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Long-term transfusion independence in del(5q) MDS patients who discontinue lenalidomide

Leukemia volume 26, pages 855–858 (2012)Cite this article

Lenalidomide is an immunomodulatory drug that has an impact on cellular responses to receptor/ligand activation signals.1 It induces 67% erythroid transfusion independence rates in myelodysplastic syndrome (MDS) patients with a del(5q) chromosomal aberration, and low or intermediate-1 risk according to the International Prognostic Score (IPSS).2 The current treatment recommendation is to treat with lenalidomide until relapse of transfusion dependence or progression of disease.3, 4 Consequences of the long-term effects of continuous immunomodulation with lenalidomide are unknown. This is particularly relevant in patients with low-risk IPSS del(5q) MDS who may be exposed to this therapy for several years. Disease progression and karyotypic evolution in del(5q) patients treated with lenalidomide have been described recently;5 however, a formal link to lenalidomide treatment is not evident. Emerging data that primitive stem cells harboring del(5q) might survive even in patients in complete cytogenetic remission6 question the therapeutic strategy of unlimited lenalidomide therapy. Furthermore, there is limited evidence that discontinuation of lenalidomide may lead to long-term transfusion freedom.7 Therefore, we evaluated the safety and efficacy of limited exposure duration to lenalidomide in patients achieving transfusion independence. We assessed the long-term outcome of these patients, as well as duration of transfusion independence and cytogenetic remission, in order to explore the correlation between the minimum exposure of lenalidomide and transfusion-free intervals. Between December 2003 and January 2010, 27 patients with transfusion-dependent low- and intermediate-1-risk del(5q) MDS were treated with lenalidomide at Katholisches Klinikum Duisburg, King's College London, Heinrich-Heine-University Düsseldorf and Technische Universität Dresden, and interrupted or discontinued treatment after becoming transfusion independent. Reasons for discontinuation of lenalidomide were attempt to reduce long-time drug exposure after achieving hematologic responses (n=5) or complete cytogenetic (n=9) remission, end of drug supply within the clinical-study protocol (n=8), intolerable side effects (n=3) and patient's withdrawal of consent (n=2). Treatment was performed within clinical trial protocols conducted according to the Declaration of Helsinki. All patients gave informed consent. Transfusion independence was counted from the day of the next anticipated transfusion, according to previous transfusion frequency. Complete cytogenetic remission (CCyR) meant absence of any del(5q) karyotype and any other karyotypic abnormalities. Partial cytogenetic remission (PCyR) was defined as reduction of del(5q) metaphases by at least 50%, but less than 100%. All patients started lenalidomide treatment at 10 mg p.o. either daily or for 21 consecutive days out of 28 days. Dose reductions were performed for both non-hematologic toxicities and hematological toxicities.

Current recommendations state that treatment with lenalidomide in del(5q) MDS should be continued until disease progression.4 The question whether interruption of lenalidomide treatment for patients in remission would be beneficial has never been formally addressed. This concept is appealing for several reasons: first, it would reduce costs and side effects. Second, the progression to AML in del(5q) disease is not entirely understood. Reducing lenalidomide exposure would prevent a notional selective pressure of the compound on del(5q) stem cells, facilitating their disease progression. Different putative mechanisms have been discussed to explain AML progression: Göhring et al.8 presented evidence that pre-therapeutic telomere length was significantly shorter in those patients who ultimately transformed to AML than in those who did not. Data presented by Jadersten et al.9 showed evidence that a number of patients with del(5q) MDS had p53 overexpression and mutations before lenalidomide administration. Those patients are prone to a higher apoptotic rate and may develop additional chromosomal aberrations in the course of the disease, leading to AML with complex karyotypes. Furthermore, a recent study in patients treated with lenalidomide for del(5q) disease achieving CCyR has shown that very early stem cells persisted with del(5q) karyotypic abnormality, despite achieving a complete hematological or cytogenetic response.6 It has been speculated that continuous administration of lenalidomide may lead to selective pressure on stem cells that induces genomic instability, resulting in acute leukemia transformation. In fact, our study shows that some patients might remain in long-term CCyR (for example, 56 months, patient no. 1, data not shown) before they show reappearance of del(5q). As reappearance of del(5q) is not equivalent to transfusion dependence, a number of patients in our series remain transfusion-free for many years without being exposed to any medication. The CCyR rate in our patient sample is high (63%), resulting from a positive selection of patients who already had achieved transfusion independence. Interestingly, the achievement of CCyR and durability after lenalidomide interruption is not confined to patients with isolated del(5q). One patient in our series with a complex karyotype remains in CCyR for 76 months. Two patients had short lenalidomide exposure duration (28 and 104 days, respectively) and achieved transfusion independence; however, both patients relapsed within 24 months. In contrast, eight patients continued lenalidomide at least 6 months beyond achievement of CCyR. Seven of those patients remain transfusion independent at a median follow-up of 4.5 years since the start of transfusion independence. As all the three patients who relapsed with erythroid transfusion dependence in our series responded to re-exposure of lenalidomide, the concept of lenalidomide discontinuation could be offered at least to the very favorably responding group of patients who achieve CCyR and are treated for at least an additional 6 months.

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Author notes

  1. A A N Giagounidis and A Kulasekararaj: These authors contributed equally to this work.

Authors and Affiliations

  1. Katholisches Klinikum Duisburg, St Johannes Hospital, Duisburg, Germany

    A A N Giagounidis, R Radkowski, S Haase, P Petersen & C Aul

  2. King's College Hospital, Denmark Hill, London, UK

    A Kulasekararaj & G J Mufti

  3. Heinrich-Heine-Universität, Düsseldorf, Germany

    U Germing

  4. Medizinische Hochschule Hannover, Hannover, Germany

    G Göhring & G Büsche

  5. Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Dresden, Germany

    U Platzbecker

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  1. A A N Giagounidis
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Correspondence to A A N Giagounidis.

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Competing interests

AG, UG, GJM, and UP are consultants for Celgene and have received research support and honoraria for lectures. The remaining authors declare no conflict of interest.

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Giagounidis, A., Kulasekararaj, A., Germing, U. et al. Long-term transfusion independence in del(5q) MDS patients who discontinue lenalidomide. Leukemia 26, 855–858 (2012). https://doi.org/10.1038/leu.2011.268

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