Second-line treatment for primary central nervous system lymphoma.
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Failure after first-line treatment was reported in 35-60% of immunocompetent patients with primary central nervous system lymphoma (PCNSL). There are currently no reports focusing on salvage therapy. This review analyses prognostic factors and the efficacy of salvage therapy by focusing on data from papers reporting results of first-line treatment in 355 cases. The study group consisted of 173 patients presenting treatment failure. The interval between failure and death (TTD) was compared for age at relapse (< or =60 vs. >60 years), type of failure (relapse vs. progression), time to relapse (< or =12 vs. >12 months) and salvage treatment (yes vs no). Median TTD was similar in younger and older patients (P = 0.09). Relapsed patients had a longer TTD than patients with progressive disease (P = 0.002). Early relapse led to a shorter TTD than late relapse (P = 0.005). Median TTD was 14 months for patients who underwent salvage therapy and 2 months for untreated cases (P<0.00001). A multivariate analysis showed an independent prognostic role for salvage therapy and time to relapse. Age and type of failure had no predictive value. Salvage therapy significantly improves outcome and, possibly, quality of life. As many different treatments were used conclusions cannot be made regarding an optimal treatment schedule. (+info)
ESHAP as salvage therapy for refractory non-Hodgkin's lymphoma: Taiwan experience.
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BACKGROUND: The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin, has been shown to be active against refractory non-Hodgkin's lymphoma in therapeutic trials. We were interested in determining whether this regimen would be effective and tolerable for Chinese patients. METHODS: Thirty-two patients with refractory/relapsed non-Hodgkins lymphoma (23 intermediate-grade and nine high-grade) were enrolled in this study. Etoposide was administered at a dose of 40 mg/m2/day as a 1 h intravenous infusion from day 1 to day 4, solumedrol 500 mg/day was given as a 15 min intravenous infusion from day 1 to day 5, ara-C 2 g/m2 was given as a 2 h intravenous infusion on day 5 and cisplatin was given at a dose of 25 mg/m2/day as a continuous infusion from day 1 to day 4. Clinical efficacy and toxicity were assessed on the basis of the WHO criteria. RESULTS: Ten patients (31.3%, 95% Cl 15.2-47.4%) attained complete remission (CR) and seven had partial remission (PR). The overall response rate was 53.1% (95% Cl 35.8-70.4%). In eight of the 10 CR patients, the remission lasted for more than 8 months. The remaining two patients had CR of 5 and 6 months. The median duration of CR was 12.2 months (range 5-22 months). Myelosuppression with subsequent infections was the major toxicity. Severe leukopenia (WBC < 1000/microliter) lasted for an average of 12 days and thrombocytopenia (< 25,000/microliter) 18 days. One patient (3.1%) died of neutropenia-associated sepsis within 4 weeks after treatment. Non-myeloid toxicities included alopecia in 66% (28% grade 2, 22% grade 3), stomatitis in 72% (25% grade 2, 28% grade 3, 13% grade 4), hepatotoxicity in 9% (3% grade 2), renal toxicity in 13% (6% grade 2, 3% grade 3) and infection in 56% (18% grade 2, 25% grade 3, 13% grade 4). The majority of the responders relapsed within 2 years after ESHAP treatment. Median survival for all patients was 8.6 months. CONCLUSIONS: ESHAP is an active and tolerable regimen in Chinese patients with relapsed/refractory lymphoma, but the duration of remission is brief and without significant impact on survival. (+info)
Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma.
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Transplantation after high-dose chemotherapy prolongs survival in patients with multiple myeloma compared with standard therapy. It is unclear whether the optimal timing of transplantation is immediately after induction chemotherapy or whether stem cells may be cryopreserved for transplantation at subsequent progression or relapse. In this study, stem cells were collected within 6 months of diagnosis, followed by transplantation only at progression of myeloma. One hundred and eighteen patients with multiple myeloma had stem cells collected and cryopreserved. Eleven had transplants early in the disease after they demonstrated failure to respond to primary therapy. The remaining 107 were eligible for transplants when there was evidence of progressive disease. Of the 118 patients, 67 had transplants, nine died of progressive disease before transplantation, and 42 remain alive in plateau phase. The median survival of the group is 58.5 months; 67 are alive. Serum beta2-microglobulin, bone marrow labeling index (S phase), and hemoglobin level predicted overall survival (P < 0.006, P < 0.001, and P < 0.01, respectively). We conclude that early cryopreservation of blood stem cells followed by transplantation at progression is a feasible approach to therapy in patients with myeloma. The underlying biology of the disease has a greater impact on survival than the timing of transplantation. A prospective randomized trial is required to answer definitively the question of the optimal timing of blood cell transplantation. (+info)
High-dose therapy with autologous or allogeneic transplantation as salvage therapy for small cleaved cell lymphoma of follicular center cell origin.
