prospective randomized trials. For patients with favorable clinical features in chronic phase, compared to HU and BUS, rIFN-alpha improves survival by a median of about 20 months. Most evidence suggests that rIFN-alpha is most effective when combined with other drugs and when given during the earliest stage of the chronic phase. Adding cytarabine to rIFN-alpha adds further survival benefit but increases toxicity. Limitations for evaluating the long-term benefits of allogeneic BMT include the retrospective nature of most studies, incomplete documentation of the clinical characteristics of the patients, paucity of the details on patient selection, lack of control groups, and limitations of survival calculations. Survival curves for BMT show that at least half of the patients transplanted remain alive 5 to 10 years after treatment, whereas similar curves for rIFN-alpha show a continuous relapse rate over time with the curves crossing at about 7 to 8 years. Estimates of long-term survival may be confounded by the selection biases mentioned and the analytic methods used. The magnitude of the incremental increase in benefit with BMT must be weighed against the potential serious harm and death that may accompany the procedure in the short term. The best results with BMT have been obtained when it is performed within 1 to 2 years from diagnosis. Since each treatment option involves tradeoffs between benefit and harm, patient choice must be based on the examination of facts presented in an unbiased fashion. Newly diagnosed younger patients and older patients who are candidates for BMT should also be offered information about IFN-based regimens, the tradeoffs involved, and, if possible, share in the treatment decision. Hopefully this analysis will provide the stimulus for evaluation of other important aspects of CML. more...
- Published
- 1999
24. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study.
- Author
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Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR, and Willman CL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, ATP-Binding Cassette Transporters biosynthesis, Acute Disease, Adolescent, Adult, Aged, Female, Gene Frequency, Humans, Leukemia, Myeloid drug therapy, Leukemia, Myeloid physiopathology, Male, Middle Aged, Multidrug Resistance-Associated Proteins, Neoplasm Proteins immunology, Prognosis, Treatment Outcome, Vault Ribonucleoprotein Particles immunology, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP-Binding Cassette Transporters genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid genetics, Neoplasm Proteins genetics, Vault Ribonucleoprotein Particles genetics
- Abstract
Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease. more...
- Published
- 1999
25. High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer.
- Author
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Holmberg LA, Demirer T, Rowley S, Buckner CD, Goodman G, Maziarz R, Klarnet J, Zuckerman N, Harrer G, McCloskey R, Gersh R, Goldberg R, Nichols W, Jacobs A, Weiden P, Montgomery P, Rivkin S, Appelbaum FR, and Bensinger WI more...
- Subjects
- Adult, Combined Modality Therapy, Female, Humans, Middle Aged, Ovarian Neoplasms pathology, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Busulfan administration & dosage, Hematopoietic Stem Cell Transplantation, Melphalan administration & dosage, Ovarian Neoplasms therapy, Thiotepa administration & dosage
- Abstract
The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens. more...
- Published
- 1998
- Full Text
- View/download PDF
26. Long-term survival after chemotherapy for acute myeloid leukemia: the experience of the Southwest Oncology Group.
- Author
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Appelbaum FR and Kopecky KJ
- Subjects
- Acute Disease, Disease-Free Survival, Follow-Up Studies, Humans, Middle Aged, Multicenter Studies as Topic, Prognosis, Randomized Controlled Trials as Topic, Risk Factors, Survival Analysis, Time Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy, Leukemia, Myeloid mortality
- Abstract
Background: Reports on outcomes of chemotherapy trials in acute myeloid leukemia (AML) have rarely included results of long-term follow-up beyond 10 years. The authors therefore chose to review long-term follow-up data from 3 studies conducted by the Southwest Oncology Group (SWOG) between 1978 and 1990., Methods: The analysis included data on 2083 patients enrolled in SWOG studies S7823, S8124, and S8600. The results were based on data available as of November 15, 1996., Results: The probability of survival 8 years after entry was 9% in Study S7823, 14% in S8124, and 15% in S8600. For patients age < 50 years, the probabilities were 14%, 24%, and 20%, respectively. For patients ages 50-64 years, the probabilities were 7%, 8%, and 8%, respectively. For those age < 50 years who achieved complete remission, the 8-year probability of disease free survival was 17% in Study S7823, 28% in S8124, 17% with standard dose cytarabine in S8600, and 26% with high dose cytarabine in S8600. Relapse was the major reason for failure after complete remission in all three studies. When the results of the 3 studies were combined, most of the 743 relapses had occurred by Year 3 and nearly all the rest by Year 5. Among the prognostic factors universally available for study, three were highly associated with survival in all three studies: age, French-American-British disease classification, and white blood cell count at diagnosis., Conclusions: In view of the fact that most deaths occurred during the first 3 years, it is appropriate to report the results of clinical trials after patients have been followed for 4 years. Despite modest gains, the results of chemotherapy for AML remain disappointing, especially in the treatment of older patients. more...
- Published
- 1997
- Full Text
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27. Safeguarding the administration of high-dose chemotherapy: a national practice survey by the American Society for Blood and Marrow Transplantation.
