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Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (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 while RBC-transfusion independent. We enrolled 118 patients with 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 again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Genetic alterations are increasingly being recognized to play an important role in both diagnosis and prognosis of MDS. In general, MDS patients with SF3B1 mutations (MT) are known to have favorable outcomes whereas those with TP53 mutations have dismal survivals. However, it is unclear if the impact of these mutations applies to all subtypes of MDS including del(5q) which is known for its response to lenalidomide and better prognosis., Materials and Methods: We retrospectively reviewed 132 del(5q) MDS patients who were treated at the Moffitt Cancer Center (2001-2019)., Results: Among patients who received lenalidomide (n = 98), 50%, 42.9%, and 7.1% achieved hematologic improvement or better, no response, and disease progression/death with a median overall survival (mOS) of 93.2, 72.4, and 25.6 months, respectively (P < .0001). The mOS was 73.3 months but only 25.6 months after patients stopped lenalidomide. TP53 was the most common mutation accounting for 23.8% of the patients. Of the 63 patients with molecular data available, 23.8% harbored TP53 MT and 10% with SF3B1 MT. TP53 status did not impact OS (MT 86.4 vs. wild-type (WT) 73.3 months; P = .72) but those with SF3B1 mutations had a significantly shorter mOS compared to WT (23.9 vs. 83.5 months; P = .001). Multivariate analysis confirmed lenalidomide response and SF3B1 mutations are independently associated with outcomes., Conclusion: Our findings indicate many del(5q) MDS patients will benefit from lenalidomide but survival after its failure is limited. Mutations known to have prognostic impact in MDS at large may not have the same implications in the del(5q) subset., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Anemia in myelofibrosis (MF) occurs frequently, is poorly addressed by US Food and Drug Administration-approved JAK inhibitors, and negatively impacts quality of life. Immunomodulatory imide agents (IMiDs) such as thalidomide and lenalidomide are among the limited treatment options that have demonstrated anemia benefit in single-arm studies., Patients and Methods: To better understand the comparative impact of lenalidomide and thalidomide in MF patients, we analyzed 176 consecutive MF patients who received lenalidomide or thalidomide for at least 4 weeks. We sought to understand the variability in patient populations receiving lenalidomide versus thalidomide, to assess the efficacy of these agents, and to investigate clinical or genomic features that predict response., Results: Clinical benefit (CB) was assessable in 83 lenalidomide- and 67 thalidomide-treated patients. Thalidomide-treated patients were more likely to have thrombocytopenia (P < .001) and high-risk disease (P = .02). Forty-one (49%) lenalidomide-treated patients were deemed to have CB, predominantly due to anemia benefit. Similarly, 28 (42%) of thalidomide-treated patients had CB attributable to anemia benefit. Overall survival was similar for lenalidomide- and thalidomide-treated patients (P = .51). Lenalidomide-treated patients with CB had longer overall survival than those who did not (P = .01). High-risk mutations were found in 12 (41%) of 29 and 20 (57%) of 35 patients treated with lenalidomide and thalidomide, respectively (P = .32). Splicing mutations were common in both cohorts, though thalidomide-treated patients were more likely to have a high-risk SRSF2 or U2AF1 Q157 mutation (P = .01)., Conclusion: Overall, in this retrospective analysis, lenalidomide and thalidomide showed similar rates of CB in a cohort of MF patients that frequently harbored splicing mutations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anemia is a key survival prognostic factor in lower-risk myelodysplastic syndromes (MDS). Lenalidomide (LEN) can correct anemia in 25% of MDS patients without deletion 5q (del5q). As this therapy will inevitably fail, understanding the outcome of these patients will facilitate development of subsequent treatment strategies. To answer this question, an international retrospective study focused on LEN-treated lower-risk, non-del5q, MDS patients was performed. We analyzed the overall survival after LEN failure, its prognostic factors and the impact of post LEN treatment options. We included a total of 384 patients. The median overall survival after failure of LEN was 43 months. In multivariate analysis, adverse cytogenetics, excess of blasts at the initiation of LEN, and the type of failure (classified as stable disease, relapse, intolerance, or progression) were the main determinants of outcome. Subsequent therapy with hypomethylating agents was associated with a prolonged survival compared to BSC (median OS= 51m vs. 36m, p=0.01). In conclusion, the survival for non-del5q MDS patients after failure of LEN remains relatively prolonged, though with a wide range. Clinical trial participation remains the recommendation for these patients even if options such as hypomethylating agents may be considered.