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Between 1985 and 1996, 51 patients with relapsed or refractory small cleaved cell lymphoma (SCCL) received high-dose chemotherapy +/- TBI in conjunction with autologous (ABMT) (36 patients) or allogeneic transplantation (15 patients). Patients were eligible for ABMT if the bone marrow biopsy done prior to the planned transplant did not reveal microscopic involvement with SCCL. Patients receiving ABMT had a median age of 48 years, had received a median of 2.5 chemotherapy regimens prior to transplantation, and were transplanted a median of 35.5 months from diagnosis. Among patients receiving ABMT, 5 year actuarial survival was 56+/-11%. Median survival was 126+ months, and median survival from diagnosis was 191 months. Univariate and multivariate analysis identified sensitive disease as the best predictor of a favorable response. Five-year actuarial survival was 66+/-12% for patients with sensitive disease at the time of transplant as compared to 29+/-17% for patients with resistant disease, P = 0.015. Median survival in patients with sensitive disease at the time of ABMT was 126+ months. By univariate analysis, survival was significantly better for patients receiving ABMT as compared to patients receiving allogeneic transplants. Median survival following allogeneic transplantation was 5 months; 5 year actuarial survival was 15+/-13%. In a multivariate analysis, which considered autologous vs allogeneic transplantation, sensitive vs resistant disease, <3 vs > or = 3 prior treatments, and prior bone marrow involvement, allogeneic transplantation was significantly associated with poor survival. Treatment-related mortality occurred in eight of 15 patients receiving allogeneic transplantation and limited the effectiveness of this therapy. High-dose therapy in conjunction with ABMT is effective therapy for patients with SCCL whose disease is sensitive to chemotherapy and whose marrows are microscopically free of disease. Because of possible selection bias, it has not been proven that this approach increases survival in these patients. Treatment-related mortality limits the effectiveness of allogeneic transplantation in SCCL. (+info)
Autologous transplantation of chemotherapy-purged PBSC collections from high-risk leukemia patients: a pilot study.
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We have recently demonstrated that the combination of the alkylating agent nitrogen mustard (NM) and etoposide (VP-16) is capable of eliminating, ex vivo, leukemic cells contaminating PBSC collections and this is associated with a significant recovery of primitive and committed hematopoietic progenitor cells. Based on these data a pilot study on autologous transplantation of NM/VP-16 purged PBSC for high-risk leukemic patients was recently initiated. Twelve patients (seven females and five males) with a median age of 46 years (range 18-57) have been treated. Two patients had acute myeloblastic leukemia (AML) resistant to conventional induction treatment, four patients had secondary AML in I complete remission (CR), one patient was in II CR after failing a previous autologous BM transplantation, while two additional AML individuals were in I CR achieved after three or more cycles of induction treatment. Two patients with high-risk acute lymphoblastic leukemia (ALL) in I CR and one patient with mantle cell lymphoma and leukemic dissemination were also included. Eight patients showed karyotypic abnormalities associated with a poor clinical outcome. The mobilizing regimens included cytosine arabinoside and mitoxantrone with (n = 6) or without fludarabine (n = 3) followed by subcutaneous administration of G-CSF (5 microg/kg/day until the completion of PBSC collection) and G-CSF alone (n = 3) (15 microg/kg/day). A median of two aphereses (range 1-3) allowed the collection of 7.2 x 10(8) TNC/kg (range 3.4-11.5), 5 x 10(6) CD34+ cells/kg (range 2.1-15.3) and 9.2 x 10(4) CFU-GM/kg (0.3-236). PBSC were treated with a constant dose of 20 microg of VP-16/ml and a median individual-adjusted dose (survival < or = 5% of steady-state BM CFU-GM) of NM of 0.7 microg/ml (range 0.25-1.25). Eleven patients were reinfused after busulfan (16 mg/kg) and Cy (120 mg/kg) conditioning with a median residual dose of 0.3 x 10(4) CFU-GM/kg (0-11.5). The median time to neutrophil engraftment (>0.5 x 10(9)/l) for evaluable patients was 25 days (range 12-59); the median time to platelet transfusion independence (>20 and >50 x 10(9)/l) was 40 days (18-95) and 69 days (29-235), respectively. Hospital discharge occurred at a median of 25 days (18-58) after stem cell reinfusion. Four individuals are alive in CR (n = 3) or with residual nodal disease (n = 1 lymphoma patient) with a follow-up of 32, 26, 3 and 14 months, respectively. Seven patients died due to disease progression or relapse (n = 5) or extrahematological transplant toxicity (n = 2). Our data suggest that pharmacological purging of leukapheresis collections of leukemic patients at high-risk of relapse is feasible and ex vivo treated cells reconstitute autologous hematopoiesis. (+info)
Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens.
