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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Lenalidomide

Last Update: August 30, 2022.

OVERVIEW

Introduction

Lenalidomide is an immunomodulatory and antineoplastic agent that is used in the therapy of multiple myeloma. Lenalidomide is associated with a low rate of serum aminotransferase elevations during therapy and has been implicated in causing rare instances of clinically apparent liver injury which can be severe.

Background

Lenalidomide (len" a lid' oh mide) is a thalidomide derivative that has similar but more potent activity as an antineoplastic agent. Thalidomide and its derivatives have immunomodulatory, antiinflammatory antiangiogenic and antineoplastic activities. The mechanism of action of these agents in the treatment of multiple myeloma is not well defined but may relate to inhibition of tumor necrosis factor (TNF) alpha, a potent proinflammatory cytokine or to stimulation of T and NK cell activity. The thalidomide derivatives have direct cytotoxic effects against myeloma cells in culture and have potent antiangiogenic activities. Lenalidomide was approved for use in multiple myeloma in 2005 and was subsequently approved for use in myelodysplastic syndromes and mantle cell lymphoma. Lenalidomide is available in capsules of 2.5, 5, 10, 15, 20 and 25 mg under the brand name Revlimid. The recommended doses vary by indication and, like thalidomide, its use is restricted because of proven teratogenicity. Side effects of lenalidomide are common and include sedation, dizziness, orthostatic hypotension, neutropenia, lymphopenia, peripheral neuropathy, and arterial and venous thromboembolism (for which reason it is often given with anticoagulation). Rare but potentially severe adverse events include severe cutaneous reactions, seizures, tumor lysis syndrome and hypersensitivity reactions. Lenalidomide is a teratogen and possible cause of severe birth defects and is available only as a part of a strict Risk Evaluation and Mitigation Strategy (REMS), which requires physician training, written patient informed consent, strict birth control measures, regular monitoring and reporting.

Hepatotoxicity

Serum enzyme elevations occur in 8% to 15% of patients taking lenalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, lenalidomide has been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with lenalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Lenalidomide has also been shown to increase indirect bilirubin levels in patients with underlying Gilbert syndrome, causing a mild hyperbilirubinemia during therapy that soon resolves with stopping treatment and is otherwise benign.

Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) as well as after liver, kidney and heart transplantation. There appears to be cross reactivity to this complication among lenalidomide, pomalidomide and thalidomide. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus. Furthermore, hepatic graft-vs-host disease can occasionally present with an acute hepatitis that resembles hepatocellular drug induced liver injury.

Reactivation of hepatitis B has been reported in patients receiving thalidomide, lenalidomide and pomalidomide, but generally only after HSCT and the role of these agents in causing reactivation is not always clear. Indeed, in studies of large numbers of patients treated for multiple myeloma, the major risk factor for reactivation was found to be HSCT rather than the specific antineoplastic drugs being used. Indeed, lenalidomide therapy is associated with a reduced risk of reactivation in patients with HSCT (although dexamethasone, thalidomide and bortezomib were not), perhaps because of the immune enhancement typically caused by lenalidomide.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of lenalidomide hepatotoxicity is not clear, but it may be related to its activity in reducing TNF-α production, a potent inflammatory cytokine that activates T cells and promotes inflammation, but is also necessary for normal liver regeneration. Several of the reported cases of hepatotoxicity have occurred in patients with underlying chronic liver disease (hepatitis B, C or nonalcoholic fatty liver), and another possibility is that lenalidomide may worsen preexisting hepatic conditions.

Outcome and Management

The severity of lenalidomide induced liver injury ranges from transient, asymptomatic elevations in serum enzymes to acute liver injury with jaundice to severe acute liver failure and death. The liver injury usually starts to resolve within a week of stopping the medication, but prolonged jaundice with bile duct injury and possible vanishing bile duct syndrome have also been reported. Rechallenge should be reserved for cases of mild liver injury in which the agent is considered very necessary and done with caution and careful monitoring. Nevertheless, instances of reinitiation of therapy without subsequent recurrence of liver injury have been reported.

Drug Class: Antineoplastic Agents, Miscellaneous

Other Related Drugs: Pomalidomide, Thalidomide

CASE REPORT

Case 1. Acute liver injury during lenalidomide therapy of multiple myeloma.(1)

A 50 year old man with refractory and relapsed multiple myeloma was started on a course of lenalidomide after multiple cycles of chemotherapy and both autologous and allogeneic hematopoietic stem cell transplants that provided only temporary remissions. Ten days after starting lenalidomide [10 mg daily], he was found to have abnormal liver tests with a serum ALT of 505 U/L, AST 246 U/L, Alk P 198 U/L, but bilirubin and INR normal. Serum enzyme levels had been normal before starting lenalidomide. He did not drink alcohol and had no risk factors for viral hepatitis. Of note, 3 years earlier he had developed angioedema and a severe skin rash without liver test abnormalities after three months of cyclic lenalidomide therapy. In the interim he had undergone an allogeneic HSCT.

