Del 5q Cytogenetic Abnormality Research Articles

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Most patients with lower-risk myelodysplastic syndrome (LR-MDS) develop anemia and a high proportion of patients become dependent on red blood cell (RBC) transfusions. MDS-related anemia is associated with low hemoglobin (Hb) levels, iron overload and poor quality of life. Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population. Etavopivat is an investigational, once-daily, selective erythrocyte pyruvate kinase (PKR) activator in development for the treatment of sickle cell disease (SCD) and anemia in patients with LR-MDS. In a phase 1 study in adult and adolescent patients with SCD by Saraf et al. HemaSphere. (2022), etavopivat 400 mg once daily was considered well tolerated and showed sustained Hb increases up to 12 weeks for most patients. Additional studies in healthy volunteers and patients with SCD support an acceptable safety profile together with improved RBC health and function during continuous treatment with etavopivat. In patients with LR-MDS, ineffective hematopoiesis may be due, in part, to insufficient ATP production, leading to increased erythroid lineage apoptosis. By activating PKR, etavopivat may improve RBC health and function by stimulating energy production (increasing ATP levels), increasing Hb levels (decreasing anemia), and decreasing erythroid lineage apoptosis. Aims:Describe the design of a multicenter, open-label, phase 2 study (FORTITUDE; NCT05568225) evaluating hematologic improvements in patients with very low-, low- and intermediate-risk MDS during treatment with etavopivat. Study design:Key eligibility criteria include age ≥18 years; very low-, low- and intermediate-risk MDS per the Revised International Prognostic Scoring System; and anemia defined by mean Hb <10.0 g/dL and <3 RBC transfusions <16 weeks prior to first dose for non-transfusion-dependent (NTD) patients or ≥3 units of RBCs for anemia <16 weeks prior to first dose for transfusion-dependent (TD) patients. Key exclusion criteria include MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality, history of acute myeloid leukemia, and an absolute neutrophil count <0.5 × 10 9/L. Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients. Patients will receive etavopivat 400 mg once daily for at least 48 weeks. Treatment may be continued beyond 48 weeks in patients demonstrating clinical benefit. The primary objective of the study is to assess hematologic improvements based on an erythroid response over any continuous period ≥8 weeks within 24 weeks on etavopivat treatment in patients with LR-MDS. The primary endpoint will be based on the combined incidence of: ≥1.5 g/dL increase in Hb from baseline maintained for ≥8 consecutive weeks for NTD patients; absence of any transfusion for ≥8 consecutive weeks for low transfusion-burden patients; and reduction by ≥50% of RBC units for ≥8 consecutive weeks for high transfusion-burden patients. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of etavopivat will be evaluated. FORTITUDE is open for enrollment in Canada, France, Germany, and the USA. Planned enrollment includes approximately 15 patients in each of the three transfusion requirement-based groups (Figure). Statistical analysis: The primary endpoint (pooled incidence) will be tested with a one-sided Fisher's exact test at the significance level of 0.025 where 0.2 is the assumed null proportion. Summary:Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

External validation of the Molecular International Prognostic Scoring System (IPSS-M) for myelodysplastic syndromes.