- Author
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Chen CS, Seidel K, Armitage JO, Fay JW, Appelbaum FR, Horowitz MM, Shpall EJ, Weiden PL, Antman KS, Champlin RE, Kersey JH, and Sullivan KM
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blood Banks, Child, Drug Administration Schedule, Health Care Surveys, Hematopoietic Stem Cell Transplantation, Humans, Neoplasms therapy, Surveys and Questionnaires, Tissue Banks, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Blood Transfusion, Bone Marrow Transplantation, Practice Patterns, Physicians', Societies, Scientific
- Abstract
Overdoses of high-dose chemotherapy before hematopoietic cell transplantation are serious adverse events, but their frequency and etiology are unknown. The American Society for Blood and Marrow Transplantation (ASBMT) conducted an anonymous national survey to identify errors in safety practices during the administration of high-dose chemotherapy. The questionnaire was returned from 115 (68%) of 170 hematopoietic transplant centers in the United States. Ninety-four of the programs were university or affiliated centers, 19 were community hospitals, and 41 were founded since 1990. A total of 7650 transplants were reported for 1994: 22% of the programs performed 1-20 transplants, 60% performed 21-100 transplants, and 18% performed more than 100 transplants. Fifteen of the 115 responding centers reported a total of 18 patients inadvertently given overdoses of cisplatin (n=3), carboplatin (n=2), busulfan (n=2), cytosine arabinoside (n=2), cyclophosphamide (n=2), interleukin-2 (n=2), or other agents (n=5) between 1989 and 1994. Cumulative drug doses given as a daily dose (six cases) and nursing infusion errors (six cases) were the most common errors. The estimated chemotherapy overdose error rate was 0.06%, or 6 cases/10,000 transplants, with 95% confidence limits of 0.03-0.11%. The overdose rate among more experienced centers in operation before 1990 was lower than that among newer centers (p < 0.01). Large centers (> 100 transplants performed in 1994) experienced errors at rates lower than those in medium-sized centers (21-100 transplants, p = 0.03). Although the number of events was small in this self-reporting survey, overdoses were noted in 13% of the responding centers, especially among more recently established units. Safety practices need to emphasize multidisciplinary checkpoints at the physician, pharmacist, nursing, and institutional levels. Based on these survey results, ASBMT recommendations for further safeguards for high-dose chemotherapy administration are proposed. more...
- Published
- 1997
28. High-dose busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell transplantation in patients with aggressive lymphoma or relapsed Hodgkin's disease.
- Author
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Schiffman K, Buckner CD, Maziarz R, Maloney DG, Appelbaum FR, Press O, Gooley T, Holmberg L, Lilleby K, Clift R, Zuckerman N, Klarnet J, Weaver C, Chauncey T, and Bensinger WI
- Subjects
- Adolescent, Adult, Aged, Busulfan administration & dosage, Combined Modality Therapy, Disease-Free Survival, Female, Hodgkin Disease drug therapy, Hodgkin Disease mortality, Humans, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality, Male, Melphalan administration & dosage, Middle Aged, Remission Induction, Salvage Therapy, Survival Analysis, Thiotepa administration & dosage, Transplantation Conditioning, Treatment Outcome, Whole-Body Irradiation, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Hodgkin Disease therapy, Lymphoma, Non-Hodgkin therapy
- Abstract
The purpose of this study was to evaluate the efficacy of high-dose chemotherapy with busulfan (Bu), melphalan (Mel), and thiotepa (TT), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or relapsed Hodgkin's disease (HD). Forty patients, 23 with intermediate (n= 18) or high-grade (n=5) NHL and 17 with HD received Bu (12 mg/kg), Mel (100 mg/kg), TT (450-500 mg/m2) [corrected], and autologous PBSC infusion. Of 27 patients with more advanced disease, 16 had primary refractory disease, 8 were in refractory relapse, and 3 were in third remission. Of 13 patients with less advanced disease, 7 were in untreated or responding first relapse and 3 were in second remission, whereas 3 with high-grade NHL were in first remission. Twenty-nine patients (73%) had received prior radiotherapy (RT) prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival, and relapse for all patients were 0.60, 0.46, and 0.31 (0.85, 0.85, and 0.15 for patients with less advanced disease and 0.48, 0.30, and 0.37 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.17. Severe idiopathic pneumonia syndrome was not observed in any patients with less advanced disease and in only one patient with more advanced disease. A regimen of BuMelTT is well tolerated in patients with aggressive NHL or relapsed HD, and results obtained to date are at least equivalent to other published regimens, including TBI-based regimens. This regimen appears to be a particularly attractive alternative for patients who have already received dose-limiting RT and should be evaluated further in prospective, randomized studies. more...
- Published
- 1997
29. All-trans-retinoic acid in acute promyelocytic leukemia.
- Author
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Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, and Wiernik PH
- Subjects
- Adolescent, Adult, Antineoplastic Agents adverse effects, Child, Child, Preschool, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Disease-Free Survival, Female, Humans, Leukemia, Promyelocytic, Acute mortality, Male, Middle Aged, Remission Induction methods, Survival Rate, Treatment Failure, Tretinoin adverse effects, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
Background: All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome., Methods: Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation., Results: Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003)., Conclusions: All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia. more...
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- 1997
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30. High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer.
- Author
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Bensinger WI, Schiffman KS, Holmberg L, Appelbaum FR, Maziarz R, Montgomery P, Ellis E, Rivkin S, Weiden P, Lilleby K, Rowley S, Petersdorf S, Klarnet JP, Nichols W, Hertler A, McCroskey R, Weaver CH, and Buckner CD more...
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms secondary, Busulfan administration & dosage, Combined Modality Therapy, Drug Resistance, Female, Graft Survival, Humans, Melphalan administration & dosage, Middle Aged, Prognosis, Survival Rate, Thiotepa administration & dosage, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens. more...
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- 1997
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31. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study.
- Author
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Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR, and Willman CL
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antigens, CD biosynthesis, Antigens, CD34 biosynthesis, Cytarabine administration & dosage, Daunorubicin administration & dosage, Double-Blind Method, Female, Humans, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute genetics, Male, Middle Aged, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary genetics, Recombinant Proteins therapeutic use, ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chromosome Aberrations, Chromosome Disorders, Drug Resistance, Multiple genetics, Granulocyte Colony-Stimulating Factor therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Compared with younger patients, elderly patients with acute myeloid leukemia (AML) respond poorly to conventional chemotherapy. To determine if this poor response is due to differences in the biologic characteristics of AML in the elderly, we studied 211 patients (161 de novo, 50 secondary AML) over 55 years of age (median, 68 years) registered to a single clinical trial for previously untreated AML (SWOG 9031, Phase III randomized trial of standard dose cytosine arabinoside and daunomycin + rhG-CSF). Pretreatment leukemic blasts were karyotyped and were also analyzed for intrinsic drug resistance by quantitating expression of the multidrug resistance glycoprotein MDR1 and functional drug efflux using sensitive flow cytometric techniques. Results were correlated with clinical variables and outcome. These elderly AML patients had a high frequency of unfavorable cytogenetics (32%), MDR1 protein expression (71%), and functional drug efflux (58%); each of these factors occurred at high frequencies in both de novo and secondary AML patients and was associated with a significantly poorer complete remission (CR) rate. In multivariate analysis, secondary AML (P = .0035), unfavorable cytogenetics (P = .0031), and MDR1 (P = .0041) were each significantly and independently associated with lower CR rates. Resistant disease was associated with unfavorable cytogenetics (P = .017) and MDR1 expression (P = .0007). Strikingly, elderly MDR1(-) de novo AML patients with favorable/intermediate cytogenetics had a CR rate of 81%; with increasing MDR1 expression, CR rate decreased in this cytogenetic group. MDR1(+) secondary AML patients with unfavorable cytogenetics had a CR rate of only 12%. Thus, AML in the elderly is associated with an increased frequency of unfavorable cytogenetics and MDR1 expression, both of which independently contribute to poor outcomes. The high frequencies of these features in both de novo and secondary elderly AML patients suggest a common biologic mechanism for these leukemias distinct from that in younger patients. Investigation of biologic parameters at diagnosis in AML in the elderly may help identify patients with a high likelihood of achieving CR with conventional regimens, as well as those who may require alternate regimens designed to overcome therapy resistance. more...
