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![Grade 3/4 neutropenia (A) and thrombocytopenia (B) associated with lenalidomide (LEN) treatment by cycle in MDS-004 [32, 33].](profile/Rami-Komrokji/publication/283292911/figure/fig1/AS:324976696676390@1454491890824/Grade-3-4-neutropenia-A-and-thrombocytopenia-B-associated-with-lenalidomide-LEN.png)
Grade 3/4 neutropenia (A) and thrombocytopenia (B) associated with lenalidomide (LEN) treatment by cycle in MDS-004 [32, 33].
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The treatment of patients with myelodysplastic syndromes (MDS) begins with assessment of karyotype and risk. Lenalidomide is approved for the treatment of patients who have transfusion-dependent (TD) anemia due to lower-risk MDS with chromosome 5q deletion (del(5q)) with or without additional cytogenetic abnormalities, and isolated del(5q) only in...
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Citations
... Moreover, although treatment with LEN is usually well tolerated, serious side effects may occur. Indeed, the most common grade 3/4 adverse events (AEs) reported in del(5q) MDS are cytopenias, which may be a result of direct cytotoxic effects of LEN on the del(5q) clone, and are more frequent and severe during the rst cycles of treatment (11). Among extra-hematological toxicities, cutaneous rash and diarrhea are the most common AEs. ...
Lenalidomide (LEN) can induce RBC transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic syndrome (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN in RBC-TI. We enrolled 118 patients with an IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients in RBC-TI allows prolonged maintenance of TI in a large subset of patients.
... The 10-mg dose is more effective than the 5-mg dose in inducing transfusion independence (61% vs. 49%), and cytogenetic response, with a similar safety profile [1][2][3]. Achievement of durable transfusion independence with lenalidomide was associated with a significantly reduced risk of AML progression and death [18,19]. Lenalidomide treatment is maintained until loss of response [1]. ...
... Very few lower-risk MDS del(5q) patients, i.e., those with severe renal insufficiency and those with significant cytopenias in addition to anemia, are ineligible for lenalidomide treatment. Half of the patients start responding to lenalidomide after the first cycle [18]. Karyotype complexity has a negative impact both on OS and AML evolution of lenalidomide treated patients [19]. ...
Introduction. We present the recommendations for treatment of the lower-risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations for treatment of lower-risk myelodysplastic syndromes are based on expert opinion based on review of the literature and contemporary recommendations for treatment of lower risk myelodysplastic syndromes. Recommendations. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk myelodysplastic syndromes, and may be treated successfully with erythropoietic stimulating agents, with or without granulocyte growth factor, provided a careful selection is performed on the basis of Revised International Prognostic Scoring System, endogenous erythropoietin levels, and transfusion independence. In case a patient fails erythropoietic stimulating agents treatment, the available options may include lenalidomide, hypomethylating agents, and a rather large number of experimental agents. Chelation therapy is recommended in patients who have received or are anticipated to receive > 20 red blood cell transfusions and those with serum ferritin levels > 2500 ng/mL. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Severe neutropenia is targeted symptomatically with growth factor supportive care. The immunosuppressive treatments are indicated mainly for pancytopenia, hypoplastic lowerrisk myelodysplastic syndromes. Finally, hematopoietic stem cell transplantation is the curative option for younger, good performance (fit) lower-risk patient with poor risk features, according to European Blood and Marrow Transplantation/European Leukemia Net International expert panel and myelodysplastic syndrome-RIGHT group. Conclusion. Treatment of myelodysplastic syndromes is mainly based on resolution of symptoms due to particular cytopenia(s).
... This is consistent with superior clinical response to lenalidomide in del(5q) MDS patients than those with non-del(5q) myeloid malignancies [27][28][29]104]. This is also consistent with the observation that del(5q) MDS patients with wild type p53 are more sensitive to lenalidomide than those with mutant p53 [105,106]. ...
Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.
... Lenalidomide is an approved treatment for patients with lower-risk MDS associated with transfusiondependent anemia and loss of part of the long arm of chromosome 5 (del(5q)) [9,10]. Several cases have been reported in which red blood cell transfusion independence (RBC-TI) was achieved with the use of daily lenalidomide therapy in patients with previously red blood cell transfusion-dependent (RBC-TD) MDS/ MPN-RS-T [11][12][13][14][15]. ...
Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.
