Melphalan

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.^[3][4][6][7] It is taken by mouth or by injection into a vein.^[7]

Melphalan

Clinical data
Trade names	Alkeran, Evomela, Phelinun, others
Other names	(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid
AHFS/Drugs.com	Monograph
MedlinePlus	a682220
License data	US DailyMed: Melphalan
Routes of administration	By mouth, intravenous, intra-arterial
ATC code	L01AA03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)^[2] US: WARNING^[1]Rx-only^[3]^[4]^[5] EU: Rx-only^[6]
Pharmacokinetic data
Bioavailability	25–89% (By mouth)
Metabolism	Hydrolysis to inactive metabolites
Elimination half-life	1.5 ± 0.8 hours
Excretion	Kidney (IV: 5.8–21.3%)
Identifiers
IUPAC name 4-[bis(2-Chloroethyl)amino]-L-phenylalanine
CAS Number	148-82-3^Y
PubChem CID	460612
IUPHAR/BPS	7620
DrugBank	DB01042^Y
ChemSpider	405297^Y
UNII	Q41OR9510P
KEGG	D00369^Y
ChEBI	CHEBI:28876^Y
ChEMBL	ChEMBL852^Y
CompTox Dashboard (EPA)	DTXSID6020804
ECHA InfoCard	100.005.207
Chemical and physical data
Formula	C13H18Cl2N2O2
Molar mass	305.20 g·mol^−1
3D model (JSmol)	Interactive image
SMILES c1cc(ccc1C[C@@H](C(=O)O)N)N(CCCl)CCCl
InChI InChI=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^Y Key:SGDBTWWWUNNDEQ-LBPRGKRZSA-N^Y
(verify)

Common side effects include nausea and bone marrow suppression.^[7] Other severe side effects may include anaphylaxis and the development of other cancers.^[7] Use during pregnancy may result in harm to the fetus.^[8] Melphalan belongs to the class of nitrogen mustard alkylating agents.^[7] It works by interfering with the creation of DNA and RNA.^[7]

Melphalan was approved for medical use in the United States in 1964.^[7] It is on the World Health Organization's List of Essential Medicines.^[9] It is available as a generic medication.^[10]

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.^[6]

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.^[4][11] 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.^[6]

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.^[12][13]

Side effects

Common side effects include:^[7]

• 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^[7]
• 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

Mechanism of action

Melphalan chemically alters the DNA nucleotide guanine through alkylation, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells.^[14]

Synthesis

 

Syntheses:^[15][16][17] U.S. patent 3,032,584; U.S. patent 3,032,585 (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.^[18] The applicant for this medicinal product is Adienne S.r.l. S.U.^[18] Melphalan was approved for medical use in the European Union in November 2020.^[6]

References

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
2. "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
3. "Alkeran- melphalan tablet, film coated". DailyMed. 18 November 2019. Retrieved 23 April 2022.
4. "Evomela- melphalan injection, powder, lyophilized, for solution". DailyMed. 31 December 2021. Retrieved 23 April 2022.
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf
6. "Phelinun EPAR". European Medicines Agency (EMA). 15 September 2020. Retrieved 23 April 2022. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
7. "Melphalan Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 9 October 2019.
8. "Melphalan Use During Pregnancy". Drugs.com. Retrieved 9 October 2019.
9. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
10. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 873–874. ISBN 9780857113382.
11. "Evomela (Captisol-enabled melphalan HCl) for Injection". U.S. Food and Drug Administration (FDA). 30 November 2016. Retrieved 7 September 2023.
12. "Oncology (Cancer) / Hematologic Malignancies Approval Notifications". U.S. Food and Drug Administration (FDA). 14 August 2023. Retrieved 7 September 2023.   This article incorporates text from this source, which is in the public domain.
13. "Delcath Systems, Inc. Announces FDA Approval of Hepzato Kit for the Treatment of Adult Patients with Unresectable Hepatic-Dominant Metastatic Uveal Melanoma" (Press release). Delcath Systems. 14 August 2023. Retrieved 7 September 2023 – via PR Newswire.
14. "Melphalan". National Cancer Institute. Retrieved 4 August 2014.
15. Bergel F, Stock JA (1954). "Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines". Journal of the Chemical Society (Resumed): 2409. doi:10.1039/JR9540002409.
16. Bergel F, Burnop VC, Stock JA (1955). "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 of the Chemical Society (Resumed): 1223–1230. doi:10.1039/JR9550001223.
17. Larionov LF, Khokhlov AS, Shkodinskaja EN, Vasina OS, Troosheikina VI, Novikova MA (1955). "Studies on the anti-tumour activity of p-di-(2-chloroethyl) aminophenylalanine (sarcolysine)". Lancet. 266 (6882): 169–71. doi:10.1016/S0140-6736(55)92736-7. PMID 13243678.
18. "Phelinun: Pending EC decision". European Medicines Agency (EMA). 18 September 2020. Retrieved 21 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.