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Haematologica Mar 2018Melphalan at a dose of 200 mg/m is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m is... (Clinical Trial)
Clinical Trial
Melphalan 140 mg/m or 200 mg/m for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.
Melphalan at a dose of 200 mg/m is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m and melphalan 140 mg/m are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m (n=245) and melphalan 200 mg/m (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m melphalan 140 mg/m: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m and melphalan 140 mg/m patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m or melphalan 140 mg/m for key transplant outcomes (NCT01362972).
Topics: Adult; Aged; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
PubMed: 29217776
DOI: 10.3324/haematol.2017.181339 -
British Journal of Haematology May 1986
Topics: Animals; Cell Line; DNA; Drug Resistance; Humans; Leukemia L1210; Melphalan; Multiple Myeloma
PubMed: 3707856
DOI: 10.1111/j.1365-2141.1986.tb07488.x -
Carbohydrate Polymers Oct 2014The clinical application of melphalan (Me), an anticancer drug for the treatment of hematologic malignancies, has been limited due to its poor water solubility, rapid...
The clinical application of melphalan (Me), an anticancer drug for the treatment of hematologic malignancies, has been limited due to its poor water solubility, rapid elimination and lack of target specificity. To solve these problems, O,N-carboxymethyl chitosan-peptide-melphalan conjugates were synthesized and characterized. All polymeric prodrugs showed satisfactory water solubility. It was found that the molecular weight of O,N-carboxymethyl chitosan (O,N-CMCS) and the peptide spacer played a crucial role in controlling the drug content, diameter and drug release properties of O,N-carboxymethyl chitosan-peptide-melphalan conjugates. The studies of in vitro drug release and cell cytotoxicity by MTT assay revealed that, employing the polymeric conjugation strategy and using the peptides glycylglycine (Gly-Gly) as a spacer, the conjugates have good cathepsin X-sensitivity and lower toxicity and the drug release behavior improved remarkably. In conclusion, O,N-carboxymethyl chitosan-peptide-melphalan conjugates could be promising prodrugs for anticancer application.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chitosan; Drug Carriers; Glycylglycine; Humans; Melphalan; Multiple Myeloma; Nanoparticles; Polymers; Prodrugs; Solubility
PubMed: 25037433
DOI: 10.1016/j.carbpol.2014.04.062 -
Lancet (London, England) Nov 1984
Topics: Humans; Infant; Male; Medication Errors; Melphalan
PubMed: 6149436
DOI: 10.1016/s0140-6736(84)91155-3 -
An overview of high-dose melphalan and stem cell transplantation in the treatment of AL amyloidosis.Amyloid : the International Journal of... Dec 2007AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. This review outlines an overview of high-dose... (Review)
Review
AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. This review outlines an overview of high-dose intravenous melphalan and stem cell transplantation in the treatment of AL amyloidosis. An algorithm of our recommendations for the treatment of AL amyloidosis is also outlined.
Topics: Algorithms; Amyloidosis; Dose-Response Relationship, Drug; Humans; Melphalan; Myeloablative Agonists; Practice Guidelines as Topic; Stem Cell Transplantation
PubMed: 17968685
DOI: 10.1080/13506120701613984 -
World Journal of Surgery 1992In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35-40% of... (Comparative Study)
Comparative Study Review
In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35-40% of cases and partial remission in a further 35-40%. Mild or moderate limb toxicity is usual, but severe toxic reactions in the limb sometimes occur. After preliminary reports suggested that cisplatin administered by ILP was even more effective than melphalan yet less toxic, a study was undertaken to further assess the value of hyperthermic ILP with cisplatin in the management of limb melanoma. Ten patients were treated. The procedure failed to eliminate melanoma in the limb in 5 of the 6 who received therapeutic ILPs for recurrent disease, and recurrence developed in 2 of the 4 patients who received prophylactic ILPs. Toxicity in the perfused limbs was unacceptably high, with 2 of the 10 patients having severe reactions, one necessitating amputation. We conclude from the results of this study and from a review of literature that neither cisplatin nor any other drug or drug combination so far used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan. Studies are currently in progress investigating double perfusion protocols, new strategies with regional hyperthermia, and the administration by ILP of biological response modifiers such as tumor necrosis factor and interferon. However, for the present, hyperthermic ILP with melphalan remains the treatment most likely to be successful in eliminating or controlling advanced or recurrent melanoma in a limb.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Time Factors
PubMed: 1561803
DOI: 10.1007/BF02071525 -
The Journal of Pharmacology and... Jun 2003The optimum conditions (duration and concentration) of a fixed dose, intra-arterial melphalan infusion in relation to its antitumor effect and toxicity in the liver were...
