Lenalidomide in the treatment of chronic lymphocytic leukemia

Abstract

Lenalidomide is an immunomodulatory drug (IMiD) with a unique mode of action (MOA) that may vary across disease-type. It is currently approved in multiple myeloma (MM), myelodysplastic syndrome (MDS) and mantle cell lymphoma (MCL), yet is also clinically active in a host of lymphoproliferative diseases, including chronic lymphocytic leukemia (CLL). Due to its protean effects on the immune system, lenalidomide may be particularly appealing in CLL, which is distinct in its ability to evade immune recognition and cause immunosuppression. Areas covered: This review recaps the biological mechanisms of lenalidomide specific for CLL, and summarizes the clinical data in previously untreated and relapsed/refractory (R/R) CLL patients, with emphasis on toxicity. Moreover, lenalidomide treatment is put into the context of the highly effective targeted agents that are drastically changing the therapeutic approach in CLL. Expert opinion: Lenalidomide is a potent drug in CLL, both in first line and relapse. However, in comparison to other newly available agents, lenalidomide has slow onset of efficacy and notable toxicity profile that limits both its single agent use and combinations with chemotherapy. Future trials will hopefully direct our ability to harness lenalidomide MOA to best incorporate it in the rapidly evolving landscape of CLL treatment.

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Immunomodulatory drugs (IMiDs) have also been-and currently are-under evaluation for their anti-tumor effects in CLL. In the past 15 years, several clinical trials enrolling CLL patients have demonstrated the clinical efficacy of lenalidomide ( Table 1), but have also highlighted its unique toxicity profile and a rate of adverse events that suggests caution in incorporating this agent in treatment strategies [as reviewed in (195)]. One aspect of lenalidomide that has been considered worth of investigation consists in its pleiotropic effects on the immune system.…”

“…In addition, lenalidomide induces wide-range immunomodulatory effects on different immune cell compartments, among which i) a decrease in Tregs count, ii) an increase in Th17 cell number, iii) an upregulation of the NKG2D activating receptor on NK cells, and iv) a rise in Ig production by normal polyclonal B cells. Besides the immune system re-education, treatment with lenalidomide also modulates interactions of CLL cells with NLC and stromal cells within the tumor microenvironment (155) [and reviewed in (195,196)].…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…As described in detail in recent reviews, lenalidomide is regarded as a possible therapeutic target not only in multiple myeloma but also in other haematological malignancies, including AML and chronic lymphocytic leukaemia (CLL) [390][391][392][393][394].…”

Trial Watch: Toll-like receptor agonists in cancer immunotherapy

“…In particular, imiquimod is being tested (1) in combination with neoadjuvant sonidegib followed by surgery or imiquimod for the treatment of basal cell carcinoma (NCT03534947); (2) in combination with curettage surgery as compared to surgery alone in patients with basal cell carcinoma (NCT02242929); (3) in combination with 5-fluorouracil for the treatment of squamous cell carcinoma (NCT03370406); (4) in combination with pembrolizumab, an FDA-approved immune checkpoint blocker specific for PD-1, 169 in patients with melanoma 157 (NCT03276832); (5) compared to 5-flurouracil-based e1526250-4 chemotherapy or observation for the treatment of anal carcinoma (NCT02059499); (6) as a standalone immunotherapeutic agent or following large loop excision of the transformation zone (LLETZ) in patients with cervical intraepithelial neoplasms (CINs) (NCT02917746); (7) in combination with a DNA-based vaccine, GX-188E 170 (NCT03206138); (8) in combination with 5-flurouracil for the treatment of patients with high-grade cervical intraepithelial neoplasia (NCT03196180); (9) in combination with conization of the uterine cervix based on loop electrosurgical excision procedure (LEEP) as compared to LEEP alone for patients with CIN (NCT03233412); (10) as standalone therapy or in combination with a nonavalent HPVspecific vaccine for patients with CINs (NCT02864147); (11) as a single agent compared to LLETZ for patients with CINs (NCT02669459); (12) in combination with a DNA vaccine, VGX-3100, [171][172][173][174] for patients with HPV-16 and/or HPV-18related high grade squamous intraepithelial lesion (HSIL) of the vulva (NCT03180684); (13) in combination with doxycycline for the treatment of cutaneous T cell lymphoma (NCT03116659); (14) in combination with a peptide vaccine, iVAC-L-CLL01, 175,176 and the immunomodulatory agent lenalidomide [177][178][179][180] in patients with chronic lymphocytic lymphoma (NCT02802943); (15) combined with a DRibble-based vaccine 181 and DC-activated cytokine-induced killer (DC/CIK) cells and GM-CSF in NSCLC patients (NCT03057340); (16) as adjuvant therapy for patients with anal HPV lesions (NCT03289260); and (17) in combination with DPV-001, another DRibble-based vaccine, 107,[182][183][184] in patients with advanced prostate carcinoma (NCT02234921). BCG is being investigated in clinical settings: (1) in combination with rapamycin 185 for bladder carcinoma ...…”