... Lenalidomide is a 4-amino-glutamyl analogue of thalidomide and is approved for the treatment of certain hematologic malignancies. Lenalidomide is used for the treatment of lower-risk red blood cell (RBC) transfusiondependent myelodysplastic syndromes (MDS) with deletion of chromosome 5q (del(5q)) with or without additional cytogenetic abnormalities [2][3][4]. MDS patients with del(5q) exhibit much higher hematologic and cytogenetic responses than those without del(5q) [3][4][5][6]. In contrast to lower-risk MDS patients, the response to lenalidomide monotherapy is poor in patients with higherrisk del(5q) MDS and acute myeloid leukemia (AML), especially in those with TP53 mutations [7,8]. ...
... Surprisingly, cotreatment with lenalidomide and cyclosporine induced apoptosis in the two PDX models that were resistant to lenalidomide. Intriguingly, the lenalidomidesensitive PDX model contained wild type p53, while the lenalidomide-resistant PDX models contained mutant p53, which was consistent with clinical observations in that p53 mutation was associated with resistance to lenalidomide [2,8]. In addition, the three PDX models contained MLL arrangements and complex karyotypes, indicating that cyclosporine enhanced the sensitivity to lenalidomide in AML irrespective of the cytogenetic aberrations. ...
The immunomodulatory drug lenalidomide is used for the treatment of certain hematologic malignancies, including myelodysplastic syndromes (MDS). Lenalidomide interacts with cereblon (CRBN), a component of the CRL4CRBN E3 ubiquitin ligase complex, leading to ubiquitination and subsequent degradation of substrates, such as transcription factor Ikaros (Ikaros family zinc finger 1, IKZF1). With a genome loss of function screen, we recently identified two novel pathways mediated by lenalidomide in MDS. In this review, we summarized the major findings of these two pathways and their clinical implications. Depletion of G protein-coupled receptor 68 (GPR68) or an endogenous calcineurin (CaN) inhibitor, regulator of calcineurin 1 (RCAN1), reversed the inhibitory effect of lenalidomide on MDSL cells, an MDS cell line. Intriguingly, both GPR68 and RCAN1 expression levels were upregulated in MDSL cells after treatment with lenalidomide that was dependent on diminishment of IKZF1, indicating that IKZF1 functioned as a transcription repressor for GPR68 and RCAN1. Mechanistic studies revealed that upregulation or activation of GPR68 induced a Ca2+/calpain pro-apoptotic pathway, while upregulation of RCAN1 inhibited the CaN pro-survival pathway in MDSL cells. Notably, the pharmacological CaN inhibitor, cyclosporine, enhanced the sensitivity to lenalidomide in MDS as well as acute myeloid leukemia (AML). Surprisingly, pretreatment with lenalidomide reversed the immunosuppressive effects of cyclosporine on T lymphocytes. Our studies suggest that lenalidomide mediates degradation of IKZF1, leading to derepression of GPR68 and RCAN1 that activates the Ca2+/calpain pro- apoptotic pathway and inhibits the CaN pro-survival pathway, respectively. Our studies implicate that cyclosporine extends the therapeutic potential of lenalidomide to myeloid malignancies without compromising immune function.
... Receiving erythropoiesisstimulating agents (ESAs) has no impact on progression to AML but early failure of ESAs is associated with a higher incidence of AML transformation [40]. For MDS del(5q) patients, achievement of durable transfusion independence with lenalidomide was associated with a significantly reduced risk of AML progression [41]. ...
Purpose of review:
To understand how myelodysplastic syndromes (MDS) transform to AML and to describe how transformation can be predicted and prevented.
Recent findings:
Recent genomic analyses have shown that MDS progression to AML is associated with clonal expansion and clonal evolution. Mutation profiles of MDS change during progression and new mutations in signaling genes and transcription factors emerge. AML transformation can be predicted by several parameters including International Prognostic Scoring System IPSS risk category and transfusion requirements. The prognostic relevance of the acquisition of some gene mutations (i.e., IDH1 and 2, CBL, FT3, RAS, NPM1, TP53, and ASXL1) has to be prospectively validated. The most effective preventive therapy for AML transformation is allogeneic stem cell transplantation. Hypomethylating agents have been associated with prolonged time to AML transformation even in patients who did not achieve an objective response. The recent progress in the understanding of the molecular events leading to transformation and the event of new effective therapies open new avenues for a better prediction and prevention of AML transformation in patients with MDS.
