Memory loss during lenalidomide treatment: a report on two cases
© Rollin-Sillaire et al.; licensee BioMed Central Ltd. 2013
Received: 30 March 2012
Accepted: 11 June 2013
Published: 12 August 2013
There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as “chemo brain” or “chemo fog”.
Two male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment. On withdrawal of the drug, one patient recovered normal cognitive function and independence in activities of daily living, whereas mild cognitive impairment persisted in the other patient. The Naranjo Adverse Drug Reaction Probability Scale score was 6 out of 13 for the first patient and 5 out of 13 for the second, suggesting a probable causal relationship between the adverse event and lenalidomide administration.
Lenalidomide may induce particular cognitive disorders (notably episodic memory impairments) in some patients. The drug’s putative neurotoxicity is probably promoted by specific risk factors (such as previous chemotherapy, prior mild cognitive impairment, age and the presence of cerebrovascular lesions).
KeywordsLenalidomide Chemo brain Chemo fog Cognitive impairment Episodic memory Dementia
Several studies have suggested that both malignant tumors and their treatments (such as chemotherapy, targeted therapy and radiotherapy) may induce cognitive impairment[1–4]. Indeed, the terms “chemo brain” and “chemo fog” are often used to describe cognitive impairment observed before, during or after chemotherapy or systemic administration of other antineoplastic agents. Disabling cognitive disorders may affect between 15% and 50% of patients undergoing chemotherapy. However, literature reports diverge as to the types and durations of cognitive impairments observed during chemotherapy. In most cases, the manifestations of chemo brain are mild but may have a slight impact on activities of daily living (ADL). The most common reported symptoms are fatigue, feelings of confusion or mental fogginess, inability to focus or concentrate, decreased attention span, slower thinking and impairments in remembering details, handling multiple tasks or learning new skills. Although a range of cognitive adverse effects have been observed during chemotherapy, impairments in memory, processing speed and executive function appear to be the most frequently reported[6, 7]. The duration of the symptoms varies and long-term cognitive impairment has been observed. Although most of the studies in this field concern cognitive complaints in women receiving adjuvant chemotherapy for breast cancer, cognitive complaints can occur in many cancer settings. Atrophy in some brain areas on magnetic resonance imaging (MRI) may be correlated with attention or visual memory performances[8, 9].
Preliminary studies have suggested the existence of host-related risk factors (e.g. age, genetic polymorphisms, immune reactivity, nutritional factors, hormone profile and the lack of cognitive reserve) and disease-related factors (e.g. tumor gene mutations, the induction of pro-inflammatory cytokines and paraneoplastic disorders) that contribute to cognitive decline[10–12]. Little is known about the mechanism(s) of chemo brain, although several hypotheses have been put forward: direct neurotoxic effects, oxidative stress and DNA damage, induced hormonal changes, immune dysregulation, cytokine release, vascular injury and blood clotting in small vessels and a genetic predisposition[11, 12]. There are number of guidelines and consensus statements on the assessment of cognitive function in chemotherapy trials[5, 12–14].
Here, we report on two multiple myeloma (MM) patients who presented with memory impairments and reduced independence in ADL during treatment with lenalidomide.
Performance of Patient 1 in the free and cued selective reminding test (FCSRT) during follow-up
FCSRT free recall
FCSRT total recall (free and cued recall)
FCSRT delayed free recall
FCSRT delayed total recall
Before lenalidomide treatment
During lenalidomide treatment
After lenalidomide withdrawal
1 year after lenalidomide withdrawal
Performance of Patient 2 in the free and cued selective reminding test (FCSRT) during follow-up
FCSRT free recall
FCSRT total recall (free and cued recall)
FCSRT delayed free recall
FCSRT delayed total recall
During lenalidomide treatment
6 months after lenalidomide withdrawal
12 months after lenalidomide withdrawal
Here, we described two patients in whom cognitive impairments developed or worsened significantly during lenalidomide treatment. In both cases, the neuropsychological manifestations and the impact on ADL appeared within one month of lenalidomide initiation. Both patients presented with a severe impairment in episodic memory, i.e. the ability to learn and retain new information. This impairment was evidenced in both cases by poor performance in the FCSRT. Moreover, the patients showed also evidence of a significant impairment in social and occupational functioning.
