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Lenalidomide and chronic lymphocytic leukemia.

ABSTRACT: Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS) and tumor flare reaction (TFR), that make its management different from other hematologic malignancies.

SUBMITTER: Gonzalez-Rodriguez AP

PROVIDER: S-EPMC3791640 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Lenalidomide and chronic lymphocytic leukemia.

González-Rodríguez Ana Pilar AP González-Rodríguez Ana Pilar AP Payer Angel R AR Acebes-Huerta Andrea A Huergo-Zapico Leticia L Villa-Alvarez Monica M Gonzalez-García Esther E Gonzalez Segundo S

BioMed research international 20130919

Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potenti ...[more]

PMID: 24163824

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Lenalidomide in the treatment of chronic lymphocytic leukemia.

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Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.

Project description:The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.

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Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation.

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| S-EPMC7141702 | biostudies-literature

Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia.

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Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia.

Project description:PurposeLenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.Patients and methodsUsing a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.ResultsTwenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.ConclusionLenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.

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Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium.

Project description:PurposeLenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.Patients and methodsLenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis.ResultsSixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort.ConclusionIntrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.

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Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia.

Project description:Patients receiving lenalidomide are at an increased risk for deep venous thrombosis (DVT). Here, we prospectively investigated the DVT risk in patients with relapsed chronic lymphocytic leukemia (CLL) treated with lenalidomide (n = 32). Five patients developed six incidents of DVT over 1 year for an annual incidence of 16%. Three of these were considered drug-related. Median time to DVT was 105 days (range 56-259 days). No pulmonary embolism was detected. Hypercoagulability screen before study entry was negative in all patients who subsequently developed DVTs. Compared to normal volunteers CLL patients had increased baseline levels of D-dimer, thrombin-antithrombin, soluble vascular endothelial adhesion molecule 1 (sVCAM-1), and thrombomodulin (p < 0.001). After 1 week on lenalidomide D-dimer, thrombomodulin, sVCAM-1, factor VIII, TNFα, and C-reactive protein were significantly increased while protein C was decreased (p < 0.001). In patients with lenalidomide-related DVTs, TNFα, and sVCAM-1 were more strongly upregulated than in all other patients (p < 0.05) and TNFα and sVCAM-1 levels were significantly correlated (r = 0.65, p < 0.001). These data link lenalidomide associated DVTs with TNFα upregulation and endothelial cell dysfunction and suggest that aspirin may have a role for DVT prophylaxis in these patients.

| S-EPMC3414537 | biostudies-literature

A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia.

Project description:Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5mg followed by 5.0mg continuous. In Cohort A, tumor flare grade 1-2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD.

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