The optimum conditions (duration and concentration) of a fixed dose, intra-arterial melphalan infusion in relation to its antitumor effect and toxicity in the liver were investigated in a rat colon tumor model (CC531) of liver metastases. We studied the difference in tumor and liver uptake, as well as antitumor effect and hepatotoxicity after 5- and 20-min hepatic arterial infusion (HAI) of a fixed melphalan dose. Melphalan content in perfusate, liver, and tumor tissue was analyzed by high-performance liquid chromatography. The antitumor effect and hepatotoxicity in rats treated either systemically or with 5- and 20-min HAI, with a fixed dose melphalan (4.4 micromol), were assessed 2 weeks after treatment. No difference in melphalan content of tumor/liver tissue or antitumor effect was observed between rats treated with 5- and 20-min HAI. Hepatotoxicity was strongly affected by perfusion duration/concentration, however. Rats treated with 5-min HAI weighed significantly less, and liver toxicity parameters were significantly increased compared with those of all other groups; eight of nine rats showed severe cholangiofibrosis. Body weights and liver toxicity parameters of the rats treated with 20-min HAI were not statistically different from the control group. In conclusion, duration of HAI with 4.4 micromol of fixed dose melphalan did not affect tumor uptake and antitumor effect, but the resulting increase in melphalan concentration had major impact on hepatobiliary toxicity. Therefore, in a clinical setting, caution should be taken when infusion duration and concentration of melphalan are changed.
Topics: Animals; Antineoplastic Agents, Alkylating; Disease Models, Animal; Hepatic Artery; Infusions, Intra-Arterial; Liver Neoplasms; Male; Melphalan; Neoplasm Transplantation; Rats; Treatment Outcome
PubMed: 12606622
DOI: 10.1124/jpet.103.049379 -
Chemico-biological Interactions May 2002
Review
Topics: Animals; Antineoplastic Agents, Alkylating; Female; Glutathione; Humans; Melphalan; Neoplasms
PubMed: 12076518
DOI: 10.1016/s0009-2797(02)00014-5 -
International Journal of Molecular... Feb 2022Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases...
Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM-T-MEL), indoline (EM-I-MEL), or 4-(4-morpholinyl) piperidine (EM-MORPIP-MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol carbocyanine). The EM-T-MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.
Topics: Apoptosis; Caspases; Cell Line, Tumor; DNA Fragmentation; Hematologic Neoplasms; Humans; Leukemia; Melphalan; Membrane Potential, Mitochondrial; Models, Biological; Staining and Labeling
PubMed: 35163680
DOI: 10.3390/ijms23031760 -
Materials Science & Engineering. C,... Jun 2020Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However,...
Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However, elucidating its pharmacokinetic behavior and preparing it for administration are challenging since it undergoes spontaneous hydrolysis. In this study, melphalan is transformed into a macromolecular prodrug by copolymerizing with p-dioxanone. The hydrophobicity of copolymer chains protects melphalan from hydrolysis. Poly(p-dioxanone-co-melphalan; PDCM) is electrosprayed and converted into nanoparticles (PDCM NPs) with diameters of ~300-350 nm to facilitate its intracellular delivery. UPLC-MS and HPLC are applied to verify and monitor the release of melphalan from PDCM NPs. PDCM NPs could suppress the proliferation of SKOV-3 cells. The IC50 of 4.3% melphalan-containing PDCM-3 NP was 70 mg/L, 72 h post administration. These suppression characteristics not only affected by the degradation and then the extracellular release of melphalan from PDCM NPs, but also the uptake via phagocytosis phenomenon in SKOV-3 cells. As revealed by flow cytometry, phagocytosis is a first-order process. Once phagocytosed, PDCM NPs are digested by lysosomes, causing a rapid release of melphalan into the cytoplasm, which ultimately causes suppression of SKOV-3 cell proliferation. Finally, the in vivo antitumor effects of PDCM NPs are verified in xenograft ovarian carcinoma. After a 20-day treatment, the tumor growth rate of the PDCM-3 NP group was (266 ± 178%) which was lower than those in the free melphalan group (367 ± 150%) and control group (648 ± 149%). Besides, significant tissue necrosis and growth suppression were observed in animals administered injections of PDCM NPs. Furthermore, the in vivo tracing results of Nile red-labeled PDCM NPs demonstrated that PDCM-3 NPs might be phagocytosed by macrophages and then taken to adjacent lymph nodes, which is a way of prevention or early treatment of lymphatic metastasis of tumors.
Topics: Animals; Cell Line, Tumor; Dioxanes; Drug Carriers; Female; Humans; Macrophages; Male; Melphalan; Mice; Mice, Nude; Nanoparticles; Ovarian Neoplasms; Particle Size; Phagocytosis; Polymers; Prodrugs; Xenograft Model Antitumor Assays
PubMed: 32279799
DOI: 10.1016/j.msec.2020.110759