Thalidomide Analogues Research Articles

Pomalidomide in Hereditary Hemorrhagic Telangiectasia: Interim Results of a Phase I Study

BackgroundHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by telangiectasias on mucocutaneous surfaces and arteriovenous malformations in visceral organs. Most patients present with epistaxis and gastrointestinal (GI) bleeding requiring iron supplementation and blood transfusion. There is no accepted medical treatment for HHT, although several studies suggest the potential efficacy of thalidomide. However, thalidomide is not available for treatment of patients with HHT. To address this, we initiated a Phase I trial of pomalidomide, a third generation thalidomide analogue with a lower incidence of cytopenias and neuropathy than thalidomide, in patients with HHT and dependence on iron infusion or blood transfusion. The aim of this phase 1 trial is to investigate the safety and efficacy of pomalidomide in HHT related epistaxis and GI bleeding.MethodsAdult HHT patients with GI bleeding requiring at least 4 units transfusion or four doses of intravenous iron in the preceding four months, and patients with epistaxis requiring 2 units transfusion or 500 mg of intravenous iron in the preceding four months, and with an epistaxis severity score (ESS) ≥ 4 were enrolled. Pomalidomide was initiated at a 1 mg daily dose, which was increased by 1 mg/month to a maximal dose of 5 mg/day if bleeding did not entirely stop as judged by clinical evaluation. If bleeding stopped, patients were maintained on the dose of pomalidomide they were taking at the time of bleeding cessation for an additional 4 months. If bleeding did not stop, but improved, and patients escalated to the 5 mg/daily dose, they were maintained on this dose for an additional 4 months. After treatment with a stable dose of pomalidomide for 4 months, it was tapered by 1 mg/month until discontinued. The primary endpoint was a 50% reduction in the need for transfusion or parenteral iron therapy. A secondary endpoint was a reduction in the ESS of at least 1 point.ResultsThe trial was designed for 9 patients and is continuing to accrue. Six patients, 5 males and 1 female, aged 48-70 with clinically diagnosed HHT provided informed consent. One patient withdrew consent before initiating therapy due to valvular heart disease requiring surgery. One patient had a drug-related adverse event (rash) soon after starting pomalidomide, which required removal from the study. Two patients (brothers) had non-drug related adverse events (diagnosis of a neuroendocrine tumor and recurrence of a perianal abscess requiring surgery) and were removed from the study within 5-7 months after initiation. One of these also had significant cramping after 7 months of treatment. Both of these siblings had presented with epistaxis and GI bleeding and reported a decrease in frequency of melanotic stools. Both required one course of IV iron soon after entering the study (prior to pomalidomide, they received iron every 2-3 months), however both maintained hemoglobin levels at least 1 gm higher than their previous baseline during study, and iron studies remained in the normal range after initiation of therapy. Two patients had primarily epistaxis. Both responded to pomalidomide within 1-2 months with decreases of > 50% (2-3 points) in the ESS; this was associated with an increase in quality of life. One of these patients required weekly iron infusions as well as red blood cell transfusions every 3-6 weeks before study; however, she has currently been on study for more than 6 months with a hemoglobin of 10-11 gm/dl, has not required blood transfusion, and has not received intravenous iron for more than 3 months with iron studies remaining normal. An additional patient has recently entered the study at the time of this abstract preparation. Pre- and post-treatment blood sampling has been performed and will be analyzed for biomarker changes prior to the ASH meeting. Toxicity has consisted primarily of grade 1-2 fatigue (n = 2), and cramps (n = 2), but these were not felt to be of sufficient severity to stop pomalidomide.ConclusionsPreliminary interim findings from this phase I study provide an efficacy signal for patients with HHT and refractory bleeding. As with thalidomide, we speculate that pomalidomide causes remodeling of abnormal vasculature leading to decreases in AVMs and improvements in vessel stability. These findings support the development of a larger, multi-institutional HHT study.(NCT02287558) DisclosuresNo relevant conflicts of interest to declare.