Lenalidomide was discontinued and he was admitted for evaluation and liver biopsy. Blood counts demonstrated eosinophilia (1344/µL). Tests for hepatitis A, B, C and E as well as CMV, EBV, HIV and herpes simplex and zoster infection were negative. Ultrasound showed normal appearing liver without evidence of biliary obstruction. Liver biopsy showed prominent portal and lobular inflammation with a mixed cellular infiltrate rich in eosinophils, lobular areas with confluent necrosis and mild endothelitis and occasional biliary cell injury in portal areas. The liver histology was considered consistent with an acute drug induced hepatitis superimposed upon mild graft-vs-host disease. In further follow up, liver tests improved and were normal 6 weeks later (Table).

Key Points

Medication:Lenalidomide (10 mg daily for 10 days)
Pattern:Hepatocellular (R value 8.4)
Severity:1+ (anicteric, asymptomatic)
Latency:10 days
Recovery:Complete within 35 days
Other medications:None mentioned

Laboratory Values

Time After
Starting		Time After
Stopping		ALT*
(U/L)		Alk P*
(U/L)		Bilirubin*
(mg/dL)		Other
PreNormalNormalNormal
10 days0505198Normal
11 days1 day510230
12 days2 days515255
17 days7 days219157NormalAdmission, Liver Biopsy
24 days1480110
4 weeks21 days4595
6 weeks35 days3585
Upper limits of normal <40 <130 <1.2
*

Some values estimated from Figure 1. Upper limits of normal used standard values

Comment

This man developed asymptomatic and anicteric hepatitis within 10 days of starting lenalidomide. Typical of lenalidomide hepatotoxicity was the rapid latency to onset (less than one month), the hepatocellular pattern of injury, and the rapid improvement with stopping the medication. Also typical was the previous history of autologous or allogeneic HSCT. Indeed, one possibility is that this represented the worsening of an underlying graft-vs-host disease by lenalidomide therapy, an indirect form of drug induced liver injury. In preparation of use of lenalidomide to treat multiple myeloma, maintenance immunosuppressive therapy for prevention of graft-vs-host disease is typically withdrawn. In this case, it was unclear whether maintenance immunosuppression was continued.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAME

Lenalidomide – Revlimid®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Thalidomide 50-35-1 C13-H10-N2-O4 image 134971183 in the ncbi pubchem database
Lenalidomide 191732-72-6 C13-H13-N3-O3 image 135134887 in the ncbi pubchem database
Pomalidomide 19171-19-8 C13-H11-N3-O4 image 135089995 in the ncbi pubchem database

CITED REFERENCE

1.
Zanella MC, Rubbia-Brandt L, Giostra E, Chalandon Y, Hadengue A, Spahr L. A case of drug-induced hepatitis due to lenalidomide. Case Rep Gastroenterol. 2011;5:217–22. [PMC free article: PMC3088752] [PubMed: 21552449]