- Published
- 1997
32. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy.
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Anderson JE, Gooley TA, Schoch G, Anasetti C, Bensinger WI, Clift RA, Hansen JA, Sanders JE, Storb R, and Appelbaum FR
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Disease Progression, Disease-Free Survival, Female, Humans, Leukemia, Myeloid drug therapy, Leukemia, Myeloid etiology, Leukemia, Myeloid mortality, Leukemia, Radiation-Induced drug therapy, Leukemia, Radiation-Induced mortality, Leukemia, Radiation-Induced therapy, Life Tables, Male, Middle Aged, Myelodysplastic Syndromes pathology, Neoplasms drug therapy, Neoplasms radiotherapy, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary etiology, Neoplasms, Second Primary mortality, Proportional Hazards Models, Radiotherapy adverse effects, Remission Induction, Retrospective Studies, Transplantation Conditioning, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid therapy, Neoplasms, Second Primary therapy
- Abstract
The purpose of this report is to describe the results of stem cell transplantation as initial treatment for secondary acute myeloid leukemia (AML). Forty-six patients (median age 42 years) with secondary AML (17 therapy-related, 29 myelodysplasia-related) who had not received remission induction chemotherapy underwent allogeneic (n = 43) or syngeneic (n = 3) transplantation. The 5-year actuarial disease-free survival was 24.4%, and the cumulative incidences of relapse and nonrelapse mortality were 31.3% and 44.3%, respectively. Lower peripheral blood blast count was associated with a lower risk of relapse (P = .05) and shorter time from AML diagnosis to transplant was associated with a lower risk of nonrelapse mortality (P = .02) and improved disease-free survival (P = .026). Patients with therapy-related secondary AML tended to have lower disease-free survival (P = .16) and a higher relapse rate (P = .16) than patients whose leukemia was not therapy-related. The results of these 46 previously untreated patients were compared to 20 patients (median age 36 years, 12 therapy-related, 8 myelodysplasia-related) transplanted with chemotherapy-sensitive disease after induction chemotherapy (first complete remission [n = 6], second complete remission [n = 3], first untreated relapse [n = 11]). We found no statistically significant difference in outcome between these 2 groups of patients. These results suggest that prompt transplantation should be considered after diagnosis of secondary AML or, if possible, high-risk myelodysplasia, particularly in patients with low peripheral blast counts. Innovative transplant strategies are needed to reduce the high risks of relapse and nonrelapse mortality seen in this patient population. more...
- Published
- 1997
33. Effect of different chemotherapy regimens on peripheral-blood stem-cell collections in patients with breast cancer receiving granulocyte colony-stimulating factor.
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Demirer T, Buckner CD, Storer B, Lilleby K, Rowley S, Clift R, Appelbaum FR, Storb R, and Bensinger WI
- Subjects
- Female, Humans, Multivariate Analysis, Antigens, CD34, Antineoplastic Combined Chemotherapy Protocols pharmacology, Blood Specimen Collection, Breast Neoplasms drug therapy, Granulocyte Colony-Stimulating Factor therapeutic use, Hematopoietic Stem Cells
- Abstract
Purpose: To evaluate the effects of chemotherapy regimens on peripheral-blood stem-cell (PBSC) yields in patients with breast cancer who receive granulocyte colony-stimulating factor (G-CSF)., Patients and Methods: One hundred patients with breast cancer received cyclophosphamide 4 g/m2 for dose (CY) (n = 10), CY and etoposide 600 mg/m2 (CE) (n = 13), CE and cisplatin 105 mg/m2 (CEP) (n = 19), or CY and paclitaxel 170 mg/m2 (n = 58), followed by G-CSF. PBSC collections were initiated when the WBC count recovered to greater than 1 x 10(9)/L. A multivariate analysis was undertaken to evaluate the effects of different chemotherapy regimens and patient variables on PBSC collections as measured by the yield of CD34+ cells., Results: The medians of average daily CD34+ cell yields for patients who received paclitaxel plus CY, CE, and CEP with G-CSF were 12.9, 11.03, and 5.37 x 10(6)/kg, respectively, compared with 2.02 x 10(6)/kg in the reference group that received CY with G-CSF (P = < .0001, .002, and .09, respectively). On first-day collections, patients who received paclitaxel plus CY, CE, and CEP with G-CSF yielded medians of 11.07, 8.09, and 3.52 x 10(6) CD34+ cells/kg, respectively, compared with 0.90 x 10(6)/kg in the reference group that received CY with G-CSF (P = .0006, .02, and .09, respectively). The number of previous cycles of chemotherapy, previous radiotherapy, marrow involvement, and phase and stage of disease did not have statistically significant effects on CD34+ cell yield., Conclusion: Combination chemotherapy regimens were superior to single-agent CY for the mobilization of CD34+ cells. more...
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- 1997
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34. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study.
- Author
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Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, and Grever M
- Subjects
- Acute Disease, Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Disease-Free Survival, Female, Humans, Leukemia, Myeloid mortality, Life Tables, Male, Middle Aged, Remission Induction, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy
- Abstract
Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation. more...
