Melphalan is an orally and parenterally administered nitrogen mustard-like alkylating agent used in the therapy of multiple myeloma and ovarian cancer. Melphalan therapy has been associated with low rates of serum enzyme elevations during therapy, but when used in high doses as myeloablative therapy in preparation for hematopoietic cell transplantation, it is associated with high rates of enzyme elevations and acute liver injury due to sinusoidal obstruction syndrome.


Melphalan (mel' fa lan) is a phenylalanine derivative of nitrogen mustard and an alkylating agent that resembles cyclophosphamide and chlorambucil. It acts by causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing programmed cell death (apoptosis) in rapidly dividing cells. Melphalan was approved for use in the United States in 1964. Current indications for oral melphalan include multiple myeloma and some forms of ovarian carcinoma, usually in combination with other antineoplastic agents. Melphalan is also used parenterally in myeloablative regimens in preparation for hematopoietic cell transplantation and experimentally in high doses in local-regional therapy of metastatic cancer. Melphalan is available as tablets of 2 mg and as a powder for intravenous use in vials of 50 mg generically and under the trade name of Alkeran. The recommended dose varies by indication, body weight and renal function. Melphalan is often given in cycles of 1 to 3 weeks, with 2 to 4 week intervals between cycles. Melphalan shares common side effects with nitrogen mustards and other alkylating agents; these side effects include nausea, vomiting, diarrhea, alopecia, pruritus, bone marrow suppression, oral ulceration, rash and hypersensitivity reactions. Uncommon, but potentially severe adverse reactions include irreversible myelosuppression, hemoloytic anemia, pulmonary fibrosis and interstitial pneumonitis, hepatotoxicity and anaphylaxis.


Mild and transient elevations in serum aminotransferase levels are uncommon with standard doses of melphalan, but occur more commonly with high dose intravenous regimens. The enzyme elevations are usually mild and asymptomatic and do not require dose modification. Clinically apparent liver disease has not been reported with standard doses of melphalan in chemotherapeutic regimens. However, use of high doses of melphalan in preparation for hematopoietic cell (bone marrow and stem cell) transplantation or in local-regional therapy has been associated with sinusoidal obstruction syndrome that can be severe, leading to acute liver failure and death. Onset of sinusoidal obstruction syndrome is usually within 1 to 3 weeks of the myeloablative or high dose therapy, and is characterized by the onset of abdominal pain, hepatomegaly, weight gain and ascites followed by jaundice. The pattern of serum enzyme elevations is usually hepatocellular, with marked increases in serum aminotransferase and lactic dehydrogenase levels and minimal increase in alkaline phosphatase. The severity of injury varies considerably. In mild forms there is serum enzyme elevations without jaundice and with few or no symptoms. In severe instances, there are elevations in prothrombin time and progressive jaundice and hepatic failure. Immunoallergic and autoimmune features are uncommon. The fatality rate is high. Liver biopsy shows centrolobular necrosis and congestion with occlusion of small veins and red cells in sinusoids.

Melphalan has also been used in the regional therapy of nonresectable cancers in a limb, solid organ or even the liver. In isolated, hyperthermic hepatic perfusion with chemotherapeutic agents, the liver is isolated surgically and perfused with melphalan, with or without tumor necrosis factor (or other antineoplastic agents). The perfusion typically lasts for at least 1 hour and results in a high rate of tumor regression, but with a high rate of hepatotoxicity. At least 80% of patients develop significant serum aminotransferase elevations (5 to 20 times ULN) and two-thirds develop jaundice transiently. The liver injury can be severe and even fatal if complicated by severe sinusoidal obstruction syndrome, direct cytotoxicity or hyperthermia or ischemic injury.