Pembrolizumab in Combination with Pomalidomide and Dexamethasone (PEMBRO/POM/DEX) for Pomalidomide Exposed Relapsed or Refractory Multiple Myeloma

Introduction: Modern therapy for multiple myeloma including generations of thalidomide analogues, proteasome inhibitors and alkylating agents has substantially improved the survival for this disease. Patients who have progressed through these agents have limited options and a very poor prognosis. Programmed death ligand 1 (PD-L1) is expressed by myeloma cells and associated cells in the microenvironment. Blockade of the PD1-PDL1 axis enhances anti-myeloma activity in pre-clinical models. Pembrolizumab, a monoclonal antibody that blocks PD1-PD-L1 signaling, has shown clinical activity when combined with pomalidomide and dexamethasone in pomalidomide naïve patients with relapsed or refractory multiple myeloma (Badros et al, ASH 2015). Here we report the clinical experience of a previously pomalidomide exposed patient population receiving PEMBRO/POM/DEX.Methods: We retrospectively analyzed the efficacy of PEMBRO/POM/DEX in 9 heavily, pre-treated pomalidomide exposed patients with relapsed or refractory multiple myeloma between February 2016 and July 2016. All patients had been treated with ≥ 5 prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and alkylating agents including high dose melphalan and autologous stem cell transplantation. The PEMBRO/POM/DEX regimen included pembrolizumab 2 mg/kg administered intravenously over 30 minutes every 2 or 3 weeks with pomalidomide 4 mg (range 2-4 mg) orally daily 21/28 days and dexamethasone 40 mg (range 4-40 mg) weekly until evidence of progression (PD) or unacceptable toxicity. Adverse events were captured via chart review. Responses were assessed as per IMWG criteria.Results: The median age of the patients was 65 years (range 51-77) with 66% females. The patients had a median of 8 prior lines of therapy (range 5-14). The majority of subjects (78%) had cytogenetic abnormalities: 33% were gain of 1q21, 44% monosomy 17, and 11% t(11;14). Prior to therapy, 89% had significant anemia, 78% lytic bone lesions and 2 with significant renal insufficiency (creatinine 2.32 and 3.32 mg/dl respectively) though no one was on dialysis. Isotype included 5 IgA, 2 IgG, 2 lambda light chain. All patients progressed after prior lenalidomide and 8 of 9 patients progressed on previous pomalidomide the other one having stable disease. Patients received a median 3 cycles (range 2-7) of PEMBRO/POM/DEX, with modifications of pomalidomide and dexamethasone dosage dependent on toxicity. Seven patients received aspirin DVT prophylaxis. The overall response rate of PEMBRO/POM/DEX was 33%. Eighty-nine percent of patients achieved clinical benefit (3 PR, 2 MR, 3 SD). Median PFS was 57 days (0-85 days). There were no observed discontinuations of treatment or deaths attributed to drug toxicity and no pneumonitis was seen. However, adverse events consistent with previous reports from pembrolizumab as well as pomalidomide and dexamethasone were observed across all 9 patients. These AEs included: fatigue (n=9), anemia (n=9), thrombocytopenia (n=7), neutropenia (n=5), diarrhea (n=5), fevers (n= 4), shortness of breath (n=4), lower extremity edema (n=4), nausea/ vomiting (n=3), and renal insufficiency (n=3). Two patients experienced non-infectious colitis that responded to prednisone. Overall survival at 6 months for the 9 patients was 56%. 4 patients have died from progressive disease.Conclusion: PEMBRO/POM/DEX is an active regimen for relapsed and refractory multiple myeloma with acceptable toxicity even in a heavily treated pomalidomide exposed patient population. Further investigation of this combination earlier in the course of the disease is warranted. DisclosuresCohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy. Vogl:Constellation: Research Funding; Karyopharm: Consultancy; Teva: Consultancy; Calithera: Research Funding; GSK: Research Funding; Acetylon: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Mangan:Novartis: Speakers Bureau. Stadtmauer:Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Teva: Consultancy.

Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2

Lung cancer is one of the major causes of cancer-related mortality worldwide, and non-small-cell lung cancer is the most common form of lung cancer. Several studies had shown that thalidomide has potential for prevention and therapy of cancer. Therefore, the current study aimed to investigate the antitumor effects of two novel thalidomide analogs in human lung cancer A549 cells. The antiproliferative, antimigratory, and apoptotic effects in A549 cells induced by thalidomide analogs were examined. In addition, their effects on the expression of mRNAs encoding vascular endothelial growth factor165 (VEGF165) and matrix metalloproteinase-2 (MMP-2) were evaluated. Their influence on the tumor volume in nude mice was also determined. Results revealed that thalidomide analogs exhibited antiproliferative, antimigratory, and apoptotic activities with more pronounced effect than thalidomide drug. Furthermore, analogs 1 and 2 suppressed the expression levels of VEGF165 by 42% and 53.2% and those of MMP-2 by 45% and 52%, respectively. Thalidomide analogs 1 and 2 also reduced the tumor volume by 30.11% and 53.52%, respectively. Therefore, this study provides evidence that thalidomide analogs may serve as a new therapeutic option for treating lung cancer.

Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice

1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity – attributable to metabolites formed by cytochrome P450 enzymes – but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs.2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice.3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans.4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

Lenalidomide for refractory cutaneous manifestations of pediatric systemic lupus erythematosus.

Objective Cutaneous manifestations of pediatric systemic lupus erythematosus cause significant morbidity. Lenalidomide, a thalidomide analogue, has shown promise treating cutaneous lupus erythematosus in adults. Our objective was to evaluate lenalidomide's efficacy and safety in treating refractory cutaneous manifestations of pediatric systemic lupus erythematosus. Methods We performed a retrospective chart review of 10 adolescents who received lenalidomide for recalcitrant cutaneous lupus erythematosus. Information was gathered at drug initiation and 6-month follow-up. The Wilcoxon matched-pairs signed-rank test was used to assess change in quantitative parameters of disease activity. Results Nine subjects were girls and six were African-American. Indications for lenalidomide treatment included alopecia, nasal and oral ulcers, extensive malar rash, discoid lesions, bullous lesions, panniculitis, cutaneous vasculitis, and Raynaud's phenomenon with digital ulcerations. Within 6 months, all patients demonstrated complete or near resolution based on physician report. Prednisone dose decreased from a mean 23.5 mg (SD± 13.3) to 12.25 mg (SD± 9.2) ( P= 0.008). Sedimentation rate decreased from a mean 29 mm/hour (SD± 31.5) to 17 mm/hour (SD± 18.1) ( P= 0.004). Lenalidomide was well tolerated. Conclusion Lenalidomide is an effective and safe treatment for a spectrum of dermatological conditions in pediatric systemic lupus erythematosus. Its use may allow a reduction in prednisone dose and decreased disfigurement. Prospective study is needed to clarify lenalidomide's role in treating cutaneous manifestations of systemic lupus erythematosus.

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade.

Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K+-induced tonic, and Ca2+-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

Lenalidomide induces apoptosis and inhibits angiogenesis via caspase‑3 and VEGF in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) remains a disease with a high mortality rate, and the treatment for HCC remains limited. It is necessary to develop efficient and low toxicity drugs for the clinical treatment of HCC. Lenalidomide is a novel analogue of thalidomide and has anti‑inflammatory, immunomodulatory and anti‑angiogenic effects. The current study investigated the inhibitory effect against HCC cells of lenalidomide and thalidomide. The MTT assay was used to determine the cytotoxicity of lenalidomide and thalidomide, and morphological changes were observed by fluorescence microscopy. Caspase and VEGF protein expression were measured by ELISA analysis and western blotting. It was identified that treatment of cells with lenalidomide and thalidomide led to a dose‑dependent inhibition of cell proliferation, and the two drugs were able to induce cells apoptosis and inhibit VEGF expression in HCC cells. In addition, lenalidomide was identified to exhibit greater effects than thalidomide at the same concentration. In conclusion, the results indicated that lenalidomide induces apoptosis and inhibits angiogenesis in HCC cells via caspase‑3 and VEGF pathway, and these may provide a potential perspective for lenalidomide's application in clinical.

GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes.