- Published
- 1996
35. High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: comparison of autologous bone marrow and peripheral blood stem cells.
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Brunvand MW, Bensinger WI, Soll E, Weaver CH, Rowley SD, Appelbaum FR, Lilleby K, Clift RA, Gooley TA, Press OW, Fefer A, Storb R, Sanders JE, Martin PL, Chauncey T, Maziarz RT, Zuckerman N, Montgomery P, Dorn R, Weiden PL, Demirer T, Holmberg LA, Schiffman K, McSweeney PA, and Buckner CD more...
- Subjects
- Adolescent, Adult, Bone Marrow Purging, Child, Child, Preschool, Clinical Trials as Topic, Combined Modality Therapy, Cyclophosphamide administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Graft Survival, Hematopoietic Cell Growth Factors pharmacology, Hematopoietic Cell Growth Factors therapeutic use, Humans, Life Tables, Lymphoma drug therapy, Lymphoma mortality, Lymphoma radiotherapy, Male, Middle Aged, Prospective Studies, Transplantation Conditioning adverse effects, Transplantation Conditioning mortality, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation mortality, Bone Marrow Transplantation statistics & numerical data, Hematopoietic Stem Cell Transplantation, Lymphoma therapy, Whole-Body Irradiation
- Abstract
Consecutive patients with non-Hodgkin's lymphoma (NHL, n = 133) or Hodgkin's disease (HD, n = 20) were treated with 12.0 Gy of fractionated total body irradiation, etoposide 60 mg/kg, and CY 100 mg/kg followed by infusion of autologous hematopoietic stem cells. Seventy-nine patients received purged (n = 62) or unpurged BM (n = 17), and 74 received unpurged PBSCs alone (n = 56) or with BM (n = 18). The median day for achieving a sustained granulocyte count of 0.5 x 10(9)/I was 14 range (7-66) for BM recipients and 10 (7-30) for PBSC +/- BM recipients (P = 0.03). A platelet count of 20 x 10(9)/I was achieved at a median of day 24 (6-145) in BM recipients and day 11 (range, 7-56) in PBSC +/- BM recipients (P = 0.007). The median number of platelet units transfused was 86 (0-1432) for BM recipients and 30 (6-786) for PBSC +/- BM recipients (P = 0.001). The median number of hospital days was 36 (10-88) for BM recipients and 27 (14-76) for PBSC +/- BM recipients (P = 0.0001). The unadjusted Kaplan-Meier (KM) estimates of survival, event-free survival (EFS) and relapse at 2 years were 0.57, 0.45 and 0.43 for patients receiving BM and 0.55, 0.36 and 0.59 for patients receiving PBSC +/- BM. After adjusting for confounding variables, the estimated relative risk (RR) of death from any cause was 0.92 (P = 0.75), of relapse was 1.25 (P = 0.39), of non-relapse mortality was 0.71 (P = 0.42) and of mortality and/or relapse was 1.17 (P = 0.48) for patients receiving PBSC +/- BM as compared to BM. For 46 patients with NHL receiving unpurged PBSC alone, the unadjusted KM estimate of relapse was 0.61 compared with 0.48 for 52 comparable patients receiving purged BM, while the RR for relapse for patients receiving unpurged PBSCs was 1.37 (P = 0.33) after adjusting for other significant covariates. These data confirm previous observations that patients who receive PBSC +/- BM have faster engraftment, fewer transfusions and shorter hospital stays than patients who receive only BM. There were no statistically significant differences between the two groups in survival, relapse, death from causes other than relapse and event-free survival. more...
- Published
- 1996
36. Phase II study of high-dose busulfan, melphalan and thiotepa with autologous peripheral blood stem cell support in patients with malignant disease.
- Author
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Schiffman KS, Bensinger WI, Appelbaum FR, Rowley S, Lilleby K, Clift RA, Weaver CH, Demirer T, Sanders JE, Petersdorf S, Gooley T, Weiden P, Zuckerman N, Montgomery P, Maziarz R, Klarnet JP, Rivkin S, Trueblood K, Storb R, Holmberg L, and Buckner CD more...
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms therapy, Busulfan administration & dosage, Female, Humans, Lymphoma therapy, Male, Melphalan administration & dosage, Middle Aged, Neoplasms mortality, Ovarian Neoplasms therapy, Thiotepa administration & dosage, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Neoplasms therapy
- Abstract
The purpose of this study was to determine the toxicities and potential effectiveness of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) followed by autologous peripheral blood stem cell (PBSC) infusion in patients with a variety of diseases. A phase II clinical trial of Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC infusion in 104 patients with breast cancer (n = 48), malignant lymphoma (n = 25), ovarian cancer (n = 13), multiple myeloma (n = 7) and other malignancies (n = 11) was performed. Sixty-two patients were treated in an academic medical center and 42 in a community cancer center. Grade 3-4 regimen-related toxicities occurred in 14% of patients, causing regimen-related mortality in six (6%) patients with an overall transplant-related mortality of 9%. Transplant-related deaths occurred in 6/62 patients (10%) treated in an academic medical center and in 3/42 (7%) treated in a community cancer center. Complete remissions (CR) were achieved in 1/17 (6%) patients with refractory stage IV breast cancer, 4/4 patients with responsive stage IV breast cancer, 6/13 (46%) with more-advanced lymphoma and 4/4 with less-advanced lymphoma. These patients are alive and disease-free a median of 712, 279, 461 and 404 days after transplant, respectively. Nineteen of 22 patients with stage II-III breast cancer remain alive and disease-free a median of 365 days after transplant. Complete remissions were also seen in 4/9 patients with ovarian cancer and 3/7 with multiple myeloma. The Bu/Mel/TT regimen followed by autologous PBSC infusion is associated with acceptable morbidity and mortality, appears to have significant activity in patients with breast cancer and is well tolerated in the adjuvant setting of stage II-III breast cancer. Bu/Mel/TT also appears to have significant activity in patients with lymphoma, multiple myeloma and possibly ovarian cancer. Further phase II-III studies are warranted in patients with these and other malignancies. more...
