Subject(s)
Fibroblast Growth Factor 2/biosynthesis , Multiple Myeloma/metabolism , Adult , Aged , Aged, 80 and over , Blotting, Western , Bone Marrow Cells/metabolism , Humans , Membrane Glycoproteins/biosynthesis , Middle Aged , Proteoglycans/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , SyndecansABSTRACT
BACKGROUND: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/drug therapy , Hodgkin Disease/therapy , Adolescent , Adult , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Cyclophosphamide/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Hodgkin Disease/mortality , Humans , Male , Melphalan/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Mitoxantrone/administration & dosage , Prognosis , Transplantation, Autologous , Treatment OutcomeABSTRACT
Patients with multiple myeloma (MM) have increased bone marrow (BM) angiogenesis; however, the proangiogenic properties of myeloma cells and the mechanisms of MM-induced angiogenesis are not completely clarified. The angiopoietin system has been identified as critical in the regulation of vessel formation. In this study we have demonstrated that myeloma cells express several proangiogenic factors, and, in particular, we found that angiopoietin-1 (Ang-1), but not its antagonist Ang-2, was expressed by several human myeloma cell lines (HMCLs) at the mRNA and the protein levels. In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells. Moreover, in an experimental model of angiogenesis, the conditioned medium of HMCLs significantly stimulated vessel formation compared with control or vascular endothelial growth factor (VEGF) treatment. The presence of anti-Tie2 blocking antibody completely blunted the proangiogenic effect of XG-6. Finally, our in vitro results were supported by the in vivo finding of Ang-1, but not Ang-2, mRNA and protein expression in purified MM cells obtained from approximately 47% of patients and by high BM angiogenesis in patients with MM positive for Ang-1, suggesting that the angiopoietin system could be involved, at least in part, in MM-induced angiogenesis.
Subject(s)
Angiogenesis Inducing Agents/physiology , Membrane Glycoproteins/physiology , Multiple Myeloma/metabolism , Neoplasm Proteins/physiology , Neovascularization, Pathologic/metabolism , Proto-Oncogene Proteins , Adult , Angiogenesis Inducing Agents/analysis , Angiogenesis Inducing Agents/biosynthesis , Angiogenesis Inducing Agents/genetics , Angiopoietin-1 , Angiopoietin-2 , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Bone Marrow Cells/metabolism , Coculture Techniques , Culture Media, Conditioned/pharmacology , Endothelial Growth Factors/pharmacology , Endothelium/metabolism , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Leukemia, Plasma Cell/metabolism , Leukemia, Plasma Cell/pathology , Lymphokines/pharmacology , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/genetics , Middle Aged , Multiple Myeloma/blood supply , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neovascularization, Pathologic/genetics , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Receptor, TIE-2 , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
Single-center experiences have shown that intensified treatments with autologous transplantation are a promising therapeutic strategy for patients with high-risk follicle-center lymphoma (FCL) at diagnosis, whereas data from prospective multicenter trials are still lacking. This paper describes the results of a prospective multicenter study of an intensified purging-free high-dose sequential (i-HDS) chemotherapy schedule with peripheral blood progenitor cell (PBPC) autografting. The main feature of this program is harvesting stem cells after intensified chemotherapeutic debulking, with no ex vivo manipulation of PBPCs. Ninety-two previously untreated patients aged 60 or younger with advanced-stage FCL were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. i-HDS proved feasible with limited toxicity (87% patients completed the planned treatment schedule). i-HDS led to a complete remission rate of 88%. The projected overall survival and disease-free survival (DFS) were, respectively, 84% and 67% at 4 years. Centralized molecular analysis showed that polymerase chain reaction-negative harvests could be collected in 47% of cases. Following autograft, 65% of molecularly evaluable patients achieved clinical and molecular remission. The projected DFS at 4 years of this subgroup is 85%. This result emphasizes the importance of achieving maximal tumor reduction in these patients. In conclusion, our data show that highly effective intensified treatments can now be routinely offered to young patients with poor-risk FCL even at small institutions, with no need for sophisticated and expensive cell manipulation procedures.
