Expanding role of lenalidomide in hematologic malignancies

Ghosh, Nilanjan; Grunwald, Michael R.; Fasan, Omotayo; Bhutani, Manisha

doi:10.2147/cmar.s81310

Cited by 28 publications

(15 citation statements)

References 99 publications

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“…The use of very low starting doses (2.5 or 5 mg) of lenalidomide followed by stepwise dose escalation is common in clinical studies with CLL to minimize the risk of tumor lysis syndrome and tumor flare [21, 24]. Importantly, the starting dose should be adjusted according to renal function regardless of indication [23].…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration–time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3–4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug–drug interactions.

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Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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“…It is approved in combination with dexamethasone for the treatment of multiple myeloma (MM) and as monotherapy for the treatment of transfusion-dependent anemia due to myelodysplastic syndromes (MDS) associated with deletion 5q and relapsed or refractory mantle cell lymphoma (MCL). [1][2][3][4][5][6][7] Further clinical trials of lenalidomide are being investigated for patients with cancers.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

Connarn¹,

Hwang²,

Gao³

et al. 2017

Clinical Pharm in Drug Dev

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A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs.

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“…Phase 1 testing of haploidentical NK cells primed ex vivo with CTV-1 lysate has been completed, and preliminary reports show that this approach is safe (NCT01520558) [70]. Lenalidomide is an immunomodulatory agent that has been demonstrated to enhance ADCC by NK cells [46,71]. Multiple trials are utilizing lenalidomide in combination with anti-tumor monoclonal antibodies, in order to enhance NK cell mediated ADCC and to improve clinical outcomes for patients (Table 2).…”

Section: Press the Gas Pedal: Function-enabling Nk Cellsmentioning

confidence: 99%

Improving natural killer cell cancer immunotherapy

Berrien-Elliott

Romee

Fehniger

2015

Current Opinion in Organ Transplantation

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Purpose of review Natural killer (NK) cells are innate lymphoid cells specialized to eliminate malignant cells via direct cytotoxicity and immunoregulatory cytokine production. As such, NK cells are ideal as cellular therapy for cancer patients, and a number of studies have provided proof-of-principle that adoptively transferred NK cells can induce remissions in patients with leukemia. A clear understanding of the mechanisms underlying NK cell anti-tumor responses, including target cell recognition, activation status, and negative regulatory signals will improve NK cellular therapy for cancer patients. Recent findings Clinical studies have demonstrated the safety and preliminary efficacy of NK cell adoptive transfer, especially in hematologic malignancies. A variety of NK cell sources, isolation techniques, activation approaches, and ex vivo expansion strategies are under investigation. New approaches have been developed and are being tested to optimize NK cell therapy, including ways to better target NK cells to malignant cells, increase their functional competence, facilitate expansion in patients, and limit inhibitory signals or cells. Summary NK cells represent a promising cellular immunotherapy for the treatment of cancer. In addition to adoptive cellular therapy, adjunct treatments that optimize NK cell targeting and function will enhance their potency and broaden their potential use to many cancer types.

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Expanding role of lenalidomide in hematologic malignancies

Cited by 28 publications

References 99 publications

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

Improving natural killer cell cancer immunotherapy

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