- Published
- 1996
37. Busulfan, cyclophosphamide and fractionated total body irradiation for allogeneic marrow transplantation in advanced acute and chronic myelogenous leukemia: phase I dose escalation of busulfan based on targeted plasma levels.
- Author
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Demirer T, Buckner CD, Appelbaum FR, Lambert K, Bensinger WI, Clift R, Storb R, and Slattery JT
- Subjects
- Adolescent, Adult, Antineoplastic Agents, Alkylating adverse effects, Antineoplastic Agents, Alkylating therapeutic use, Busulfan adverse effects, Busulfan blood, Busulfan therapeutic use, Child, Child, Preschool, Combined Modality Therapy, Cyclophosphamide therapeutic use, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Infant, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Recurrence, Reproducibility of Results, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Leukemia, Myeloid, Acute therapy, Whole-Body Irradiation
- Abstract
A previous phase I study determined that the maximum tolerated dose (MTD) of busulfan (BU) that could be given with a fixed dose of cyclophosphamide (CY) of 50 mg/kg and total body irradiation (TBI) dose of 12.0 Gy was 7 mg/kg. A phase II study was carried out in patients with advanced myeloid malignancies receiving allogeneic transplants without improvement in outcome as compared to historical controls. In that study, steady-state concentration (Css) of BU in 13 patients receiving a fixed dose of BU varied from 209 to 735 ng/ml. In an attempt to decrease the variability of the Css of BU, a study of targeting specific plasma concentrations was performed. In this study, BU dose was adjusted up or down based on first dose pharmacokinetics. The first dose level evaluated was 7.5 mg/kg with a target BU plasma level of 460 ng/ml. Six patients were entered at this level and the median BU plasma concentration achieved was 410 (range 390-533). One of six patients developed grade 3-4 regimen-related toxicities (RRT). Dose level II was a target of 559 ng/ml with a starting oral dose of BU of 9.6 mg/kg. Twelve patients were entered at this level and median plasma BU level was 548 (range 427-689). Three of 12 (25%) patients developed grade 3-4 RRTs and this was considered to be the MTD. The actuarial probability of grade II-IV acute GVHD was 0.70. Eight of 21 evaluable patients (38%) developed chronic GVHD. Of 18 patients who died, seven died of relapse at a median of 160 days (range 65-353) and 11 (61%) died of causes other than relapse at a median of 152 days (range 18-570). The actuarial probabilities of DFS, relapse and relapse-free mortality at 2 years in all patients were 0.13, 0.50 and 0.75, respectively. This study showed that targeted BU plasma levels within 10% of target can reliably be achieved with a bias of -2.07% and mean absolute error of 7.47%. Overall, targeting made a -31.8% to 100% in plasma BU Css as compared to expected BU Css based on first dose pharmacokinetics if targeting were not performed in this study. Thus targeting avoided much of the variability in BU concentrations seen in other studies. When compared with our previous phase II experience in same group of patients receiving same regimen, dose escalation of BU based on targeted plasma levels did not improve the outcome. more...
- Published
- 1996
38. Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors.
- Author
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Anderson JE, Appelbaum FR, Schoch G, Gooley T, Anasetti C, Bensinger WI, Bryant E, Buckner CD, Chauncey T, and Clift RA
- Subjects
- Adolescent, Adult, Analysis of Variance, Busulfan administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Cyclosporine administration & dosage, Disease-Free Survival, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Humans, Immunosuppression Therapy adverse effects, Infections etiology, Karyotyping, Methotrexate administration & dosage, Methylprednisolone administration & dosage, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Prognosis, Recurrence, Regression Analysis, Survival Rate, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Myelodysplastic Syndromes therapy, Whole-Body Irradiation
- Abstract
Purpose: To determine if an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total-body irradiation (TBI) could improve outcome after marrow transplantation for advanced morphology myelodysplasia (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML]) compared with that obtained with conventional CY/TBI and to analyze prognostic factors for transplantation for myelodysplasia., Patients and Methods: A phase II study was conducted of 31 patients (median age, 41 years) treated with BU (7 mg/kg), CY (50 mg/kg), TBI (12 Gy), and human leukocyte antigen (HLA)-matched (n = 23) or -mismatched (n = 2) related or unrelated donor (n = 6) marrow transplantation. Results were compared with 44 historical control patients treated with CY (120 mg/kg) and TBI., Results: The 3-year actuarial disease-free survival (DFS) rate was similar for the BU/CY/TBI group and the CY/TBI group (23% v 30%, P = .6), but there were trends toward lower relapse rates (28% v 54%, P = .27) and higher nonrelapse mortality rates (68% v 36%, P = .12) among the current patients compared with historical controls. Multivariate analysis showed that a normal karyotype pretransplant and the use of methotrexate as part of posttransplant immunosuppression were associated with improved survival and reduced nonrelapse mortality. Univariate analysis showed significant differences in relapse rates based on marrow source (57% for HLA genotypically matched marrow v 18% for all others, P = .04) and on disease morphology (66% for RAEB-T v 38% for RAEB and CMML, P = .05)., Conclusion: Patients with advanced morphology myelodysplasia tolerated the intensified BU/CY/TBI preparative regimen and reduced posttransplant immunosuppression poorly. Novel transplant procedures are needed to reduce relapse rates without increasing nonrelapse mortality rates. In addition, transplantation before progression to RAEB-T, if possible, may reduce the risk of relapse. more...
- Published
- 1996
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39. Peripheral-blood stem-cell collections after paclitaxel, cyclophosphamide, and recombinant human granulocyte colony-stimulating factor in patients with breast and ovarian cancer.
