Introduction Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and leading to peripheral cytopenias and a genetic instability with enhanced risk of disease transformation to acute myeloid leukemia (AML). 1 2 3 4 5 6 4 7 3 5 8 8 8 8 8 9 Selection of patients for lenalidomide therapy only 1 3 Table 1 International prognostic scoring system for myelodysplastic syndromes: survival and evolution of acute myeloid leukemia   Score value Prognostic variable 0 0.5 1.0 1.5 2.0 Bone marrow blasts, % <5 5–10 – 11–20 21–30 a Good Intermediate Poor     b 0/1 2/3       Scores for risk groups are as follows: Low, 0; Int-1, 0.5–1.0; Int-2, 1.5–2.0; and High, ≥2.5 a b 6 9 3 8 9 9 8 10 11 2 11 3 Table 2 a Renal impairment Dose Mild 10 mg (full dose) every 24 h cr Moderate 5 mg every 24 h cr Severe 5 mg every 48 h cr End-stage renal disease 5 mg three times a week after each dialysis cr a 11 CL cr 11 Table 3 Recommendations for laboratory monitoring during treatment Function Test Recommendation(s) Kidney function Creatinine Every 4 weeks in patients aged 65 years and older Blood FBC Weekly monitoring of full blood count mandatory for the first 2 months (it may be continued for 5 months). Biweekly or monthly monitoring should be considered thereafter, depending on hematological status. If treatment is interrupted in patients who had a previous episode of neutropenia or thrombocytopenia while on lenalidomide treatment, the same monitoring guidelines apply at re-initiation Thyroid function 4 Monitor every month during the course of treatment In case of loss of response during lenalidomide treatment Gonadal function Testosterone In case of loss of response during lenalidomide treatment Digoxin Digoxin In patients concomitantly taking Digoxin, the plasma level should be monitored periodically Pregnancy test Urine test Day −14 and day 0 at initiation of therapy, monthly thereafter (in women of childbearing potential) Bone marrow BM aspiration and cytogenetic testing; Trephine biopsy optional At commencement of therapy. In case of loss of response to rule out progressive disease or cytogenetic evolution BM FBC T 4 TSH Likewise, the safety, efficacy, and pharmacokinetics of lenalidomide therapy have not been fully investigated in patients with evidence of hepatic impairment, or those with frank hepatic dysfunction. Clinical trials conducted to date have excluded patients with inadequate hepatic function, with individual trials using different serum transaminase measures as exclusion criteria; most trials excluded patients with serum transaminase levels greater than three times the upper limit of normal. 10 10 3 Treatment with lenalidomide in del(5q) MDS 8 8 4 8 9 12 4 4 13 8 Table 4 Recommendations for treatment duration   Recommendation(s) Initial treatment Treatment should be continued for at least 4 months in order to obtain an initial response Patients who  Have a complete hematological response Continue lenalidomide therapy for as long as it continues to be well tolerated to avoid relapse (both erythroid and cytogenetic)  Have a partial response Continue lenalidomide therapy, and consider an escalation of the lenalidomide dose to a maximum of 10 mg per day, if tolerable  Discontinue treatment because of adverse events Patients should not begin another therapy immediately; it is recommended to wait 8–12 weeks to determine whether the response continues Tolerability of lenalidomide in del(5q) MDS 8 9 8 Management of hematological adverse events 9 14 3 8 8 3 5 1 8 5 8 5 1 6 9 Fig. 1 a b a G-CSF  Table 5 Recommendations for the management of hematological adverse events   Recommendation(s) Neutropenia 1 Febrile neutropenia Provide patients with clear guidance on how to react in the event of febrile neutropenia (patient education, specialized hematological care at all times, and broad-spectrum antibiotics within 3 h of fever onset) Thrombocytopenia 1 VTE VTE prophylaxis is not generally recommended in patients with MDS. Combining lenalidomide with erythropoietin is also not recommended. If erythropoietin is used, be aware of a potentially increased risk of VTE. Patients should be informed about the risk of VTE and monitored for symptoms If VTE does occur, interrupt lenalidomide treatment, treat the VTE, and carefully re-introduce lenalidomide once stable anticoagulation has been established Polycythemia Lenalidomide should be continued and phlebotomy considered, depending on ferritin levels. Although polycythemia is usually transient, treatment interruption may be necessary if additional risk factors for VTE are present MDS VTE 6 5 1 9 5 1 9 8 5 8 15 16 17 8 5 Management of non-hematological adverse events 18 10 8 6 19 6 Table 6 Recommendations for management of non-hematological adverse events (NHAEs) NHAE Recommendation(s) Rash Usually resolves within 2–3 weeks, no interruption of lenalidomide treatment needed If required treat with unselective antihistamines (e.g. clemastine), topical steroids, or a short course (14 days) of oral 10 mg prednisone If rash is severe or persists after treatment, lenalidomide should be interrupted until rash resolves. In the experience of the panel, lenalidomide can be restarted thereafter without recurrence of rash Diarrhea Treat symptomatically after ruling out other underlying causes Hypothyroidism In case of hypothyroidism, thyroid replacement therapy must be initiated Other NHAEs Treat symptomatically after ruling out other underlying causes such as anemia or autoimmune disorders 20 10 3 6 Conclusions The approval of lenalidomide for the treatment of MDS patients with low-risk or intermediate-1-risk disease with a deletion of chromosome 5q represents a significant step forward for this underserved group of patients. The key goal of the strategies presented here is to avoid unnecessary dose delays and reductions, and to maximize probability of response. Patient selection is straightforward, as efficacy does not appear to be influenced appreciably by relevant prognostic factors including age, prior erythropoietin therapy, sex, French–American–British type, or IPSS score. Treatment should be continued for a minimum of 4months to ensure treatment response. Neutropenia and thrombocytopenia are the most common adverse events during lenalidomide therapy but can be managed by the introduction of G-CSF and dose interruption. Other side-effects are generally manageable, and a range of simple (prophylactic) interventions are recommended to address the more common and more serious associated adverse events.