Rapid reversal of nephrotic syndrome due to primary systemic AL amyloidosis after VAD and subsequent high-dose chemotherapy with autologous stem cell support.
(17/1170)
In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits. Monoclonal lambda light chains were identified in serum and urine. A low percentage of monoclonal plasma cells was detected in the bone marrow. The patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT) with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell transplantation. Proteinuria rapidly diminished during chemotherapy. Three months after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are currently detectable. Using VAD before starting HDCT may improve the condition of patients with amyloidosis and reduce transplantation-related morbidity and mortality. (+info)
Melphalan 220 mg/m2 followed by peripheral blood stem cell transplantation in 27 patients with advanced multiple myeloma.
(18/1170)
Twenty-seven patients with advanced multiple myeloma received high-dose therapy with 220 mg/m2 i.v. melphalan (HDM220) followed by autologous stem cell transplantation. At the time of HDM220, nine patients had primary refractory disease and 18 were in relapse after having responded to prior high-dose therapy. No toxic deaths were observed. The major adverse side-effect was grade 4 mucositis in 63% of patients. Two patients experienced reversible paroxysmal atrial fibrillation after HDM220. For the whole group of patients, the actuarial 3-year overall survival (OS) and event-free survival (EFS) are 36.1 and 16.9%, respectively. The probability of OS and EFS was significantly lower in patients treated for refractory relapse (22.9 and 0% at 2 years, respectively) as compared to primary refractory patients (66.7 and 64.3% at 2 years, respectively) or patients treated for chemosensitive relapse (42.9% at 2 years) (P = 0.0001). Low beta2-microglobulin and CRP levels at the time of HDM220 were associated with a better OS and EFS. Our data suggest that HDM220 followed by ASCT should be considered in patients with primary refractory disease or chemosensitive disease relapsing after prior intensive therapy. (+info)
Induction of alkylator (melphalan) resistance in HL60 cells is accompanied by increased levels of topoisomerase II expression and function.
(19/1170)
Human leukemic HL60 cells were selected for resistance to alkylating agents by stepwise exposure to increasing concentrations of L-phenylalanine mustard (melphalan). The resulting resistant cell line (R-HL60) was 4-fold resistant (melphalan IC50 value, 27.84 +/- 4.2 microM) to melphalan compared with parental HL60 cells (melphalan IC50 value, 6.9 +/- 1.78 microM). Nuclear extracts from R-HL60 cells possess a approximately 4-fold increase in DNA topoisomerase II activity compared with parental HL60 cells. As determined using Western blot analysis, the level of topoisomerase IIalpha protein expressed in R-HL60 cells was approximately 3-fold that of parental HL60 cells. However, there were no differences observed in the level of topoisomerase IIbeta protein, in the topoisomerase I activity, or in the level of topoisomerase I protein expression comparing the two cell lines. R-HL60 cells were 5-fold more sensitive than parental HL60 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. The sensitivity to the cytotoxic effects of the topoisomerase I inhibitor camptothecin did not differ in R-HL60 and parental HL60 cell lines. Preincubation with doxorubicin significantly increased melphalan-induced interstrand DNA cross-link formation and cytotoxicity in R-HL60 cells compared with the parental HL60 cells. The affinity of topoisomerase II for UV-irradiated cross-linked HL60 DNA was increased by approximately 2.5-fold compared with that of HL60 native DNA. The affinity of topoisomerase II for both UV-irradiated (cross-linked) and native DNA was significantly decreased after doxorubicin pretreatment. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for cross-linked DNA in melphalan-resistant cells seems to contribute to alkylator resistance by changing DNA topology, thereby facilitating DNA repair. (+info)
Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats.
(20/1170)
An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings. (+info)
Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma.