Lenalidomide is an immunomodulatory derivative of thalidomide that is approved for the treatment of first relapse in MM and is currently in clinical development for other malignant hematologic indications. The drug has anti-tumor, anti-angiogenesis and immunomodulatory effects. The most frequently reported adverse event (AE) for lenalidomide is immunosuppression (mainly neutropenia and thrombocytopenia), although the drug is considered as having a predictable safety profile and manageable effects. Venous thromboembolism is the most frequent non-hematologic AE. In contrast to thalidomide, lenalidomide is not associated with a significant level of peripheral neurotoxicity. The incidence of grade 3 or 4 peripheral neuropathy reported in Phase III trials is below 2% and lenalidomide does not appear to worsen preexisting peripheral neuropathy[20, 21]. A death in a Phase III study of 176 lenalidomide-treated MM patients was ascribed to leukoencephalopathy but no details were provided. However, we are not aware of any reports of major cognitive impairments and ADL difficulties associated with lenalidomide administration.
Several lines of evidence suggest that lenalidomide was responsible for the cognitive impairment observed in our two patients. Firstly, there was a temporal relationship between the observed disorders and lenalidomide administration. Even though Patient 1 complained of cognitive impairment before starting lenalidomide, his episodic memory clearly worsened after lenalidomide was administered. This worsening was very acute and unexpected. Despite wide-ranging investigations (MRI, lumbar puncture and laboratory tests), no infectious, vascular, metabolic or paraneoplastic etiologies were found. In the second case, neither the patient nor his wife reported the presence of cognitive difficulties prior to initiation of lenalidomide. The cognitive disorders occurred within one months of the start of lenalidomide treatment. Secondly, we noticed a significant improvement in episodic memory (a major improvement for the first patient and a slight improvement for the second) and independence in ADL after lenalidomide withdrawal. This improvement in memory performance was still present a year later in both cases. Thirdly, the presence of left temporal hypoperfusion on SPECT fits with the observed impairment in the FCSRT. When lenalidomide was withdrawn, the SPECT results normalized. These changes may indicate that lenalidomide has a toxic effect on temporal structures. To the best of our knowledge, this is the first report of brain hypoperfusion associated with lenalidomide treatment.
Nevertheless, it is not possible to unequivocally state that lenalidomide is directly neurotoxic. Indeed, the Naranjo Adverse Drug Reaction Probability score was 6 out of 13 for Patient 1 and 5 out 13 for Patient 2, which corresponds to a probable adverse drug reaction. A score above 9 corresponds to a definite adverse drug reaction, which was not the case here – primarily because (i) there are no previous conclusive reports on this reaction and (ii) the drug was not detected in blood (or other fluids) in concentrations known to be toxic. However, both patients had several putative risk factors for chemo brain, which may well explain their very poor cognitive tolerance of lenalidomide. Both had already undergone a cycle of chemotherapy before starting on lenalidomide and Patient 1 had already complained of cognitive impairment. The various drugs used to treat Patient 1’s MM (bortezomib, vincristine, dexamethasone and especially adriamycin[23, 24]) could have been involved in chemo brain. However, Patient 2 did not have any memory complaints prior to lenalidomide initiation – despite having already received several antineoplastic agents. Patient 2 was elderly; cognitive assessment after lenalidomide withdrawal revealed the persistence of an episodic memory impairment in the FCSRT, which is a predictive factor for prodromal Alzheimer’s disease (AD). Moreover, MRI showed overall atrophy of the brain (including the hippocampal regions) and many white matter lesions. Thus, a diagnosis of prodromal AD could be considered in this case. Cerebrospinal fluid analysis with AD biomarker assays would have refined this diagnosis. The presence of cerebrovascular lesions can also increase the risk of cognitive impairment. These observations suggest the existence of risk factors for chemo brain. Indeed, it has been suggested that age, lack of cognitive reserve, genetic risk factors, comorbid conditions and other cancer-related symptoms contribute to chemo brain. Moreover, the results of longitudinal studies have shown that 20% to 30% of patients have cognitive deficits prior to the start of treatment[5, 27–29]. Some researchers have assessed cognitive functions immediately after cancer diagnosis and prior to starting chemotherapy (which is an especially stressful period) and have suggested that cognitive deficits may be stress-related. The presence of the apolipoprotein E ϵ4 (APOE E4) allele (which constitutes a strong risk factor for AD) has also been suggest as a risk factor for chemo brain. A study found that E4 allele carriers being treated for breast cancer or lymphoma with chemotherapy tended to score less well in tests of visual memory, spatial ability and psychomotor functioning than survivors with other apolipoprotein alleles. The potential mechanism of the interaction between chemotherapy and APOE status remains unclear. We did not perform APOE genotyping here because it is not currently recommended in the diagnosis of AD or other forms of dementia.
