Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.
G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.
Summary:Four patients with chronic myelogenous leukemia (CML) that was refractory to interferon alpha (two patients) or imatinib mesylate (two patients), and who lacked donors for allogeneic stem cell transplantation, received autotransplants followed by infusions of ex vivo costimulated autologous T cells. At day þ 30 (about 14 days after Tcell infusion), the mean CD4 þ cell count was 481 cells/ll (range 270-834) and the mean CD8 þ count was 516 cells/ll (range 173-1261). One patient had a relative lymphocytosis at 3.5 months after T-cell infusion, with CD4 and CD8 levels of 750 and 1985 cells/ll, respectively. All the four patients had complete cytogenetic remissions early after transplantation, three of whom also became PCR negative for the bcr/abl fusion mRNA. One patient, who had experienced progressive CML while on interferon alpha therapy, became PCRÀ post transplant, and remained in a molecular CR at 3.0 years of follow-up. All the four patients survived at 6, 9, 40, and 44 months post transplant; the patient who remained PCR þ had a cytogenetic and hematologic relapse of CML, but entered a molecular remission on imatinib. Autotransplantation followed by costimulated autologous T cells is feasible for patients with chronic phase CML, who lack allogeneic donors and can be associated with molecular remissions.
Summary:Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI ¼ 42-76%) and 86% (95% CI ¼ 71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS ¼ 87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study. PBSCT; auto-PBSCT; high-dose therapy; consolidation chemotherapy; gemcitabine High-dose therapy followed by autologous stem cell rescue has improved the long-term event-free (EFS) and overall survival (OS) for patients with relapsed or refractory Hodgkin's disease (HD). The probability of 5-year progression-free survival (PFS) for patients with HD autografted in first relapse ranged from 37 to 63% in selected series, while the PFS for patients autografted for primary refractory disease ranged from 15 to 50%. From these studies, predictors of better outcome after autotransplantation varied, but included 'minimal' disease status, chemosensitivity, normal LDH levels, good performance status, transplant in first relapse, absence of B symptoms at diagnosis, and administration of involvedfield radiotherapy post transplantation. In addition, factors identified by the International Prognostic Factors Project on advanced HD including low serum albumin, anemia, advanced age, and lymphocytopenia were associated with inferior EFS and OS rates after autotransplantation as well. 23 The chief cause of treatment failure after autotransplantation is relapse or progression of disease, which occurs in about 50% of transplanted patients. The majority of relapses occur in sites of prior disease but new and unusual sites of recurrence have been described including the leptomeninges. 11 To prevent or delay disease relapse after auto-PBSCT, a clinical protocol was developed that contained the following novel features: (1) the standard BEAM (BCNU-etoposide-cytarabine-melphalan) conditioning regimen was modified to include gemcitabine because of its single-agent activity in relapsed/refractory HD; 24 (2) dose-intensive cyclophosphamide and etoposide were used for pre-transplant cytoreduction and stem cell mobilization; (3) involv...
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