Toll-like receptors (TLR) are crucial sensors of microbial agents such as bacterial or viral compounds. These receptors constitute key players in the induction of inflammation, e.g. in septic or chronic inflammatory diseases. Colony-stimulating factors (CSFs) such as granulocyte-macrophage-CSF (GM-CSF) or granulocyte-CSF (G-CSF) have been extensively investigated in their capacity to promote myelopoiesis in febrile neutropenia or to overcome immunosuppression in patients suffering from sepsis-associated neutropenia or from monocytic immunoincompetence. We report here that GM-CSF, downregulates TLR1, TLR2 and TLR4 in a time- and dose-dependent fashion in human monocytes. Diminished pathogen recognition receptor expression was accompanied by reduced downstream p38 and extracellular-signal-regulated kinase (ERK) signaling upon lipoteichoic acid (LTA) and lipopolysaccharide (LPS) binding—and accordingly led to impaired proinflammatory cytokine production. Knockdown experiments of the transcription factors PU.1 and VentX showed that GM-CSF driven effects on TLR regulation is entirely PU.1 but not VentX dependent. We further analysed monocyte TLR and CD14 expression upon exposure to the IMID® immunomodulatory drug Pomalidomide (CC-4047), a Thalidomide analogue known to downregulate PU.1. Indeed, Pomalidomide in part reversed the GM-CSF-mediated effects. Our data indicate a critical role of PU.1 in the regulation of TLR1, 2, 4 and of CD14, thus targeting PU.1 ultimately results in TLR modulation. The PU.1 mediated immunomodulatory properties of GM-CSF should be taken into consideration upon usage of GM-CSF in inflammatory or infection-related conditions.

The impact of thalidomide use in birth defects in Brazil

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

The molecular mechanism of thalidomide analogs in hematologic malignancies.

Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells. The underlying molecular mechanisms for these pleiotropic effects remained obscure until the identification of the cereblon (CRBN) E3 ubiquitin ligase as the primary target of thalidomide and its analogs in 2010. Binding of thalidomide or lenalidomide increases the affinity of CRBN to the transcription factors IKZF1 and IKZF3 and casein kinase 1α (CK1α). Ubiquitination and degradation of these neo-substrates results in IL-2 release and growth arrest of multiple myeloma and MDS cells. The discovery of this previously undescribed mechanism for an approved drug provides a proof-of-concept for the development of new therapeutics that exploit ubiquitin ligases for specific degradation of disease-associated proteins.

Synthesis of 1,2,3-triazole ‘click’ analogues of thalidomide

Click analogues of thalidomide were prepared from 3-azidoglutarimide and a diverse array of arylacetylenes and N-ethynyl/N-propargyl phthalimide derivatives. The sequence necessitated a new and scalable synthesis of the key click intermediate 3-azidoglutarimide. The dipolar cycloaddition reactions between the azidoglutarimide and the alkynyl coupling partners utilized a copper sulfate/sodium ascorbate reagent system in aqueous tetrahydrofuran and were first explored using substituted arylalkynes. Along with the click analogues of thalidomide, the click counterparts of the teratogenic and antiangiogenic thalidomide analogue EM-12 were prepared.

Promiscuous mechanisms underlie the antitumor effects of thalidomide analogs.

Two recent studies provide novel insights into the mechanism of action of thalidomide analogs in multiple myeloma and del(5q) myelodysplastic syndrome. They show that the role of the chaperone function of cereblon, and a calcium- and calpain-dependent pathway, are important in anticancer functions.

LNO3 AND L3 Are Associated With Antiproliferative And Pro-Apoptotic Action In Hepatoma Cells.

The identification of antitumoral substances is the focus of intense biomedical research. Two structural analogues of thalidomide, LNO3 and L3, are two synthetic compounds that might possess such antitumor properties. We evaluated the toxicological effects of these substances, including cytotoxicity, genotoxicity and induction of apoptosis in HTC cells. Additionally, the production of free radicals (nitric oxide and superoxide) was investigated, and the expression of caspases genes 3, 8, and 9 were determined by RT-qPCR. The compounds exhibited cytotoxic effects that resulted in inhibited cell proliferation. LNO3 showed to be more effective and toxic than L3 in all assays. LNO3 stimulated the release of NO and superoxide, which was accompanied by the formation of peroxynitrite. Apoptosis was induced in a dose-dependent manner by both compounds; however, the expression of caspases 3, 8 and 9 was unchanged. These results suggested that L3 and LNO3 possess antiproliferative and pro-apoptotic effects in HTC cells. Additionally, although they exhibited cytotoxicity, L3 and LNO3 might be useful coadjuvants in tumor treatment studies.