The putative mechanism by which lenalidomide may have an impact on cognition is also unknown. Lenalidomide has anti-angiogenic, anti-inflammatory and anti-neoplastic effects in preclinical models. An anti-angiogenic effect might prohibit neurogenesis in hippocampal structures. Furthermore, it is not known to what extent lenalidomide can cross the blood–brain barrier (BBB) into the central nervous system (CNS). There are two reports of the remission of CNS progressions of hematologic malignancies (one diffuse large B cell lymphoma and one blastic mantle cell lymphoma) after lenalidomide treatment[33, 34]; this suggests that lenalidomide may be able to cross a damaged BBB. We suspect that lenalidomide crossed the BBN in our two cases reports, albeit in the absence of a clearly identified mechanism. As with chemo brain in general, the mechanism of lenalidomide’s putative neurotoxicity is not clear. Several mechanisms could be suspected: direct neurotoxic effect of the drug, oxidative stress and DNA damage, induced hormonal changes, immune dysregulation, cytokine release, vascular injury and blood clotting in small vessels and a genetic predisposition.
Here, we reported on the potential negative impact of lenalidomide on episodic memory in two MM patients undergoing chemotherapy. Although the symptoms were reversible, they were severe enough to lead to a loss of independence in ADL. The mechanism of these specific cognitive deficits is unknown. Lenalidomide’s putative neurotoxicity is probably exacerbated by risk factors (e.g. previous mild cognitive impairment, prior chemotherapy, age, cerebrovascular lesions, etc.) and some patients may be particularly vulnerable to the onset of cognitive impairments and a subsequent loss of independence in ADL.
There is a need to further identify and characterize the risks of cognitive impairment in patients being treated with immunomodulators.
Written informed consent was obtained from both patients for publication of this case report and the accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Activities of daily living
Magnetic resonance imaging
Deoxyribo nucleic acid
International staging system
Montreal cognitive assessment
Free and cued selective reminding test
Cerebro spinal fluid
Single photon emission computed tomography
Mini mental state examination
Dementia rating scale
Blood brain barrier
Central nervous system.
- Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE: Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc. 2003, 9: 967-982.View ArticlePubMedGoogle Scholar
- Jansen CE, Miaskowski C, Dodd M, Dowling G, Kramer J: A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function. Cancer. 2005, 104: 2222-2233. 10.1002/cncr.21469.View ArticlePubMedGoogle Scholar
- Stewart A, Bielajew C, Collins B, Parkinson M, Tomiak E: A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. Clin Neuropsychol. 2006, 20: 76-89. 10.1080/138540491005875.View ArticlePubMedGoogle Scholar
- Falleti MG, Sanfilippo A, Maruff P, Weih L, Phillips K-A: The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature. Brain Cogn. 2005, 59: 60-70. 10.1016/j.bandc.2005.05.001.View ArticlePubMedGoogle Scholar
- Wefel JS, Vardy J, Ahles T, Schagen SB: International cognition and cancer task force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011, 12: 703-708. 10.1016/S1470-2045(10)70294-1.View ArticlePubMedGoogle Scholar
- Wefel JS, Witgert ME, Meyers CA: Neuropsychological sequelae of non-central nervous system cancer and cancer therapy. Neuropsychol Rev. 2008, 18: 121-131. 10.1007/s11065-008-9058-x.View ArticlePubMedGoogle Scholar
- Correa DD, Ahles TA: Neurocognitive changes in cancer survivors. Cancer J. 2008, 14: 396-400. 10.1097/PPO.0b013e31818d8769.View ArticlePubMedGoogle Scholar
- McDonald BC, Conroy SK, Ahles TA, West JD, Saykin AJ: Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Cancer Res Treat. 2010, 123: 819-828. 10.1007/s10549-010-1088-4.View ArticlePubMedPubMed CentralGoogle Scholar
- Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, Wada N, Imoto S, Murakami K, Uchitomi Y: Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007, 109: 146-156. 10.1002/cncr.22368.View ArticlePubMedGoogle Scholar
- Ahles TA, Saykin AJ, Noll WW, Furstenberg CT, Guerin S, Cole B, Mott LA: The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology. 2003, 12: 612-619. 10.1002/pon.742.View ArticlePubMedGoogle Scholar
- Ahles TA, Saykin AJ: Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007, 7: 192-201. 10.1038/nrc2073.View ArticlePubMedPubMed CentralGoogle Scholar
- Vardy J, Wefel JS, Ahles T, Tannock IF, Schagen SB: Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol. 2008, 19: 623-629.View ArticlePubMedGoogle Scholar
