Melphalan

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=September 2019}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 462248349 | image = Melphalan.svg | image_class = skin-invert-image | width = 240 | alt = | image2 = Melphalan ball-and-stick.png | image_class2 = bg-transparent | alt2 =

| pronounce = | tradename = Alkeran, Evomela, Hepzato, Ivra, Phelinun, others | Drugs.com = {{drugs.com|monograph|melphalan}} | MedlinePlus = a682220 | DailyMedID = Melphalan | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth, intravenous, intra-arterial | class = | ATC_prefix = L01 | ATC_suffix = AA03 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title = Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | date = 21 June 2022 | website = Therapeutic Goods Administration (TGA) | url = https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date = 30 March 2024 }}</ref> | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Alkeran FDA label">{{cite web | title = Alkeran- melphalan tablet, film coated | date = 18 November 2019 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff913271-0090-4832-a0fe-5154fe8f97b9 | access-date = 23 April 2022 }}</ref><ref name="Evomela FDA label" /><ref name="Hepzato FDA label">{{Cite web | title = Highlights of prescribing information - These highlights do not include all the information needed to use HEPZATO safely and effectively | archive-url = https://web.archive.org/web/20230816003745/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf | archive-date = 2023-08-16 | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf | website = www.accessdata.fda.gov }}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Phelinun EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status =

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 148-82-3 | CAS_supplemental = | PubChem = 460612 | IUPHAR_ligand = 7620 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01042 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 405297 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = Q41OR9510P | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00369 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 28876 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 852 | NIAID_ChemDB = | PDB_ligand = | synonyms = (2''S'')-2-amino-3-<nowiki/>{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid, levopholan, L-sarkolysin

| IUPAC_name = 4-[''bis''(2-Chloroethyl)amino]-L-phenylalanine | C = 13 | H = 18 | Cl = 2 | N = 2 | O = 2 | SMILES = c1cc(ccc1C[C@@H](C(=O)O)N)N(CCCl)CCCl | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H18Cl2N2O2/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19/h1-4,12H,5-9,16H2,(H,18,19)/t12-/m0/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = SGDBTWWWUNNDEQ-LBPRGKRZSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Melphalan''', sold under the brand name '''Alkeran''' among others, is a chemotherapy medication used to treat multiple myeloma; malignant lymphoma; lymphoblastic and myeloblastic leukemia; childhood neuroblastoma; ovarian cancer; mammary adenocarcinoma; and uveal melanoma.<ref name="Alkeran FDA label" /><ref name="Evomela FDA label" /><ref name="Phelinun EPAR" /><ref name="AHFS2019" /> It is taken by mouth or by injection into a vein.<ref name="AHFS2019" />

Common side effects include nausea and bone marrow suppression.<ref name="AHFS2019" /> Other severe side effects may include anaphylaxis and the development of other cancers.<ref name="AHFS2019" /> Use during pregnancy may result in harm to the fetus.<ref>{{cite web | title = Melphalan Use During Pregnancy | url = https://www.drugs.com/pregnancy/melphalan.html | website = Drugs.com | access-date = 9 October 2019 }}</ref> Melphalan belongs to the class of nitrogen mustard alkylating agents.<ref name="AHFS2019" /> It works by interfering with the creation of DNA and RNA.<ref name="AHFS2019" />

Melphalan was approved for medical use in the United States in 1964.<ref name=AHFS2019>{{cite web | title = Melphalan Monograph for Professionals | url = https://www.drugs.com/monograph/melphalan.html | website = Drugs.com | publisher = American Society of Health-System Pharmacists | access-date = 9 October 2019 }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO_2019">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | location = Geneva | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access = free }}</ref> It is available as a generic medication.<ref name="BNF76">{{cite book | title = British national formulary : BNF 76 | pages = 873–874 | date = 2018 | publisher = Pharmaceutical Press | isbn = 978-0-85711-338-2 | edition = 76 }}</ref>