Chronic lymphocytic leukemia (CLL) is an incurable disease in need of new therapeutic strategies. The immunomodulatory agent, lenalidomide, has shown activity as salvage therapy for CLL. In this phase II trial, we combined lenalidomide with rituximab in 25 patients (range, 41-79) with refractory/relapsed CLL. Lenalidomide was administered orally on escalating doses, with cycle 1 doses of 2.5mg daily on days 1-7, 5mg on days 8-14, and 10mg on days 15-21 followed by 7days off. On cycle 2 and beyond, lenalidomide was administered at 20mg daily on days 1-21. Rituximab was administered at 375mg/m(2) intravenously on a weekly basis for the first cycle starting on day 15 for 4 doses, with each cycle being 28days. Treatment was continued until disease progression or toxicity. Overall response rate was 45.8% on intent-to-treat and 61.1% in evaluable patients (all partial responses). Median time to treatment failure was 14.3 months for evaluable patients, and median overall survival was not reached. The most common grade 3/4 toxicity was neutropenia (72% of patients). The most common nonhematologic toxicity was infection (29% of patients). Lenalidomide combined with rituximab showed activity in heavily treated refractory CLL with an acceptable toxicity profile., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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 anemia due to lower-risk MDS with chromosome 5q deletion (del(5q)) with or without additional cytogenetic abnormalities, and isolated del(5q) only in the European Union. Mounting evidence suggests that lenalidomide is effective not only in reducing red blood cell (RBC) transfusion burden, but also in modifying the disease natural history by suppressing the malignant clone. Data discussed here from the pivotal phase 2 (MDS-003) and phase 3 (MDS-004) studies of lenalidomide demonstrate that lenalidomide treatment was associated with both short- and long-term benefits. These clinical benefits included high rates of RBC-transfusion independence (TI) with prolonged durations of response, high rates of cytogenetic response (CyR) associated with achievement of durable RBC-TI, no significant difference in rates of progression to acute myeloid leukemia (AML), and improvements in health-related quality of life (HRQOL). Achievement of RBC-TI and CyR with lenalidomide treatment was associated with extended survival and time to AML progression. Achievement of RBC-TI and hemoglobin response was additionally associated with HRQOL benefits. Recent data describing the impact of TP53 mutations and p53 expression on the prognosis of patients with del(5q) and the impact on response to lenalidomide are also discussed. The authors provide practical recommendations for the use of lenalidomide in patients with lower-risk del(5q) MDS., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Acα) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Acα overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.

Lenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis. The objective of this multicenter, phase 2 expansion trial was to determine the efficacy and safety of combination therapy with azacitidine (75 mg/m(2)/d for 5 days) and lenalidomide (10 mg/d for 21 days; 28-day cycle) in patients with higher-risk MDS. Among 36 patients enrolled (18 phase 1, 18 phase 2), median age was 68 years (range, 47-78 years) and follow-up was 12 months (range, 3-55 years). IPSS categories included intermediate-1 (n = 5 patients with excess blasts), intermediate-2 (20), and high (11). Common grade 3/4 nonhematologic adverse events included febrile neutropenia (22% of patients), other infection (11%), pulmonary (11%), cardiac (11%), constitutional (11%), and dermatologic (11%). The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response (CR), and 10 (28%) had hematologic improvement. Median CR duration was 17+ months (range, 3-39+); median overall survival was 37+ months (range, 7-55+) for CR patients, and 13.6 months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS.

This study aim was to determine the efficacy and safety of the combination of Gemcitabine 1000mg/m2 day 1 & 8 and Irinotecan 100 mg/m2 day 1 & 8 with escalating dose of thalidomide in chemonaive patients with advanced non-small cell lung cancer. Among the 20 patients who met eligibility criteria and received treatment, two patients (10%) experienced partial response and 14 (70%) experienced stable disease. The median time to disease progression was 4 months (95% CI: 2.8-6.6). The 1 year and 2 year survival rates were 36% and 27%, respectively. This combination is active in advanced NSCLC with manageable toxicity profile. [ABSTRACT FROM AUTHOR]