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Allogeneic bone marrow transplantation (BMT) is a common treatment of hematologic malignancies. Recurrence of the underlying malignancy is a major cause of treatment failure. Donor-derived cytotoxic T lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1 and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively expressed on hematopoietic cells, including leukemic cells and leukemic precursors, but not on fibroblasts, keratinocytes, or liver cells. The chemical nature of the mHags HA-1 and HA-2 is known. We investigated the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs) were used as antigen-presenting cells (APC) to stimulate autologous unprimed CD8(+) T cells. The ex vivo-generated HA-1- and HA-2-specific CTLs efficiently lyse leukemic cells derived from acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No lytic reactivity was detected against nonhematopoietic cells. Sufficient numbers of the CTLs can be obtained for the adoptive immunotherapy purposes. In conclusion, we present a feasible, novel therapy for the treatment for relapsed leukemia after BMT with a low risk of GVHD. (+info)
Treatment of multiple myeloma.
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BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies. The standard treatment with intermittent courses of melphalan and prednisone (MP) was introduced more than 30 years ago and, since then there has been little improvement in event-free and overall survival (EFS & OS). The aim of this article is to review: 1) the role of initial chemotherapy (ChT), maintenance treatment with alpha-interferon and salvage ChT, 2) the results of high-dose therapy (HDT) followed by allogeneic or autologous stem cell transplantation (allo-SCT and auto-SCT), and 3) the most important supportive measures. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing with original investigations on the treatment of MM during the last 15 years. In addition, the most relevant articles and recent abstracts published in journals covered by the Science Citation Index and Medline are also reviewed. STATE OF THE ART AND PERSPECTIVES: The importance of avoiding ChT in asymptomatic patients (smoldering MM) is emphasized. The criteria and patterns of response are reviewed. MP is still the standard initial ChT with a response rate of 50-60% and an OS of 2-3 years. Combination ChT usually increases the response rate but does not significantly influence survival when compared with MP. Exposure to melphalan should be avoided in patients in whom HDT followed by auto-SCT is planned, in order to not preclude the stem cell collection. The median response duration to initial ChT is 18 months. Interferon maintenance usually prolongs response duration but in most studies does not significantly influence survival (a large meta-analysis by the Myeloma Trialists' Collaborative Group in Oxford is being finished). In alkylating-resistant patients, the best rescue regimens are VBAD or VAD. In patients already resistant to VBAD or VAD and in those in whom these treatments are not feasible we recommend a conservative approach with alternate day prednisone and pulse cyclophosphamide. While HDT followed by autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in order to treat or prevent relapses. Finally, important supportive measures such as the treatment of anemia with erythropoietin, the management of renal failure and the use of bisphosphonates are reviewed. (+info)
Costs of high-dose salvage therapy and blood stem cell transplantation for resistant-relapsed malignant lymphomas in a southern Italian hospital.
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BACKGROUND AND OBJECTIVE: Analysis of costs of high technological procedures such as peripheral blood stem cell (PBSC) autotransplantation in lymphomas are generally finalized at disclosing whether the improvement of survival in a subset of patients is cost effective and whether the cost of the procedure could be reduced. With the aim of revealing a possibility of reducing costs with respect to conditions of safety, we present our experience with PBSC autotransplantation in a particularly poor prognosis subset of patients with lymphoma. DESIGN AND METHODS: The expenses are analyzed for groups of cost and main resources necessary at unitary cost are considered separately. Groups of cost include various phases of the PBSC autotransplantation such as preparative procedures, execution of myeloablative therapy, reinfusion of CD34 cells, supportive therapy after reinfusion until discharge of the patient, general support for the management of patient. All costs are calculated according to 1997 prices and salaries and reported in dollars. The analysis was conducted on 21 patients with lymphoma resistant to other therapies treated by myeloablative therapy and PBSC autotransplantation in an hematologic unit in an open ward; the assistance was provided by staff not exclusively dedicated to bone marrow transplant procedures, with some help from a family member. RESULTS: The PBSC procedure, including all phases, costs from $17,761.9 to $18,259.9 depending on the type of myeloablative therapy employed; the mean cost was $18,092.6. The preparative phase with mobilization of CD34 cells, cryopreservation and reinfusion costed $3,538.7 (19.6% of the total cost); a major cost of this phase was cryopreservation and CD34 manipulation ($857.1). The second phase with myeloablative therapy and reinfusion of CD34 cells had a mean cost of $2,785.9 (15.4% of the total cost); a major cost of this phase was the hospitalization ($1,119.8). The third phase of patient's support after treatment had a total cost of $7,649 (42.3% of the cost of the total procedure) with the major cost being due to hospitalization ($2,571) calculated on a mean of 15 days after the reinfusion of CD-34. The last group of costs, including management support, accounted for $4,119 (22.7%) with a major cost being amortization of the structure ($1,600). The general cost for nurse's assistance to the patient was $1,355.1 (7.5%). INTERPRETATION AND CONCLUSIONS: A procedure of PBSC autotransplantation in resistant lymphoma is affordable without the strict precautions generally given in intensive care units. This provides a substantial reduction of expenses because of the low number of specifically trained staff members and the generally low cost of the necessary supplies. Before, however, proposing PBSC autotransplantation in most patients with resistant lymphoma, an evaluation of whether costs could be further reduced and whether the procedure has a cost benefit impact is needed. (+info)