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Complexities of lenalidomide for the treatment of myelodysplastic syndromes
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After the teratogenic disaster of the early 1960s, thalidomide became obsolete. However, it has made a resurgence during the last several years to become a mainstay of therapy for multiple myeloma. Although benefit was seen with thalidomide plus dexamethasone in this cancer setting, toxicity led to high rates of drug discontinuation and restricted access has made it difficult to use.
Lenalidomide (Revlimid, Celgene) is the first thalidomide derivative approved by the FDA for the treatment of cancer, and it is associated with reduced rates of neuropathy and a lower teratogenic potential compared with thalidomide (Thalomid, Celgene). When combined with dexamethasone, it is indicated for the treatment of multiple myeloma. More recently it has been indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1–risk myelodysplasia with a deletion 5q (5q–) cytogenetic abnormality.
Although the exact mechanism of lenalidomide’s anticancer activity is largely unknown, it was engineered to possess enhanced potency and tolerability compared with thalidomide. Lenalidomide is about 2,000 times more potent than thalidomide in its inhibition of tumor necrosis factor alpha. Comparatively, lenalidomide has similar anti-angiogenic and T-cell stimulatory effects as thalidomide. In contrast to thalidomide, lenalidomide also stimulates the activity of natural killer cells and induces G1 growth arrest of tumor cells. Lenalidomide does not appear to inhibit endothelial cell production, which may explain its potentially reduced teratogenic potential.
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MDS is a heterogeneous disease, consisting of multiple subsets based on unique cytogenetic and clinical characteristics. The 5q– is the most common cytogenetic abnormality among patients with MDS, occurring with a frequency of 16% to 28%. Patients with 5q– syndrome (defined as isolated 5q– in de novo MDS) typically have an indolent course that rarely progresses to acute myelogenous leukemia and often live many years (median survival 8 to 10 years) despite the fact that few patients are cured with therapy.
Four risk groups
The International Prognostic Scoring System (IPSS) stratifies MDS patients into four risk groups, depending on the probability of transformation to AML: low, intermediate-1, intermediate-2 and high risk.
Patients with low or intermediate-1—risk MDS have a longer median time to progression to AML and a longer overall survival, compared with patients with intermediate-2 or high-risk MDS. The 5q– cytogenetic abnormality is scored beneficially in the IPSS, indicating that most patients with this abnormality will be stratified to a low- or intermediate-1–risk group.
Patients with 5q– MDS are usually transfusion-dependent and their endogenous erythropoietin levels are usually elevated, making it highly unlikely that they will respond to recombinant erythropoietin.
The only curative therapy for MDS is allogeneic stem cell transplantation, but relatively few patients are eligible for transplantation (median age at diagnosis is about 65). For patients with low- to intermediate-1–risk MDS, the risk–benefit ratio of transplantation increases, making supportive care a reasonable option for many of these patients, including 5q– MDS. Also, for transplant-ineligible patients, supportive care is an appropriate therapeutic choice. Supportive care includes the use of growth factors, blood and platelet transfusions and antibiotics.
Exploring efficacy
To explore the efficacy of lenalidomide, List and colleagues conducted an open-label, single-center, phase-2, dose-ranging trial evaluating lenalidomide in patients with primary MDS (n=43). A high hematologic response rate (83%) was noted among patients with 5q–, compared with 57% of patients with normal cytogenetics and 12% with other cytogenetic abnormalities (P=.007). Overall, 83% of 5q– patients had a cytogenetic response.
Based on these results, the same group of investigators conducted a multicenter international study (MDS-003) that served as the pivotal trial that led to lenalidomide’s FDA indication for MDS. Patients with 5q– MDS, low or intermediate-1 IPSS score and transfusion-dependence (>2 units of red cells within eight weeks prior to the study) were included (n=148). Patients were sequentially assigned to either lenalidomide 10 mg daily for 21 of every 28 days or lenalidomide 10 mg daily.
Overall, 112 patients (76%) achieved a hematologic response, with 99 patients (67%) becoming transfusion-independent by week 24. The majority (77%) of patients with isolated 5q– had a cytogenetic response, compared with 67% of patients with an additional cytogenetic abnormality and 50% with two or more additional cytogenetic abnormalities. After a median follow-up of two years, the median duration of transfusion-independence has yet to be reached in this trial.
Despite the tremendous response seen in this patient population, lenalidomide is associated with significant neutropenia and thrombocytopenia, especially during the first eight weeks of therapy. In the MDS-003 study, grade-3 or grade-4 neutropenia was seen in 55% of patients and grade-3 or -4 thrombocytopenia was seen in 44% of patients. Neutropenic fever occurred in only 4% of patients and myeloid growth factors were used if necessary. Eighty percent of patients required a dose reduction or delay in subsequent courses of treatment, whereas 34% required a second dose reduction or delay.
Recommended dose adjustments for myelosuppression are noted in table 1. If myeloid growth factors are used, pegfilgrastim (Neulasta, Amgen) should be administered with caution. Reports of splenic rupture and leukemoid reactions have been reported in patients with MDS with the standard 6 mg dose of pegfilgrastim.
Deep venous thrombosis
Deep venous thrombosis is most commonly seen with lenalidomide used for multiple myeloma (9% to 15%). There were reports of DVT in the trials with lenalidomide in MDS, but the incidence was less than 1%. There are no guidelines for DVT prophylaxis in patients receiving lenalidomide. Other adverse effects commonly associated with lenalidomide are diarrhea, itching, rash and fatigue. These adverse events are generally mild to moderate in severity and manageable with standard approaches.
Unlike thalidomide, lenalidomide did not elicit teratogenic effects in the sensitive rabbit model. However, because of its structural similarity to thalidomide, patients must be carefully counseled regarding the teratogenic risks, and lenalidomide is only available under a special restricted distribution program called RevAssist. All prescribers, pharmacists and patients must be registered with the RevAssist program prior to gaining access to the drug. Specific criteria for enrollment exist and are listed in table 2. Participation in the RevAssist program can be quite time consuming and probably limits the widespread use of this agent even when indicated.
Lenalidomide offers an exciting advance in the treatment of the 5q– MDS patient. It has the ability to alter the course of MDS by inducing hematologic and cytogenetic responses, resulting in transfusion independence. Extrapolation of these clinical findings to other myeloproliferative disorders with similar molecular features may lead to further advances in wider populations. Hopefully, access to agents such as lenalidomide will ease as more clinicians use the RevAssist program and provide feedback to the company and the FDA regarding barriers to prescribing this active medication for patients who are likely to benefit greatly from its use.
For more information:
- Daisy Yang, PharmD, BCOP, is a Clinical Pharmacy Specialist and Laura Boehnke Michaud, PharmD, BCOP, is the Manager of Clinical Pharmacy Services, at The University of Texas M.D. Anderson Cancer Center, Houston.
- Steensma DP, Tefferi A. Risk-based management of myelodysplastic syndrome. Oncology. 2007;21:43-54.
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-2302.
- Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088.
- List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549-557.
- List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.