- Vardy J, Rourke S, Tannock IF: Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research. J Clin Oncol. 2007, 25: 2455-2463. 10.1200/JCO.2006.08.1604.View ArticlePubMedGoogle Scholar
- Tannock IF, Ahles TA, Ganz PA, Van Dam FS: Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol. 2004, 22: 2233-2239. 10.1200/JCO.2004.08.094.View ArticlePubMedGoogle Scholar
- Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005, 53: 695-699. 10.1111/j.1532-5415.2005.53221.x.View ArticlePubMedGoogle Scholar
- Van Der Linden M, Coyette F, Pitrenaud J, GREMEM M: L’épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16). L’évaluation des troubles de la mémoire. Edited by: Van Der Linden M, Adam S, Agniel A, GREMEM M. 2004, Marseille: Présentation de quatre tests de mémoire épisodique (avec leur étalonnage), 25-47.Google Scholar
- Grober E, Buschke H: Guenine memory deficits in dementia. Dev Neuropsychol. 1987, 3: 13-36. 10.1080/87565648709540361.View ArticleGoogle Scholar
- Folstein MF, Folstein SE, McHugh PR: « Mini-mental state ». A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975, 12: 189-198. 10.1016/0022-3956(75)90026-6.View ArticlePubMedGoogle Scholar
- Mattis S: Mental status examination for organic mental syndrome in the elderly patients. Geriatric psychiatry: a handbook for psychiatrists and primary care physicians. Edited by: Bellak L, Karasu T. 1973, New York: Grune and Stratton, 77-101.Google Scholar
- Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD, Multiple Myeloma (010) Study Investigators: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007, 357: 2123-2132. 10.1056/NEJMoa070594.View ArticlePubMedGoogle Scholar
- Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple Myeloma (009) Study Investigators: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007, 357: 2133-2142. 10.1056/NEJMoa070596.View ArticlePubMedGoogle Scholar
- Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981, 30: 239-245. 10.1038/clpt.1981.154.View ArticlePubMedGoogle Scholar
- Ahles TA, Saykin AJ: Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer. 2002, 3 (Suppl 3): 84-90.View ArticleGoogle Scholar
- Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, Silberfarb PM: Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol. 2002, 20: 485-493. 10.1200/JCO.20.2.485.View ArticlePubMedGoogle Scholar
- Sarazin M, Berr C, De Rotrou J, Fabrigoule C, Pasquier F, Legrain S, Michel B, Puel M, Volteau M, Touchon J, Verny M, Dubois B: Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study. Neurology. 2007, 69: 1859-1867. 10.1212/01.wnl.0000279336.36610.f7.View ArticlePubMedGoogle Scholar
- Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P: Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007, 6: 734-746. 10.1016/S1474-4422(07)70178-3.View ArticlePubMedGoogle Scholar
- Hermelink K, Untch M, Lux MP, Kreienberg R, Beck T, Bauerfeind I, Münzel K: Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer. 2007, 109: 1905-1913. 10.1002/cncr.22610.View ArticlePubMedGoogle Scholar
- Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA: The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer. 2004, 100: 2292-2299. 10.1002/cncr.20272.View ArticlePubMedGoogle Scholar
- Quesnel C, Savard J, Ivers H: Cognitive impairments associated with breast cancer treatments: results from a longitudinal study. Breast Cancer Res Treat. 2009, 116: 113-123. 10.1007/s10549-008-0114-2.View ArticlePubMedGoogle Scholar
- Bickeböller H, Campion D, Brice A, Amouyel P, Hannequin D, Didierjean O, Penet C, Martin C, Pérez-Tur J, Michon A, Dubois B, Ledoze F, Thomas-Anterion C, Pasquier F, Puel M, Demonet JF, Moreaud O, Babron MC, Meulien D, Guez D, Chartier-Harlin MC, Frebourg T, Agid Y, Martinez M, Clerget-Darpoux F: Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. Am J Hum Genet. 1997, 60: 439-446.PubMedPubMed CentralGoogle Scholar
- Atkins ER, Panegyres PK: The clinical utility of gene testing for Alzheimer’s disease. Neurol Int. 2011, 3: e1-View ArticlePubMedPubMed CentralGoogle Scholar
- Cives M, Milano A, Dammacco F, Silvestris F: Lenalidomide in multiple myeloma: current experimental and clinical data. Eur J Haematol. 2012, 88: 279-291. 10.1111/j.1600-0609.2011.01735.x.View ArticlePubMedGoogle Scholar
- Rubenstein JL, Treseler PA, Stewart PJ: Regression of refractory intraocular large B-cell lymphoma with lenalidomide monotherapy. J Clin Oncol. 2011, 29: e595-e597. 10.1200/JCO.2011.34.7252.View ArticlePubMedPubMed CentralGoogle Scholar
- Cox MC, Mannino G, Lionetto L, Naso V, Simmaco M, Spiriti MAA: Lenalidomide for aggressive B-cell lymphoma involving the central nervous system?. Am J Hematol. 2011, 86: 957-10.1002/ajh.22148.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/2050-6511/14/41/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.