Finally, melphalan is a cytotoxic and immunosuppressive agent and has been linked to rare instances of reactivation of hepatitis B which can be severe and even fatal. Reactivation typically occurs in patients with inactive hepatitits B with HBsAg, but no HBeAg and no or only low levels of HBV DNA in serum before treatment. Reactivation is marked by sudden rise in HBV DNA levels and subsequent increases in ALT and, in severe instances, jaundice and signs of hepatic failure. Reactivation can also occur in patients who are HBsAg and HBV DNA negative, but have anti-HBc in serum with or without anti-HBs, a serologic pattern suggestive of recovery from hepatitis B. In this situation, referred to as “reverse seroconversion”, HBV DNA levels arise followed by HBsAg and serum enzyme elevations. Reverse seroconversion tends to be severe. Most cases of reactivation of hepatitis B attributed to cytotoxic alkylating agents such as melphalan have occurred in patients who are also receiving high doses of corticosteroids, which on their own can lead to reactivation. The combination of the two immunosuppressive agents is probably more likely to cause reactivation than either alone.

Likelihood score: B[H] (likely cause of clinically apparent liver injury when used in high doses).

Mechanism of Injury

The mechanism of hepatotoxicity from melphalan is probably direct cytotoxic injury to sinusoidal endothelial cells causing their death and extrusion into sinusoids, with subsequent obstruction of sinusoids and small hepatic veins. The cytotoxic and immunosuppressive activity of melphalan may also be responsible for the risk of reactivation of hepatitis B. Melphalan has minimal hepatic metabolism and has not been reported to have significant drug-drug interactions. Cases with features of idiosyncratic liver injury have not been described.

Outcome and Management

The severity of sinusoidal obstruction syndrome varies considerably, from transient mild asymptomatic liver injury to acute liver failure that is rapidly fatal. There is no known specific therapy of proven efficacy for sinusoidal obstruction syndrome and management should focus on avoidance of further injury and supportive care. Rechallenge should not be done. Reactivation of hepatitis B can be prevented by prophylactic therapy with antiviral agents active against HBV, such as tenofovir and entecavir. Patients with serious malignancies undergoing systemic chemotherapy, such as with melphalan, should be screened for HBsAg and anti-HBc before starting chemotherapy and offered prophylaxis if HBsAg positive and monitored closely if HBsAg negative but anti-HBc positive.

Drug Class: Antineoplastic Agents, Alkylating Agents



Melphalan – Generic, Alkeran®


Antineoplastic Agents, Alkylating Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 15 January 2020

Abbreviations used: SOS, sinusoidal obstruction syndrome; HCT, hematopoietic cell transplantation.

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    (Among 75 patients with Ewing sarcoma treated with busulfan and melphalan followed by HCT, 5 developed moderate-to-severe SOS [7%], all arising in adults [5/43: 12%], mostly males [4/48: 8%] or with a history of radiation therapy [4/32: 13%]).
  • Artzner C, Mossakowski O, Hefferman G, Grosse U, Hoffmann R, Forschner A, Eigentler T, et al. Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience. Cancer Imaging. 2019;19:31. [PMC free article: PMC6543599] [PubMed: 31146793]
    (Among 16 patients with uveal melanoma and liver metastases treated with 28 courses of percutaneous hepatic perfusion, a partial response occurred in 9 [60%] but adverse events were common, including “liver toxicity” in 46% of courses, which was mild [Grade I] in all).
  • Meijer TS, Burgmans MC, Fiocco M, de Geus-Oei LF, Kapiteijn E, de Leede EM, Martini CH, et al. Safety of percutaneous hepatic perfusion with melphalan in patients with unresectable liver metastases from ocular melanoma using the Delcath Systems' second-generation hemofiltration system: a prospective non-randomized phase II trial. Cardiovasc Intervent Radiol. 2019;42:841–52. [PMC free article: PMC6502784] [PubMed: 30767147]
    (Among 35 patients with ocular melanoma with liver metastases treated with 67 courses of percutaneous hepatic perfusion with melphalan using a new hemofiltration system, there were 14 serious mostly hematologic adverse events, none hepatic although aminotransferase elevations arose the majority of patients, all were mild and resolved within 16 days of the procedure).