(21/1170)
BACKGROUND: The combination of carmustine, etoposide, cytarabine and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a preparative regimen for allogeneic transplantation has not been established. PATIENTS AND METHODS: Thirty adults with primary refractory or recurrent intermediate- or low-grade lymphoma were treated on a prospective phase II study with carmustine 300 mg/m2 i.v. day -6, etoposide 200 mg/m2 i.v. followed by cytarabine 200 mg/m2 i.v. twice daily days -5 to -2, melphalan 140 mg/m2 i.v. day -1, and marrow or blood stem cells from an HLA-identical donor on day 0. Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD). RESULTS: Median time from transplantation was 20 mos (range 6-32 months). Median maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade 3-4 regimen-related toxicity. Two patients had idiopathic interstitial pneumonitis. One patient had primary graft failure, and a second had autologous reconstitution documented at three months posttransplant. Grades 2-4 acute GVHD occurred in 31%, grades 3-4 in 16%, and chronic GVHD in 54%. Day-100 survival was 70%. Twenty-three patients achieved a complete response. The two-year relapse rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%. CONCLUSIONS: BEAM supports engraftment of allogeneic transplants and is a tolerable preparative regimen for allogeneic transplantation for lymphoma. (+info)
Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in patients with locally advanced soft tissue sarcomas: treatment response and clinical outcome related to changes in proliferation and apoptosis.
(22/1170)
Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment. (+info)
Collection of peripheral blood stem cells after a preceding autograft: unfavorable effect of prior interferon-alpha therapy.
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Eighty-eight previously autografted (78 transplanted twice and 10 once) myeloma patients who had no cryopreserved stem cells available for possible future use received G-CSF for mobilization of stem cells. One-fourth of the patients had progressive disease at the time of apheresis. All patients had received 200 mg/m2 melphalan for the first transplant. The interval between the preceding transplant and the harvest was 5-68 months (median 29). A total of 0.46-9.16 (median 3.03) x 10(6) CD34+ cells/kg were collected. More than 2 x 10(6)/kg CD34+ cells were collected in 76% of the patients, and > or = 5 x 10(6)/kg in 14%. On multivariate analysis, patients with platelet counts of > or = 200 x 10(9)/l (P < 0.0001), those who had not received any myelosuppressive chemotherapy between the last transplant and the collection (P = 0.02), and those who had received interferon-alpha for < or = 6 months (P = 0.03) had better collections. Eleven of 12 patients autografted with these cells had prompt neutrophil recovery (median 10 days to 0.5 x 10(9)/l) but recovery to 50 x 10(9)/l platelets was delayed or incomplete in 11 of 12. We conclude that it is possible to harvest peripheral blood stem cells with G-CSF stimulation in patients who have been autografted previously. Limited data suggest that platelet recovery may be suboptimal when these cells are used. These findings have practical implications for patients with malignant diseases in remission after autografting who may be candidates for future salvage therapy but have no stem cells stored, and for patients with chronic myeloid leukemia who are on long-term interferon-alpha therapy to attain cytogenetic remission for eventual collection of normal stem cells. (+info)
Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients.
(24/1170)
A clinical relationship between dose-intensity of melphalan and response rate has been demonstrated in multiple myeloma. Promising results have been reported after 200 mg/m(2) melphalan, especially in younger patients. It is uncertain whether 100 mg/m(2) melphalan (MEL100) can offer similar results in older patients. To address this issue, patients were treated with 2 or 3 MEL100 courses followed by stem cell support. Seventy-one patients (median age, 64 years) entered the protocol at diagnosis. Their clinical outcome was compared with that of 71 pair mates (median age, 64 years) selected from patients treated at diagnosis with oral melphalan and prednisone (MP) and matched for age and beta2-microglobulin. Complete remission was 47% after MEL100 and 5% after MP. Median event-free survival was 34 months in the MEL100 group and 17.7 months in the MP group (P <.001). Median overall survival was 56+ months for MEL100 and 48 months for MP (P <.01). In a multivariate analysis, beta2-microglobulin levels and MEL100 were independent risk factors associated with outcome: superior event-free and overall survival were observed in patients presenting low beta2-microglobulin levels at diagnosis and receiving MEL100 as induction regimen. In conclusion, MEL100 was superior to MP in terms of complete remission rate, event-free survival, and overall survival. (+info)