== Medical uses == In the European Union, melphalan is indicated for the treatment of multiple myeloma; malignant lymphoma (Hodgkin, non-Hodgkin lymphoma); acute lymphoblastic and myeloblastic leukemia; childhood neuroblastoma; ovarian cancer; and mammary adenocarcinoma.<ref name="Phelinun EPAR" />

In the United States, melphalan is used as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in people with multiple myeloma.<ref name="Evomela FDA label">{{cite web | title = Evomela- melphalan injection, powder, lyophilized, for solution | date = 31 December 2021 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5d68b96-14bd-4605-b6d2-2bf8b0c5ca8a | access-date = 23 April 2022 }}</ref><ref>{{cite web | title = Evomela (Captisol-enabled melphalan HCl) for Injection | date = 30 November 2016 | website = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207155Orig1s000_Orig2s000TOC.cfm | access-date = 7 September 2023 }}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref> In the European Union, it is indicated, in combination with other cytotoxic medicinal products, as reduced intensity conditioning treatment prior to allogeneic haematopoietic stem cell transplantation in malignant haematological diseases in adults.<ref name="Phelinun EPAR" />

In August 2023, the US Food and Drug Administration approved melphalan (Hepzato) as a liver-directed treatment for adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.<ref>{{cite web | title = Oncology (Cancer) / Hematologic Malignancies Approval Notifications | date = 14 August 2023 | website = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications | access-date = 7 September 2023 }}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}</ref><ref>{{cite press release | title = Delcath Systems, Inc. Announces FDA Approval of Hepzato Kit for the Treatment of Adult Patients with Unresectable Hepatic-Dominant Metastatic Uveal Melanoma | date = 14 August 2023 | publisher = Delcath Systems | via = PR Newswire | url = https://www.prnewswire.com/news-releases/delcath-systems-inc-announces-fda-approval-of-hepzato-kit-for-the-treatment-of-adult-patients-with-unresectable-hepatic-dominant-metastatic-uveal-melanoma-301900346.html | access-date = 7 September 2023 }}</ref>

== Side effects == Common side effects include:<ref name="AHFS2019" /> * Nausea * Bone marrow suppression, including ** Decreased white blood cell count causing increased risk of infection ** Decreased platelet count causing increased risk of bleeding

Less common side effects include: * Severe allergic reactions<ref name="AHFS2019" /> * Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use) * Hair loss * Interstitial pneumonitis * Rash * Itching * Irreversible bone marrow failure due to melphalan not being withdrawn early enough * Cardiac arrest

== Pharmacology ==

=== Pharmacokinetics === Melphalan is transported into cancer cells by L-leucine-type transporters (LAT1 and LAT2).<ref>{{cite journal | vauthors = Diethelm-Varela B, Ai Y, Liang D, Xue F | title = Nitrogen Mustards as Anticancer Chemotherapies: Historic Perspective, Current Developments and Future Trends | journal = Current Topics in Medicinal Chemistry | volume = 19 | issue = 9 | pages = 691–712 | date = 2019-06-20 | pmid = 30931858 | doi = 10.2174/1568026619666190401100519 }}</ref>

Metabolites of melphalan – mono- and dihydroxymelphalan – are pharmacologically inactive. They are created by a substitution of the chlorine atom with a hydroxyl group.<ref name="citefd7ea72f" />

=== Mechanism of action === The alkylation mechanism of melphalan is shared by all nitrogen mustards, proceeding through the formation of an aziridinium cation. This highly reactive intermediate interacts with nitrogen atoms in nucleotide bases, generating positively charged adducts.<ref name="Molphy_2018">{{cite journal | vauthors = Molphy Z, Montagner D, Bhat SS, Slator C, Long C, Erxleben A, Kellett A | title = A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage | journal = Nucleic Acids Research | volume = 46 | issue = 19 | pages = 9918–9931 | date = November 2018 | pmid = 30239938 | doi = 10.1093/nar/gky806 | pmc = 6212767 }}</ref>