ANNOTATED BIBLIOGRAPHY

References updated: 30 August 2022

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    (50 year old man with refractory multiple myeloma and autologous hematopoietic stem cell transplant developed severe skin rash 3 months after starting lenalidomide that resolved upon stopping, but developed serum enzyme elevations one week after restarting lenalidomide 2 years later [bilirubin normal, ALT 509 U/L, Alk P 198 U/L], resolving upon stopping).
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    (74 year old woman with multiple myeloma and chronic hepatitis C had worsening of serum ALT and increase in HCV RNA levels when treated with thalidomide and dexamethasone, which prevented continued therapy until hepatitis C was successfully treated with sofosbuvir and ribavirin).
  • Safran H, Charpentier KP, Kaubisch A, Mantripragada K, Dubel G, Perez K, Faricy-Anderson K, et al. Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study. Am J Clin Oncol. 2015;38:1–4. [PubMed: 23648434]
    (Among 40 patients with hepatocellular carcinoma with an inadequate response to sorafenib treated with lenalidomide [25 mg daily for 21 days in 28 day cycles], 6 [15%] had a partial response and toxicities were largely hematologic and rash; 5 patients had ALT elevations above 3 times ULN).
  • Kootte RS, Faber LM. Hepatitis E during lenalidomide treatment for multiple myeloma in complete remission. Neth J Med. 2017;75:117–21. [PubMed: 28469048]
    (69 year old woman with multiple myeloma on lenalidomide after HCT was found to have elevations in liver tests [bilirubin 0.5 mg/dL, ALT 328 U/L, Alk P 241 U/L] accompanied by IgM anti-HEV and HEV RNA [suggesting chronic infection sustained by immunosuppression], viremia and ALT elevations resolving with stopping lenalidomide and not returning when it was restarted).
  • Bonkovsky HL, Kleiner DE, Gu J, Odin JA, Russo MW, Navarro VM, Fontana RJ, et al. U.S. Drug Induced Liver Injury Network Investigators. Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology. 2017;65:1267–77. [PMC free article: PMC5360519] [PubMed: 27981596]
    (Among 363 patients with drug induced liver injury who underwent liver biopsy, 26 [7%] had bile duct loss, including 1 case attributed to lenalidomide and 1 to thalidomide both marked by severe, and relentlessly progressive cholestatic liver injury resulting in death from liver failure within 3 months of onset).
  • Lum EL, Huang E, Bunnapradist S, Pham T, Danovitch G. Acute kidney allograft rejection precipitated by lenalidomide treatment for multiple myeloma. Am J Kidney Dis. 2017;69:701–704. [PubMed: 28189378]
    (65 year old woman developed multiple myeloma 5 years after a successful renal transplant for polycystic kidney disease and developed acute cellular rejection during a second cycle of lenalidomide and dexamethasone that improved with immunosuppression and withdrawal of lenalidomide, later tolerating bortezomib therapy of myeloma).
  • Tsukune Y, Sasaki M, Odajima T, Sunami K, Takei T, Moriuchi Y, Iino M, et al. Incidence and risk factors of hepatitis B virus reactivation in patients with multiple myeloma in an era with novel agents: a nationwide retrospective study in Japan. Blood Cancer J. 2017;7:631. [PMC free article: PMC5802507] [PubMed: 29167420]
    (Japanese nationwide analysis of 5078 patients with multiple myeloma identified 760 with resolved hepatitis B [anti-HBc without HBsAg in serum] of whom 7.6% developed reactivation [7.9% at 2 and 14.1% at 5 years], multivariate analysis demonstrating higher rates in those undergoing autologous hematopoietic stem cell transplant [21%:odds ratio=11.6] and lower rates in those receiving lenalidomide [5.2%:odds ratio=0.5], but not thalidomide, bortezomib or dexamethasone).
  • Hammami MB, Talkin R, Al-Taee AM, Schoen MW, Goyal SD, Lai JP. Autologous graft-versus-host disease of the gastrointestinal tract in patients with multiple myeloma and hematopoietic stem cell transplantation. Gastroenterology Res. 2018;11:52–57. [PMC free article: PMC5827903] [PubMed: 29511407]
    (Two patients with multiple myeloma who underwent autologous hematopoietic cell transplantation developed autologous graft-vs-host disease with moderately severe gastrointestinal involvement after receiving several cycles of lenalidomide and dexamethasone).
  • Azmy V, Neparidze N. Hyperbilirubinemia following lenalidomide administration. Clin Case Rep. 2018;6:875–877. [PMC free article: PMC5930194] [PubMed: 29744077]
    (72 year old man with multiple myeloma developed hyperbilirubinemia after a first cycle of lenalidomide [bilirubin 3.9 with normal direct bilirubin, ALT and Alk P] suspected to be due to Gilbert syndrome).
  • Kikuchi T, Kusumoto S, Tanaka Y, Oshima Y, Fujinami H, Suzuki T, Totani H, et al. Hepatitis B virus reactivation in a myeloma patient with resolved infection who received daratumumab-containing salvage chemotherapy. J Clin Exp Hematop. 2020;60:51–54. [PMC free article: PMC7337267] [PubMed: 32404569]
    (72 year old women with multiple myeloma who was negative for HBsAg but positive for anti-HBc without anti-HBs was monitored and had no evidence for reactivation during multiple courses of bortezomib, melphalan, dexamethasone, lenalidomide and pomalidomide over a 3 year period, but then developed HBV DNA [2.2 to 2.6 log10 per mL] and HBsAg after 3rd course of daratumumab with bortezomib and dexamethasone with rapid response upon addition of entecavir).
  • Vaxman I, Eaton J, Lee HE, Gertz MA. Acute liver rejection in a multiple myeloma patient treated with lenalidomide. Case Rep Transplant. 2020;2020:8894922. [PMC free article: PMC7749773] [PubMed: 33381347]
    (65 year old woman with primary biliary cirrhosis and liver transplant developed multiple myeloma 9 years later and acute cellular rejection 2 weeks after starting therapy with lenalidomide and dexamethasone [bilirubin 3.3 mg/dL, ALT 306 U/L, Alk P 253 U/L], responding to restarting mycophenolate and starting high dose methylprednisolone and tacrolimus).

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