... The greatest progress was achieved in the study of molecular pathogenesis of del(5q) MDS disease phenotype and its treatment by immunomodulatory or cereblon-binding drug lenalidomide [2,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Ebert et al. described that impaired ribosome biosynthesis due to RPS14 (ribosomal protein 14 of the small ribosome subunit) gene haploinsufficiency leads to the E3 ubiquitin ligase HDM2 (human homolog to mouse double minute 2, major negative regulator of p53) inactivation by free ribosomal proteins, particularly RPL11 [36]. ...
... TI is observed in almost 70% of the subjects and 50-70% experience cytogenetic responses with a median response duration of 24 months [29,30]. Obtaining TI was associated with a significantly reduced risk of AML progression and death [31]. A debate persists about the timing of lenalidomide initiation in anemic del(5q) patients: American guidelines advocate for lenalidomide as first-line, while European recommend it after a trial of ESAs [32•, 33-36]. ...
Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the microenvironment or the soil of the bone marrow (BM) as well as in the cell or the seed provide a growth advantage for clonal myeloid cells. Slowly accumulating senescent cells which can no longer divide because they have reached the end of their proliferative life cycle, but which continue to produce metabolic debris, overwhelm the natural autophagy mechanisms resulting in pro-inflammatory changes in the BM soil. In addition, the seed or stem cells acquire passenger mutations with each round of proliferation resulting from DNA copying errors. Some mutations commonly associated with MDS can be found in older, otherwise healthy individuals; however, when combined with other passenger mutations or in the setting of a noxious soil, the result could be a proliferative advantage for one stem cell over others, leading to its clonal expansion and development of the clinical syndrome. When considering therapeutic options for MDS patients, the important considerations are related to both the common co-morbidities of an elderly population along with the heterogeneous passenger mutations and the inflammatory changes in the soil. At present, allogeneic stem cell transplant is the only potentially curative option in MDS. Palliative strategies are directed at improving the quality of life and prolonging survival. Only three drugs are FDA approved, two being the hypomethylating agents azacytidine and decitabine while the third is lenalidomide which is restricted to lower risk MDS patients with deletion 5q. Promising future therapies are directed at reversing the pro-inflammatory changes in the microenvironment (luspatercept) or targeting specific mutations isocitrate dehydrogenase (IDH)1, IDH2, p53, EZH2. More durable responses are to be expected when the seed and soil are targeted simultaneously through a combination of drugs.
... Lenalidomide therapy was efficient in low risk red blood cell transfusion-dependent del(5q) MDS patients insensitive to EPO therapy (Table 1) . Very short telomere length [245] and TP53 mutations [242,[246][247][248][249][250][251] are connected with adverse prognosis, genetic instability and disease progression. Some mutated p53 are not regulated by E3 ubiquitin ligase MDM2 and are characterised by a relatively long life. ...
Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.
... Actually, there is evidence that the drug is active in MDS del(5q) patients before transfusion dependence 33 and the Spanish SINTRA-REV study (#NCT01243476) will prospectively assess whether lenalidomide delays the onset of transfusion dependence in MDS del(5q) patients. For now, based on the evidence of efficacy and safety obtained in several studies, 34,35 lenalidomide is used at the starting dose of 10 mg per day for 21 days on a 28-day cycle. The 10-mg dose is more effective than the 5-mg dose in inducing transfusion independence (61% vs 49%), 34 and cytogenetic response, 36 with a similar safety profile. ...
... For now, based on the evidence of efficacy and safety obtained in several studies, 34,35 lenalidomide is used at the starting dose of 10 mg per day for 21 days on a 28-day cycle. The 10-mg dose is more effective than the 5-mg dose in inducing transfusion independence (61% vs 49%), 34 and cytogenetic response, 36 with a similar safety profile. Achievement of durable transfusion independence with lenalidomide was associated with a significantly reduced risk of acute myeloid leukemia (AML) progression (45%; P 5 .022) ...
... and death (51%; P 5 .008). 34 Very few lower-risk MDS del(5q) patients are not eligible for lenalidomide treatment, ie, those with severe renal insufficiency and those who have severe cytopenias in addition to anemia. In any case, dose adjustment and use of G-CSF may allow therapy, 37 during which renal and thyroid function control is mandatory. ...
The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.