7056 Background: Myelodysplastic Syndromes (MDS) comprise of a group of clonal diseases characterized by dysplastic hematopoietic progenitor cells, leading to cytopenias and in select cases transformation to acute myeloid leukemia (AML). In June 2022 the Molecular International Prognostic Scoring System (IPSS-M) was developed to build on the traditional IPSS-R and is reported to be prognostic even with incomplete molecular data. We aimed to validate this scoring system with an external dataset, and utilize a patient population which typically does not contain complete molecular testing at diagnosis. Methods: This single center study at a tertiary medical center in New York, NY was conducted as an external validation of the IPSS-M. Patients with MDS who had documented peripheral blood counts, bone marrow biopsies, and cytogenetic data were identified in the institutional tissue bank. After eliminating repetitive patient samples, 405 patient entries, collected between July 7, 2010 and March 29, 2022 were included in this study. 392 patients had previously been categorized by IPSS-R score. 332 patients had at least one subsequent follow-up event. 94 patients had bone marrow biopsies that were peri-diagnostic (within 12 months of diagnosis). Results: Patients in the entire cohort had a median age of 74 years (range, 30-96). The median follow-up duration was 1.5 years (range 0.0-9.9 years). Nearly all patients had at least partial molecular diagnostic data. Other than PRPF8 mutations (0%), all other mutations included in the IPSS-M scoring system were tested in a subset of the study population. The most common mutations in the patient population were SF3B1 (20.4%), ASXL1 (17.6%), and SRSF2 (15.9%); 12.2% of patients had the del5q cytogenetic abnormality, and 5.6% were found to have at least one TP53 mutation; 2.7% were TP53 (multi-hit). 29% of all patients were up-staged from IPSS-R to IPSS-M score, while 12% were down-staged. At the time of study evaluation, there were 84 events; 61.3% of patients were alive at the time of analysis. The median overall survival was 3.6 years (25-75% range: 2.75-5.50 years). When limited to patients with peri-diagnostic bone marrow biopsies, there were statistically significant differences in overall survival between IPSS-M categories (p<0.000001) as well as IPSS-R categories (p<0.00001). There was no statistical difference in survival between IPSS-M categories (p=0.6) or IPSS-R categories (p = 0.2) if scores were calculated at any time point in the patient’s disease course. Conclusions: This study validates the utility of both the IPSS-M and the IPSS-R scoring systems, and notably retains important risk stratification with incomplete diagnostic data. Importantly, the scoring systems are not effectively prognostic as the disease progresses, and thus should only be utilized at or near the time of diagnosis.

Biological activity of lenalidomide in myelodysplastic syndromes with del5q: results of gene expression profiling from a multicenter phase II study

In vitro studies suggest that haploinsufficiency is involved in the pathogenesis of myelodysplastic syndromes (MDS). In patients with del5q cytogenetic abnormality, RPS-14 and microRNAs (miRNAs) play a major role. In a multicenter phase II single-arm trial with lenalidomide in anemic primary del5q MDS patients with low- or int-1 risk IPSS, biological changes from baseline were investigated. Gene expression profiling of selected genes was performed (TaqMan® Low Density Array Fluidic card, Applied Biosystems PRISM® 7900HT) and normalized against the expression of the 18S housekeeping gene from a pool of healthy subjects. Thirty-two patients were evaluated at baseline and after 3 and 6months of treatment. RPS-14, miR-145, and miR-146 were downregulated at baseline and significantly increased during treatment. Nuclear factor kappa B, IL-6, interferon regulatory factor-1, IFNγ-R2, IL-2, and many genes in the apoptotic pathways (TNF, IL-1B, and IL-10) were upregulated at baseline and significantly downregulated during lenalidomide treatment, while forkhead box P3, FAS, IFNγ, IL-12A, and IL-12B were downregulated at baseline and progressively upregulated during treatment. The crucial role of aberrant immunological pathways and haploinsufficiency in the pathogenesis of del5q MDS is confirmed in the present patient setting. Our results indicate that lenalidomide may act through defined immunological pathways in this condition.

Lenalidomide is active in Japanese patients with symptomatic anemia in low- or intermediate-1 risk myelodysplastic syndromes with a deletion 5q abnormality

Lenalidomide is an immunomodulatory agent recently reported to be effective in the treatment of transfusion-dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del 5q) cytogenetic abnormality. We conducted a multicenter, single-arm clinical trial to evaluate the safety and efficacy of lenalidomide in Japanese patients with anemia in low- or intermediate-1 risk MDS associated with the del 5q cytogenetic abnormality. Eleven patients (5 with transfusion-dependent anemia; 6 with transfusion-independent symptomatic anemia) received once daily oral administrations of 10 mg of lenalidomide for 21 consecutive days in a 28-day treatment cycle. The efficacy was assessed by the IWG criteria. At an interim analysis after > or =24 weeks of therapy, hemoglobin increase was noted in all 11 patients, with a median increase of 6.0 g/dL (range, 0.9-10.9) from the baseline. All transfusion-dependent patients achieved transfusion independence. Histopathologic and cytogenetic improvement was also noted. Neutropenia and thrombocytopenia were the most common adverse events related to lenalidomide. The adverse events were manageable, and no patients experienced serious adverse events or adverse events requiring treatment discontinuation. The results indicate that lenalidomide can be a useful agent for treating Japanese patients with anemia associated with low- or intermediate-1 risk MDS with the del 5q cytogenetic abnormality.