- Author
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Demirer T, Rowley S, Buckner CD, Appelbaum FR, Lilleby K, Storb R, Schiffman K, and Bensinger WI
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Blood Cell Count drug effects, Breast Neoplasms mortality, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Middle Aged, Neutropenia chemically induced, Ovarian Neoplasms mortality, Paclitaxel administration & dosage, Paclitaxel adverse effects, Platelet Count drug effects, Thrombocytopenia chemically induced, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blood Specimen Collection, Breast Neoplasms blood, Breast Neoplasms drug therapy, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells drug effects, Ovarian Neoplasms blood, Ovarian Neoplasms drug therapy
- Abstract
Purpose: Here we evaluate Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and cyclophosphamide (CY) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for mobilization of peripheral-blood stem cells (PBSCs) for autologous stem-cell transplantation in patients with breast and ovarian cancer., Patients and Methods: PBSCs were collected from 17 patients with breast (n = 11), ovarian (n = 5), and gastric (n = 1) cancer after administration of Taxol (170 mg/m2 x 1) and CY (4 g/m2 x 1) followed by rhG-CSF (10 micrograms/kg/d). PBSC collections after Taxol and CY were compared with PBSC collections from nine patients with stage IV breast (n = 8) or stage III ovarian (n = 1) cancer who had received CY (4 g/m2 x 1) followed by rhG-CSF (16 micrograms/kg/d) for mobilization., Results: Mean WBC and platelet counts on the first day of apheresis were 6.3 x 10(9)/L (range, 1.9 to 22.1) and 35 x 10(9)/L (range, 19 to 77), respectively. The median numbers of CD34+ cells, peripheral-blood mononuclear cells (PBMNC), and peripheral-blood total nucleated cells (PBTNC) collected were 13.02 x 10(6)/kg (range, 5.4 to 57.8; mean, 16.02), 6.86 x 10(8)/kg (range, 1.9 to 51.2), and 17.41 x 10(8)/kg (range, 2.4 to 106.6), respectively. In the comparison group, the median yield of CD34+ cells was 6.39 x 10(6)/kg (range, 0.2 to 28; mean, 10.01; P = .01). The mean daily yield of CD34+ cells/kg/collection was 3.5 (range, 0.8 to 28.9) after Taxol and CY, as compared with 1.3 (range, 0.1 to 7.0) for patients who received CY alone (P = .01). All patients who received CY and Taxol reached a target level of 5 x 10(6) CD34+ cells/kg, as compared with five of nine patients (55.5%) who received CY alone (P = .03)., Conclusion: These data suggest that Taxol and CY followed by rhG-CSF mobilizes PBSCs in patients with advanced breast and ovarian cancer more effectively than this regimen without Taxol. more...
- Published
- 1995
- Full Text
- View/download PDF
40. Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study.
- Author
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Bigelow CL, Kopecky K, Files JC, Head D, Lipschitz DA, Grever M, and Appelbaum FR
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Etoposide administration & dosage, Etoposide adverse effects, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Survival Analysis, Thioguanine administration & dosage, Thioguanine adverse effects, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6-thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V-TAD) in individuals greater than 50 years of age with AML. Thirty-five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty-nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara-C 75 mg/m2 days 1-5, 6-thioguanine 75 mg/m2 every 12 hr days 1-5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara-C 75 mg/m2 days 1-7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy. Thirty-one patients were evaluable for response. Thirteen patients (ten of twenty-five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1-21 months). The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia. more...
- Published
- 1995
- Full Text
- View/download PDF
41. Phase II study of busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for allogeneic bone marrow transplantation in patients with advanced myeloid malignancies.
- Author
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Lynch MH, Petersen FB, Appelbaum FR, Bensinger WI, Clift RA, Storb R, Sanders JE, Hansen JA, and Buckner CD
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Busulfan adverse effects, Busulfan therapeutic use, Child, Child, Preschool, Cyclophosphamide adverse effects, Cyclophosphamide therapeutic use, Female, Graft vs Host Disease etiology, Humans, Infant, Leukemia, Myeloid mortality, Male, Middle Aged, Recurrence, Retrospective Studies, Survival Rate, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Leukemia, Myeloid therapy, Whole-Body Irradiation
- Abstract
A previous phase I dose escalation study determined that the maximum tolerated doses of busulfan and cyclophosphamide that could be combined with 12.0 Gy of total body irradiation were 7 mg/kg and 50 mg/kg, respectively. A phase II study of these three agents was carried out in 56 patients with advanced myeloid malignancies receiving allogeneic bone marrow transplants from HLA-identical donors. Cyclosporine with methotrexate or with prednisone was administered for prophylaxis against graft-versus-host disease. Grade 3 (n = 8) and 4 (n = 3) regimen-related toxicity occurred in 20% of patients, which was the maximum predicted from the phase I study. The 2-year actuarial probabilities of non-relapse mortality and relapse were 0.52 and 0.55, respectively. Fourteen patients survive, 12 in remission, 581-1761 days post-transplant. The actuarial probabilities of disease-free survival for patients with recurrent acute myeloid leukemia and advanced chronic myeloid leukemia at 2 years were 20% and 23%, respectively. When compared with our historical experience in patients receiving other treatment regimens, there was no apparent improvement in disease-free survival. more...
- Published
- 1995
42. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.
- Author
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Weaver CH, Petersen FB, Appelbaum FR, Bensinger WI, Press O, Martin P, Sandmaier B, Deeg HJ, Hansen JA, and Brunvand M
- Subjects
- Adolescent, Adult, Cyclophosphamide administration & dosage, Etoposide administration & dosage, Female, Hodgkin Disease mortality, Humans, Lymphoma, Non-Hodgkin mortality, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Radiotherapy Dosage, Survival Rate, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Hodgkin Disease therapy, Lymphoma, Non-Hodgkin therapy, Whole-Body Irradiation
- Abstract
Purpose: To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma., Patients and Methods: Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells., Results: Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09)., Conclusion: These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems. more...
- Published
- 1994
- Full Text
- View/download PDF
43. Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies.
- Author
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Weaver CH, Bensinger WI, Appelbaum FR, Lilleby K, Sandmaier B, Brunvand M, Rowley S, Petersdorf S, Rivkin S, and Gooley T
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms therapy, Busulfan administration & dosage, Busulfan adverse effects, Combined Modality Therapy, Drug Tolerance, Female, Graft Survival, Humans, Male, Melphalan administration & dosage, Melphalan adverse effects, Middle Aged, Thiotepa administration & dosage, Thiotepa adverse effects, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation methods, Neoplasms drug therapy, Neoplasms therapy
- Abstract
The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted. more...
