Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: Results of a retrospective case review

Abstract

Lenalidomide is an antiangiogenic drug associated with hypothyroidism. We describe a case-series of lenalidomide use in hematological cancers and the prevalence of thyroid abnormalities. We reviewed medical records of patients treated with lenalidomide at a single center form 2005 to 2010 and extracted demographic, clinical, and laboratory data. Of 170 patients with confirmed lenalidomide use (age 64.9±15 years), 148 were treated for multiple myeloma and 6% had thyroid abnormalities attributable only to lenalidomide. In patients with a previous diagnosis of thyroid dysfunction, the addition of lenalidomide therapy was associated with a higher incidence of subsequent TFTF abnormality (17%) as compared to patients with no previous diagnosis of thyroid dysfunction (6%) (P=0.0001). Many patients (44%) with pre-existing disease and a change in thyroid function before or while on lenalidomide had no further follow-up of their thyroid abnormalities, Of 20 patients who did not undergo any thyroid finction testing either before starting or while on lenalidomide for a median of 9.4 months (±6.5), 35% developed new symptoms compatible with hypothyroidism, including worsened fating, constipation or cold intolerance. Symptoms of thyroid dysfunction overlap with side effects of lenalidomide. Thyroid hormone levele are not regularly evaluated in patients on lenalidomide. While on this treatment, thyroid abnormalities can occur in patients with no previous diagnoses and in patients with pre-existing abnormalities. Because symptoms of thyroid dysfunction could be alleviated by appropriate treatment, thyroid function should be evaluated during the course of lenalidomide to improve patients quality of life. Am. J. Hematol. 2011. © 2011 Wiley-Liss, Inc.

Introduction

Lenalidomide (Revlimid; CC-5013) is an immunomodulatory, antiangiogenic drug that is a structural analog of thalidomide. It is approved by the Food and Drug Administration for treatment of multiple myeloma, and myelodysplastic syndromes [1, 2], and is currently under investigation for use in solid tumors, including renal cell, ovarian, and prostate cancers [3, 4]. Lenalidomide induces endogenous cytokine release and increases the number and function of natural killer cells, inhibits growth factors necessary for angiogenesis, and induces apoptosis of tumor cells [5]. In comparison to thalidomide, lenalidomide is shown to have improved potency in the treatment of myeloma and myelodysplastic syndromes (MDS), including a longer time to disease progression, improved efficacy in cases of relapse, and improved overall survival [6–8]. In patients with MDS with 5q deletion, lenalidomide is especially associated with increased survival [9]. Furthermore, lenalidomide has a less reported frequency of side effects compared with thalidomide, which include constipation, sedation, and neuropathy [7, 8, 10, 11].

Hypothyroidism has been reported as a side effect of both thalidomide [12, 13] and lenalidomide [1, 14]. The exact cause of thyroid dysfunction is not known but proposed mechanisms include a direct injury to thyrocytes, the initiation of an immune response against the thyroid, an inhibition of iodine uptake, and a decrease in thyroid secretory capacity [12]. Unrecognized hypothyroidism, in increasing degrees of severity, can cause fatigue, constipation, pericardial effusion, and bradycardia. Unrecognized hyperthyroidism can lead to arrythmias, palpitations, and weakness. Many of these symptoms are often nonspecific and may be attributed to the underlying malignancy or other cancer therapies used concurrently with lenalidomide. In either case, unsuspected thyroid dysfunction may be left untreated and patients' quality of life may suffer.

Because of the potential effects of lenalidomide on thyroid function, some investigators have recommended that surveillance testing be performed on all patients before and during the treatment course on at least a bi-monthly basis [15]. It is not known if this recommendation is followed at present by hematologists following patients treated with lenalidomide, especially those that have preexisting thyroid abnormalities. In this study, we present a review of lenalidomide-treated cases at a single center hematology clinic and report the prevalence of thyroid dysfunction among patients while on lenalidomide therapy and the frequency of thyroid function monitoring.

Methods

We received approval from the Vanderbilt University Institutional Review Board for this retrospective chart review. Patients in this study were identified by contacting hematologists who had developed an active lenalidomide registry since 2005. We used the electronic medical record to obtain all patient data. We obtained demographic and clinical data with and extensive review of each chart. Since thalidomide and lenalidomide are in the same class of antiangiogenic agents, and tyrosine kinase inhibitors can cause hypothyroidism, we also surveyed the chart for previous tyrosine kinase inhibitor and thalidomide use and recorded the history and interval of use. We separated the patients into three groups. The first group had no recorded thyroid abnormalities, or thyroid function tests (TFTs) were not checked; the second were cases which we could find no other cause for the thyroid abnormalities besides lenalidomide use; the third group included all other cases where either preexisting thyroid abnormalities or diagnoses confounded lenalidomide use as a cause of thyroid abnormalities.

Other patient characteristics were investigated by performing a text search in the electronic medical record for specific words that could be suggestive of hypothyroidism or hyperthyroidism. We also recorded all documented TFTs including thyroid stimulating hormone (TSH), free thyroxine (FT4), and thyroid antibodies, if checked. Abnormal thyroid function testing was defined as a TSH outside our center's established normal reference range (0.3–5.0 mcU/mL); we correlated with free T4 levels if checked. We recorded the number of months that each patient was treated with lenalidomide and if stopped, the reason for discontinuation. The lenalidomide start date was defined as the date closest to the time when a patient was prescribed lenalidomide, based on chart communications.

Descriptive statistics including means with standard deviations, medians with interquartile ranges, and frequencies were calculated and used to identify correlations with normal versus abnormal thyroid laboratory values. Chi-squared tests, Wilcoxon sum rank tests, t-tests, and analyses of variance were employed to assess differences in clinical variables across thyroid function status. All analyses were conducted in SPSS version 19.