The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions

Lenalidomide (Revlimid®) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Previous reports suggest that lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of lenalidomide on the associations between cadherin 5, β-catenin and CD31, adherens junction proteins whose interaction is critical for endothelial cell cord formation. Furthermore, lenalidomide inhibited VEGF-induced PI3K–Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of lenalidomide on hypoxia-induced endothelial cell formation of cords and HIF-1α expression, the main mediator of hypoxia-mediated effects and a key driver of angiogenesis and metastasis. Anti-metastatic activity of lenalidomide in vivo was confirmed in the B16-F10 mouse melanoma model by a > 40% reduction in melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of hypoxia-induced processes support a potential anti-angiogenic and anti-metastatic mechanism for this clinically active drug.

The ratio of cyclin D1/p21kip baseline gene expression and SPARC gene expression can be potential predictors of non-Hodgkin's lymphoma (NHL) patient response to lenalidomide therapy

22150 Background: Lenalidomide (LEN) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. LEN also has activity in a variety of hematological malignancies and disorders, including amyloidosis, myelofibrosis, chronic lymphocyte leukemia, cutaneous T cell lymphoma and non-Hodgkin's lymphoma (NHL). To date, predictive markers and biomarkers of LEN response have not been reported. Methods: We have analyzed the expression of several important genes involved in cancer cell cycle, proliferation and angiogenesis using various NHL cell lines by quantitative real-time polymerase chain reaction, to identify patterns of constitutive gene expression that may predict sensitivity of NHL tumors, particularly mantle cell lymphoma (MCL), to LEN therapy. Results: We observed that the level of constitutive cyclin D1 gene expression in MCL cell lines correlates with the order of sensitivity to LEN: Rec-1> Jeko-1> Granta-519 > JVM-2. Conversely, the order of constitutive p21kip expression is: JVM-2 > Granta-519 > Jeko-1 > Rec-1, and thus constitutive p21kip gene expression is inversely proportional to LEN sensitivity. Therefore, the baseline cyclin D1 to p21kip gene expression ratio could be predictive of patient response to LEN therapy. We also found that LEN markedly increases SPARC (Osteonectin) gene expression in NHL cells in a manner that correlates with the anti-proliferative activity of LEN against that cell line. The order of sensitivity to LEN by various NHL cell lines is Namalwa (Burkitt's Lymphoma)>Rec-1>Jeko-1>Granta-519>JVM-2 (all MCL)> DB (Diffuse Large B Cell Lymphoma). Thus SPARC gene expression may be a biomarker of NHL or MCL tumor response to LEN. Conclusion: High baseline cyclin D1 and low p21kip gene expression in MCL cell lines correlates with sensitivity to LEN and may be predictive of a good clinical response to LEN. Furthermore, monitoring of SPARC expression in NHL or MCL patients may enable early identification of patients who are responding to LEN therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene

Lenalidomide Enhancement of NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) Is Mediated by Granzyme B and FasL and Is Associated with Modification of SHIP-1, PLC-g2 and pERK and Enhanced Chemokine Production.

Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory drug that is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo and we have previously shown that in an in vitro ADCC system lenalidomide is able to directly enhance human NK cell and monocyte function in response to rituximab (chimeric anti-CD20 mAb) and other IgG1 antibodies. We have now addressed the effect of lenalidomide on NK cell signaling pathways and have shown that compared to the levels seen with FC gR stimulation (with IgG) plus IL-12, there is an inhibitory effect of lenalidomide on SHIP-1 with concomitant enhancement of PLC g2 and pERK. This is associated with increased secretion of a variety of chemokines as well as GM-CSF and decreased IL-6 production. In functional ADCC assays, NHL cell lines were pre-coated with rituximab and exposed to either NK cells or monocytes pre-treated with lenalidomide. After 4 (NK cells) or 15 (monocytes) hours in culture the viability of the tumor cells was assessed. The consistent enhancement of ADCC in the presence of lenalidomide is associated with greatly increased expression of granzyme B and FasL, although perforin is maximally elevated without lenalidomide. We found that ADCC is totally blocked by an inhibitor of granzyme B and is partially blocked by anti-FasL. In conclusion, we have shown that the ability of lenalidomide to enhance ADCC-mediated killing of rituximab treated CD20+ve NHL cell lines is mediated by granzyme B and FasL and is associated with clear effects on NK cell signaling and chemokine production.

Lenalidomide Displays Direct Anti-Non-Hodgkin's Lymphoma (NHL) Cell Activity in Association with Enhanced SPARC Expression but Independent of Its Ability to Strongly Inhibit NHL Cell VEGF Production In Vitro.

Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory drug that is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin's lymphoma (NHL). We have previously shown that lenalidomide can directly inhibit the proliferation of NHL cells and synergize with dexamethasone in inducing cell cycle arrest at the G1/S transition leading to caspase activation and apoptosis. In this study we have studied the potential for lenalidomide mediated growth inhibition, apoptosis and inhibition of angiogenic factors in NHL. We have assessed proliferation, expression of p21 and SPARC tumor suppressor genes and the production of the angiogenic factor vascular endothelial growth factor (VEGF) in six established NHL cells lines in vitro. The effect of lenalidomide on NHL cells was determined after 1–3 days using 3H-thymidine incorporation, microbead array and real time PCR. We found that lenalidomide displays anti-proliferative effects on Namalwa, Jeko-1 and Rec-1 cells when used alone and in combination with dexamethasone. However, several NHL cell lines, such as Granta-519, DB, and JVM-2, appear to be resistant. We also found that lenalidomide strongly inhibited VEGF production (but not mRNA levels) by the three sensitive lines (but not the three resistant lines) at much lower concentrations than required for inhibitory effects on proliferation. Excess recombinant human VEGF or neutralizing anti-VEGF antibody had no effect on Rec-1 proliferation suggesting that there is no connection between these two effects. Lenalidomide strongly increased the expression of tumor suppressor genes, such as p21cip/kip and SPARC (secreted protein acidic and rich in cysteine). In particular, elevation of SPARC mRNA correlated with the anti-proliferative effect of lenalidomide and was not seen in the resistant cells, whereas elevated p21 was observed in both sensitive and resistant (DB) cells. The effect of SPARC gene silencing on lenalidomide-induced effects is being assessed in siRNA studies. In conclusion, lenalidomide demonstrates anti-proliferative activity against certain sensitive NHL cells, particularly in combination with dexamethasone. Potent anti-VEGF activity of lenalidomide appears to be independent of proliferation and supports its anti-angiogenic potential. Lenalidomide-induced up-regulation of SPARC mRNA appears to correlate with sensitivity and may have biomarker potential in NHL.

A case report of sarcoma regression in a patient with MDS treated with lenalidomide

20535 Background: Lenalidomide is an immunomodulatory drug recently approved for the treatment of MDS patients with del 5q cytogenetic abnormality. Here we describe a case of sarcoma regression in a patient with MDS who had been treated with lenalidomide. Method: An 84 year old man was diagnosed with low risk MDS in November 2002, he was transfusion dependent requiring 2–4 units of blood a month. He was enrolled on the MDS 002 trial in February 2004. He became transfusion independent by cycle 4. Results: In March 2005 he developed abdominal pain and a CT of the abdomen revealed a 2 x 2 cm mass involving the lesser curvature of the stomach. An MRI of the abdomen followed, confirming the presence of an enhancing gastric lesion, a biopsy of the mass revealed low grade malignant sarcoma. The patient was a poor surgical candidate and the decision was made to follow the progression of the mass with repeat imaging. In October 2005 a repeat MRI failed to visualize the previously noted mass, a recent CT performed in December 2006 was also negative for the presence of the mass. A potential therapeutic role for lenalidomide in this case which may have led to the regression of the sarcoma is possible although spontaneous regression can not be ruled out. It is not known if the mass was present at the time of enrollment on the clinic trial, it is also not clear as to why the patient presented with abdominal pain several months into the clinical trial. There had been several case reports in the literature describing similar results with thalidomide in patients with soft tissue sarcoma however, to our knowledge this clinical observation has never been reported with lenalidomide previously. Conclusion: This observation merits consideration for prospectively evaluating the efficacy of lenalidomide in patients with sarcoma for whom limited therapeutic options currently exist. No significant financial relationships to disclose.

Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) of Rituximab Treated Non-Hodkin's Lymphoma Cell Lines In Vitro.

Lenalidomide (Revlimid® is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone is for the treatment of multiple myeloma patients who have received at least one prior therapy. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin's lymphoma (NHL). Potential mechanisms of action include anti-angiogenic, anti-proliferative and immunomodulatory activities. Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Furthermore, lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo. We have utilized an in vitro ADCC system to assess the ability of lenalidomide to directly enhance human NK cell function in response to therapeutic antibodies, such as rituximab (chimeric anti-CD20 mAb). Isolated NK cells produced little or no IFN-γ in response to IgG and/or IL-2 or IL-12. However, pre-treatment of NK cells with lenalidomide greatly enhanced IFN-γ production by NK cells in a dose-dependent manner. In a functional ADCC assay, NHL cell lines (Namalwa, Farage & Raji) were pre-coated with rituximab and exposed to NK cells pre-treated with lenalidomide in the presence of either exogenous IL-2 or IL-12. After 4 hours in culture the viability of the tumor cells was assessed. Lenalidomide consistently and synergistically increased the killing of tumor cells in a dose-dependent manner and up to >4-fold compared to rituximab alone. Rituximab alone had only a small effect in this model and there was no killing of cells in the absence of rituximab. The presence of either exogenous IL-2 or IL-12 was required to see enhanced killing by lenalidomide. In cancer patients lenalidomide has been shown to increase serum IL-12 levels and is also known to induce IL-2 production by T cells in vitro. Potential mechanisms for enhanced ADCC include increased signaling through NK FCγ receptors and/or IL-2 or IL-12 receptors. However, we found that these receptors are unaffected by lenalidomide, although downstream effects on NK signaling pathways are likely and are being actively investigated. In conclusion, we have shown that lenalidomide strongly enhances the ability of rituximab to induce ADCC mediated killing of NHL cells in vitro. This provides a strong rationale for combination of these drugs in patients with NHL and CLL.

Long Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome without Del 5q Cytogenetic Abnormalities.

Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica 2006; 91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up.Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle).Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively).Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly

Lenalidomide (Revlimid ®, CC-5013) belongs to a line of compounds known as immunomodulatory drugs (IMiDs ®) that are under clinical investigation in hematopoietic and solid tumor cancers. Lenalidomide efficacy has been reported in clinical trials of multiple myeloma and myelodysplastic syndromes (MDS), particularly in MDS patients with a del 5q cytogenetic abnormality, with or without other cytogenetic abnormalities. Here we report that lenalidomide inhibits proliferation of chromosome 5 deleted hematopoietic tumor cell lines in vitro, whether from the B cell, T cell, or myeloid lineage. There was diversity in the responses of the various cell lines to lenalidomide, with one undergoing cell cycle arrest, and others undergoing apoptosis. In the most lenalidomide-sensitive chromosome 5 deleted cell line, Namalwa CSN.70, the compound induced G 0/G 1 cell cycle arrest, inhibited Akt and Gab1 phosphorylation, and inhibited the ability of Gab1 to associate with a receptor tyrosine kinase. Lenalidomide also enhanced AP-1 transcriptional activity in Namalwa, but not in the other cell lines tested. These studies provide evidence for the mechanism of action of lenalidomide in chromosome 5 deleted hematopoietic tumors in vitro, and may provide a better understanding of the drug's activity in clinical applications.