- Published
- 1994
44. Treatment outcome with chemotherapy in acute promyelocytic leukemia: the Southwest Oncology Group (SWOG) experience.
- Author
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Head DR, Kopecky KJ, Willman C, and Appelbaum FR
- Subjects
- Drug Administration Schedule, Humans, Middle Aged, Survival Analysis, Treatment Outcome, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy
- Abstract
Because of interest in new approaches to treatment of patients with acute promyelocytic leukemia (APL), we analyzed APL treatment outcome in SWOG with chemotherapy from 1982-1991. To evaluate effects of change in nonspecific patient care factors over time we evaluated outcome in two temporal groups (1982-1986, 1986-1991), corresponding to two groups of treatment protocols encompassing all new de novo AML patients entered on acute myeloblastic leukemia (AML) protocols during those years. Surprisingly, APL patients in the 1982-1986 group (n = 45) had much better treatment outcome (complete remission (CR) rate 71%, median overall survival (OS) 106 months, median disease-free survival (DFS) > 105 months) than the later group (n = 96) (CR rate 47%, median OS 13 months, median DFS 28 months) (p = 0.0063, 0.0015, and 0.0001 respectively). All APL patients but two in the 1982-1986 time period were treated on SWOG protocol 8124, which included induction with total daunorubicin (DNR) 210 mg/m2 i.v./course, consolidation with two courses with identical dosage of DNR, and intensification at 4 months including another course of identical dosage DNR. We analyzed factors affecting treatment outcome for all patients with APL treated from 1982 to 1991. In multivariate analysis, higher DNR induction dose was significantly associated with CR rate, OS, and DFS (p < 0.001, < 0.0001, and < 0.0001, respectively). Cytosine arabinoside (ARA-C) dose and inclusion of other agents did not correlate significantly with outcome. Because these studies were not randomized for DNR dosage, other factors contributing to outcome cannot be completely excluded, although none were found. Most deaths occurred within 3 months of initiation of therapy on 8124; there were no relapses with higher DNR dosage after 3 years. This excellent outcome should be considered in evaluating newer modalities of therapy such as all-trans retinoic acid (ATRA) for APL. If the high CR induction rate and minimal early deaths with ATRA therapy can be combined successfully with this chemotherapy, most patients with APL may be curable. more...
- Published
- 1994
45. High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-limiting radiation therapy.
- Author
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Weaver CH, Appelbaum FR, Petersen FB, Clift R, Singer J, Press O, Bensinger W, Bianco J, Martin P, and Anasetti C
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carmustine administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Etoposide administration & dosage, Female, Humans, Lymphoma radiotherapy, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma radiotherapy, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation adverse effects, Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Purpose: To evaluate high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in patients with lymphoid malignancy who had received prior radiation therapy., Patients and Methods: Fifty-seven patients with non-Hodgkin's lymphoma (NHL; n = 23), Hodgkin's disease (HD, n = 32), or acute lymphoblastic leukemia (ALL; n = 2) with a history of previous radiation therapy were treated with cyclophosphamide (Cy; 7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2) (CBV) followed by ABMT., Results: The projected 2-year probabilities of survival, event-free survival (EFS), and relapse were .31, .24, and .76, respectively. For patients with intermediate- and high-grade lymphoma and HD the probabilities were .27, .10, and .14 for EFS and .57, .90, and .77 for relapse. The probability of nonrelapse mortality in the first 100 days post-ABMT was 33%. Idiopathic pneumonia syndrome (IPS) was observed in no patients who received carmustine 300 mg/m2 and 23% of patients who received carmustine 600 mg/m2 (P = .05). Eight-three percent of patients who received mediastinal radiation therapy less than 3 months before transplant developed IPS, compared with 13% who received radiation therapy more than 3 months before transplant (P = .001)., Conclusion: ABMT following high-dose CBV resulted in long-term disease-free survival in 25% of patients with lymphoid malignancies who had previously received dose-limiting radiation therapy. Fatal IPS and a high relapse rate were major factors limiting successful outcome following ABMT. The morbidity and mortality rates associated with the administration of carmustine 600 mg/m2 were prohibitively high, especially in patients who received mediastinal radiation immediately before ABMT, and were not associated with a decrease in post-ABMT relapse. more...
- Published
- 1993
- Full Text
- View/download PDF
46. A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study.
- Author
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Elias L, Stock-Novack D, Head DR, Grever MR, Weick JK, Chapman RA, Godwin JE, Metz EN, and Appelbaum FR
- Subjects
- Administration, Oral, Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Blood Platelets drug effects, Chlorambucil administration & dosage, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Vidarabine Phosphate administration & dosage, Vidarabine Phosphate analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Fludarabine monophosphate is a new antimetabolite with demonstrated activity in chronic lymphocytic leukemia (CLL). We have investigated the practicality of utilizing fludarabine in combination with chlorambucil in a disease-specific phase I trial. Twenty-one patients with advanced and previously treated, relapsed or refractory CLL were treated with chlorambucil plus fludarabine. Chlorambucil was given day 1 at 15 or 20 mg/m2 per os and fludarabine days 1-5 at 10, 15, or 20 mg/m2 intravenously, every 28 days. We concluded that with chlorambucil 15 mg/m2, the maximum tolerated dose for fludarabine was 20 mg/m2 in this patient population with this scheduling. Dose-limiting toxicity was thrombocytopenia. A low incidence of peripheral neuropathy, rash, pulmonary fungal infection, and acute tumor lysis syndrome was also encountered. Although responses were observed, it was impossible from this study to determine whether the combination was better than fludarabine alone in this heavily pretreated population. This study does, however, demonstrate the feasibility of exploring the utility of such a combination in previously untreated patients. An intergroup phase III trial utilizing this combination has been initiated. more...
- Published
- 1993
47. Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation.