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems.

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.

New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (−786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles −786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2–5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis, Diagnosis and Treatment.

Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations, which may or may not be associated with systemic disease. Recent studies in this area continue to shape our understanding of this disease and treatment options. Epidemiologic studies have found an incidence of CLE of 4.30 per 100,000, which approaches similar analysis for systemic lupus erythematosus (SLE). Although there have been extensive efforts to define SLE, the classification of CLE and its subgroups remains a challenge. Currently, diagnosis relies on clinical and laboratory findings as well as skin histology. The Cutaneous Lupus Area and Severity Index™ (CLASI™) is a validated measure of disease activity and damage. CLE pathogenesis is multifactorial and includes genetic contributions as well as effects of ultraviolet (UV) light. Immune dysregulation and aberrant cell signaling pathways through cytokine cascades are also implicated. Patient education and avoidance of triggers are key to disease prevention. Antimalarials and topical steroids continue to be the standard of care; however, immunosuppressants, thalidomide analogs and monoclonal antibodies are possible systemic therapies for the treatment of recalcitrant disease.

Thyroid Complications of Cancer Therapy: An Increasing Challenge

Thyroid Complications of Cancer Therapy: An Increasing Challenge

Lenalidomide Induced Stroke in Multiple Myeloma

Lenalidomide (Revlimid) is a novel agent used in treatment of multiple myeloma (MM) with an adverse effect of thromboembolic episodes, more commonly, deep vein thrombosis and pulmonary embolism [1]. Venous thromboembolism has emerged as one of the leading complications of the life saving drug [2]. In addition, there is an increased burden of Lenalidomide induced stroke and myocardial infarction [3,4]. Recently, the antiangiogenic agents, in general, and Lenalidomide in particular have been associated with stroke [5, 6]. Furthermore, it was hypothesized that Lenalidomide, a Thalidomide analog, induces less neurotoxicity compared to thalidomide [7, 8].

Lenalidomide induced stroke in multiple myeloma

Lenalidomide (Revlimid) is a novel agent used in treatment of multiple myeloma (MM) with an adverse effect of thromboembolic episodes, more commonly, deep vein thrombosis and pulmonary embolism [1]. Venous thromboembolism has emerged as one of the leading complications of the life saving drug [2]. In addition, there is an increased burden of Lenalidomide induced stroke and myocardial infarction [3,4]. Recently, the antiangiogenic agents, in general, and Lenalidomide in particular have been associated with stroke [5, 6]. Furthermore, it was hypothesized that Lenalidomide, a Thalidomide analog, induces less neurotoxicity compared to thalidomide [7, 8].

Recurrent Painless Thyroiditis With Sequential Thyrotoxicosis and Hypothyroidism After 2 Courses of Lenalidomide

ABSTRACT Objective: Lenalidomide is a thalidomide analogue used to treat multiple myeloma, myelodysplastic syndromes, and solid cancers. It has been associated with thyroid abnormalities, mostly primary hypothyroidism, though rarely thyrotoxicosis. We present a case of lenalidomide-induced painless thyroiditis with initial thyrotoxicosis presentation followed by hypothyroidism requiring levothyroxine treatment in a 62-year old male with diffuse large B-cell lymphoma. Methods: The identified case is described. Results: The patient had no history of thyroid disease, with normal baseline thyroid function tests prior to lenalidomide treatment. He developed painless thyrotoxicosis after 1 week of treatment. The thyrotoxicosis resolved spontaneously, and he became euthyroid after withholding lenalidomide for 6 weeks. He was then restarted on a lower dose and developed recurrent painless thyroiditis 2 weeks later, with suppressed thyroid-stimulating hormone (TSH) of 0.05 μU/mL and elevated free thyroxine (FT4) o...