Melphalan chemically modifies DNA nucleotides through alkylation, primarily targeting guanine at the N7 position within the major groove, and to a lesser extent adenine at the N3 position within the minor groove.<ref>{{cite journal | vauthors = Wang P, Bauer GB, Bennett RA, Povirk LF | title = Thermolabile adenine adducts and A.T base pair substitutions induced by nitrogen mustard analogues in an SV40-based shuttle plasmid | journal = Biochemistry | volume = 30 | issue = 49 | pages = 11515–11521 | date = December 1991 | pmid = 1660721 | doi = 10.1021/bi00113a005 }}</ref><ref name="citefd7ea72f" />

center|thumb|758x758px|Mechanism of nucleotide alkylation by melphalan<ref name="Molphy_2018" />

Alkylation of guanine is the principal pharmacologically relevant event underlying melphalan’s therapeutic activity. This reaction produces crosslinks either between complementary DNA strands or within a single strand, typically involving guanine–guanine or adenine–adenine pairs. Such crosslinking disrupts DNA synthesis and RNA synthesis, processes essential for cell survival, leading to cytotoxicity in both dividing and non-dividing tumor cells.<ref name="citefd7ea72f">{{cite web | title = Melphalan | url = https://www.cancer.gov/drugdictionary?cdrid=42973 | publisher = National Cancer Institute | access-date = 4 August 2014 }}</ref>

== Synthesis == [[File:Melphalan synthesis.svg|class=skin-invert-image|thumb|center|800px|Syntheses:<ref>{{Cite journal | vauthors = Bergel F, Stock JA | title = Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines | journal = Journal of the Chemical Society (Resumed) | pages = 2409 | year = 1954 | doi = 10.1039/JR9540002409 }}</ref><ref>{{Cite journal | vauthors = Bergel F, Burnop VC, Stock JA | title = Cyto-active amino-acids and peptides. Part II. Resolution of para-substituted phenylalanines and synthesis of p-di-(2-chloroethyl)amino-DL-phenyl[?-14C]alanine | journal = Journal of the Chemical Society (Resumed) | pages = 1223–1230 | year = 1955 | doi = 10.1039/JR9550001223 }}</ref><ref>{{cite journal | vauthors = Larionov LF, Shkodinskaja EN, Troosheikina VI, Khokhlov AS, Vasina OS, Novikova MA | title = Studies on the anti-tumour activity of p-di-(2-chloroethyl) aminophenylalanine (sarcolysine) | journal = Lancet | volume = 269 | issue = 6882 | pages = 169–171 | date = July 1955 | pmid = 13243678 | doi = 10.1016/S0140-6736(55)92736-7 }}</ref> {{US patent|3032584}}; {{US patent|3032585}} (both 1962 to NRDC).]] 4-Nitro-L-phenylalanine ('''1''') was converted to its phthalimide by heating with phthalic anhydride, and this was converted to its ethyl ester ('''2'''). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with oxirane, followed by treatment with phosphorus oxychloride provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan ('''3''').

== Society and culture == === Legal status === On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for melphalan.<ref name="Phelinun: Pending EC decision">{{cite web | title = Phelinun: Pending EC decision | date = 18 September 2020 | website = European Medicines Agency (EMA) | url = https://www.ema.europa.eu/en/medicines/human/summaries-opinion/phelinun | access-date = 21 September 2020 | archive-date = 23 September 2020 | archive-url = https://web.archive.org/web/20200923011322/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/phelinun | url-status = dead }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> The applicant for this medicinal product is Adienne S.r.l. S.U.<ref name="Phelinun: Pending EC decision" /> Melphalan was approved for medical use in the European Union in November 2020.<ref name="Phelinun EPAR">{{cite web | title = Phelinun EPAR | date = 15 September 2020 | website = European Medicines Agency (EMA) | url = https://www.ema.europa.eu/en/medicines/human/EPAR/phelinun | access-date = 23 April 2022 }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

== References == {{reflist}}

Category:Chloroethyl compounds Category:IARC Group 1 carcinogens Category:Nitrogen mustards Category:Specialty drugs Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate Category:Orphan drugs