- Author
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Press OW, Livingston R, Mortimer J, Collins C, and Appelbaum F
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cisplatin administration & dosage, Cisplatin adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Dexamethasone administration & dosage, Dexamethasone adverse effects, Female, Humans, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Lymphoma, Non-Hodgkin therapy, Neoplasm Recurrence, Local therapy
- Abstract
Combination chemotherapy is capable of curing many patients with newly diagnosed intermediate- and high-grade non-Hodgkin's lymphomas (NHL), but treatment of relapsed NHL remains problematic. Bone marrow transplantation (BMT) offers the best chance for disease-free survival, but interim chemotherapy is often necessary while awaiting BMT, especially for patients with bulky disease. We report here 39 patients (median age, 44 years) who failed primary therapy with doxorubicin-based regimens and subsequently were treated with one to six cycles of dexamethasone, 40 mg intravenous (IV) every day on days 1 to 4, cisplatin 100 mg/m2 by continuous infusion on day 1, and cytarabine 2 g/m2 IV every 12 hours x two doses on day 2 (DHAP) before the planned BMT. Histologies included 16 diffuse large-cell, six diffuse mixed, five diffuse small-cleaved, four lymphoblastic, and eight other. Twenty-eight patients had stage IV disease, 13 had B symptoms, and 20 had an elevated lactate dehydrogenase (LDH). Patients had been treated with a median of three previous chemotherapy regimens. Sixty-one percent of patients had high tumor burdens according to the MD Anderson criteria. Objective responses to DHAP were seen in 26 patients (67%) including nine complete responses (CRs) (23%) and 17 partial responses (PRs) (44%), and responses lasted a median of 7.5 months. Myelosuppression was the major toxicity, but there were no treatment-related deaths. To date, 17 patients have undergone subsequent BMT with a projected 3-year disease-free survival of 15%. We conclude that the DHAP regimen is effective short-term salvage therapy for relapsed NHL patients, but the long-term prognosis of multiply relapsed patients remains poor. more...
- Published
- 1991
- Full Text
- View/download PDF
48. Phenotyping of canine lymphoma with monoclonal antibodies directed at cell surface antigens: classification, morphology, clinical presentation and response to chemotherapy.
- Author
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Appelbaum FR, Sale GE, Storb R, Charrier K, Deeg HJ, Graham T, and Wulff JC
- Subjects
- Animals, Antibodies, Monoclonal, Asparaginase therapeutic use, Dog Diseases drug therapy, Dogs, Female, Lymph Nodes immunology, Lymph Nodes pathology, Lymphoma drug therapy, Lymphoma immunology, Male, Mechlorethamine therapeutic use, Mercaptopurine therapeutic use, Phenotype, Prednisolone therapeutic use, Vincristine therapeutic use, Antigens, Neoplasm analysis, Antigens, Surface analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dog Diseases immunology, Lymphoma veterinary
- Abstract
Forty cases of naturally occurring canine lymphoma were studied using a panel of murine monoclonal antibodies which identify defined subsets of normal canine lymphocytes. The distribution of phenotypes was similar to that which is seen in man in that the majority (78 per cent) of canine lymphomas were of B-cell origin but a definite minority were phenotypically of T-cell (10 per cent) or non-B, non-T-cell (12 per cent) origin. The expression of Ia-like antigens was restricted to B-cell neoplasms. Within each histologic subgroup of canine lymphomas there was considerable heterogeneity of cell surface marker expression. Immunophenotype appeared to correlate with clinical presentation. Finally, the reactivity of lymphoma cells with murine monoclonal antibody DLy-6, an antibody which appears to react with a differentiation antigen on canine B and T cells, strongly predicted the outcome of initial induction chemotherapy in that all ten evaluable dogs with DLy-6-tumors achieved complete responses to initial chemotherapy while only four of 11 dogs with DLy-6+ tumors responded completely. more...
- Published
- 1984
- Full Text
- View/download PDF
49. High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia.
- Author
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Riddell S, Appelbaum FR, Buckner CD, Stewart P, Clift R, Sanders J, Storb R, Sullivan K, and Thomas ED
- Subjects
- Acute Disease, Adolescent, Adult, Child, Clinical Trials as Topic, Cyclophosphamide administration & dosage, Cytarabine administration & dosage, Humans, Immunosuppression Therapy, Infant, Leukemia drug therapy, Leukemia, Lymphoid drug therapy, Leukemia, Lymphoid therapy, Leukemia, Myeloid drug therapy, Leukemia, Myeloid therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Cyclophosphamide therapeutic use, Cytarabine therapeutic use, Leukemia therapy
- Abstract
Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens. more...
- Published
- 1988
- Full Text
- View/download PDF
50. Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission.
- Author
-
Tallman MS, Kopecky KJ, Amos D, Dahlberg S, Hewlett JS, Files JC, Coltman CA, Thomas ED, and Appelbaum FR
- Subjects
- Adolescent, Adult, Age Factors, Child, Child, Preschool, Combined Modality Therapy, Female, Humans, Infant, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prognosis, Regression Analysis, Remission Induction, Sex Factors, Whole-Body Irradiation, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Leukemia, Myeloid, Acute mortality
- Abstract
To test whether variables at diagnosis can identify patients with acute nonlymphoblastic leukemia (ANL) for whom bone marrow transplantation (BMT) is more likely to be of benefit and those for whom continued chemotherapy is a better approach, the association of 15 clinical and laboratory factors with outcome was investigated among 220 patients (ages 1 to 53 years) treated with cyclophosphamide and total body irradiation (TBI) followed by allogeneic BMT, and among 392 patients (ages 13 to 50) administered intensive chemotherapy. In the BMT group, female sex, younger age, the absence of hepatitis during induction, a larger percentage of circulating blasts, and a shorter duration of symptoms were associated with longer survival, whereas only female sex and younger age favorably influenced disease-free survival (DFS). In the chemotherapy group, younger age, lower WBC at diagnosis, a single successful induction course, and the absence of circulating promyelocytes were associated with longer survival, whereas only a lower WBC and a lower percentage of peripheral neutrophils were associated with longer DFS. Estimated regression coefficients for treatment-by-prognostic-factor interactions were used to characterize subgroups of patients in which one treatment or the other produced better outcomes. BMT and chemotherapy produced similar durations of survival in a subset of patients characterized by many or all of the following: older age, male sex, achievement of complete remission (CR) after one induction, and absence of circulating blast cells at presentation. These data suggest that, using pretreatment variables, subgroups of patients can be identified for whom either BMT or continued chemotherapy is most likely to be beneficial. more...
- Published
- 1989
- Full Text
- View/download PDF
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