Results

One hundred and seventy patients were prescribed lenalidomide at our institution during the 5-year period of retrospective review. The demographic characteristics of all patients treated are presented in Table I. The majority (N = 148) were being treated for multiple myeloma either for induction therapy or for relapse. Patients received between 5 and 25 mg of lenalidomide for a time period between 0.5 and 48 months. The rate of lenalidomide discontinuation was similar in all three groups and the major reason for cessation was due to bone marrow suppression (25%) or for lack of effectiveness (18.7%).

Table I. Characteristics of the 170 Patients with Cancer and Lenalidomide Use by Group

Overall sample characteristics	Normal thyroid function (N = 142)	Lenalidomide-associated thyroid abnormalities (N = 10)	Preexisting thyroid abnormality on lenalidomide (N = 18)
BMI, body mass index, TSH, thyroid stimulating hormone; IR, interquartile range; CBCL, cutaneous B-cell lymphoma; AML, acute myelogenous leukemia; BMI, baseline TSH: medians reported. a Includes one Hispanic participant, race unknown. Values with b and c indicate a statistically significant difference of means at P < 0.05 according to an ANOVA with post hoc tests.
Age, median (IR) total = 65 (15)	65.0 (15)	64.5 (22)	67.5 (14)
Gender, number (%)
Male, 90 (52.9)	77 (55)	6 (70)	7 (33)
Female, 80 (47.1)	64 (45)	4 (30)	11 (67)
Race, number (%)
White, 137 (80.6)	110 (78)	9 (7.9)	19 (14.0)
Black, 29 (17.1)	28 (97.0)	1	–
Unknown, 4 (2.3)a	4 (100)	–	–
Cancer type, number (%)
Multiple myeloma, 148 (88.1)	124	8	16
Myelodysplastic syndrome, 8 (4.8)	6	2	0
Mantle cell lymphoma, 2 (1.2)	1	0	1
CBCL, 3 (1.8)	3	0	0
Chronic lymphocytic leukemia, 4 (2.4)	3	0	1
AML, 3 (1.8)	3	0	0
Castleman's disease (0.6)	1	0	0
Amyloid (0.6)	1	0	0
Baseline TSH, median (IR) mcU/mL	1.82 (1.7)^b	1.1 (2.4)	3.85 (6.4)^c
Number of months on lenalidomide, median (IR) 8.0 (14.0)	8.0 (13.0)	5.0 (17.3)	10 (16.0)
Previous thalidomide use, number, (%)	72 (51)	4 (40)	12 (66)
Previous CT scan with IV contrast (within 6 months of lenalidomide), number (%)	0	1	4
Previous craniocervical irradiation, number (%)	16 (9)	1 (10)	3 (16)
Lenalidomide stopped, number (%) 10 (63.5)	89 (63)	7 (70)	12 (67)
BMI kg/m^2, median, IR 28.1 (5.8)	28.0 (7)^b	30.5 (11)^c	27.6 (8.5)^b
Months until thyroid disorder, median, IR		5.0 (6.25)

Among the 170 patients treated with lenalidomide, the mean age was 65 years. Table I shows demographic information by group: normals (Group 1), lenalidomide cases (Group 2), and those with preexisting thyroid abnormalities (Group 3). There were more male patients (53%), and the majority of the sample was of white race (80%). Baseline TSH was higher among all Group 3 compared with Group 1, since the majority of those had preexisting hypothyroidism (TSH = 3.85 vs. 1.82, P = < 0.05). Roughly half of patients in the three groups had been treated previously with thalidomide. Ten patients (6%) developed newly-discovered thyroid abnormalities while on lenalidomide therapy with no documented previous abnormalities or other causes found on chart review. Eighteen patients (11%) had previous documented thyroid abnormalities before start of lenalidomide. Only four patients in the sample had thyroglobulin autoantibodies recorded and one had a positive antithyroglobulin antibody. No patients had received tyrosine kinase inhibitors before changes in TFTs. Of the 170 patients, 126 had one or more thyroid function tests recorded in their medical record before lenalidomide treatment.

Table II presents individual patients with presumed lenalidomide-associated thyroid dysfunction. Six patients experienced new laboratory values consistent with hypothyroidism, whereas four had hyperthyroidism by TSH measurement. Of the ten, two had a previous diagnosis, one of nonfunctioning goiter, and one of resolved thyroiditis; neither had preexisting TFT abnormalities. One patient had a bone marrow transplant previously with documented normal thyroid function thereafter. None had a documented family history of thyroid disease. Patients 1, 3, and 9 had two checks with abnormalities after starting lenalidomide. Patients 3 and 9 had abnormalities with hypothyroidism followed by hyperthyroidism. Patient 3 had elevation of TSH directly before transplant and start of lenalidomide and then developed frank hyperthyroidism 3 months after starting lenalidomide. Patient 7 had received prior craniocervical irradiation to C5-6 for metastases associated with MM. New-onset TSH abnormalities occurred at a median of 5 months.

Table II. Characteristics of Individual Patients with Thyroid Abnormalities on Lenalidomide

Patient	Indication	Dose (mg)	Length of time on drug (months)	First TSH abnormality	Second TSH abnormality	Other testinga Yes/No	Time to 1st TSH abnormality (months)	Previous thalidomide
Normal TSH values −0.3 to 5.0. a Mild abnormality before lenalidomide. b Thyroglobulin and other immunological work up. c Previous nonfunctional goiter.
1	MM	10	25	0.0600	0.370	No	5	Yes
2	MM	25	19	0.13		No	21	Yes
3	MM	25	4	5.64b	0.26	No	3	No
4	MM	10	10	5.75		No	7	No
5	MM	10	23	5.57		No	3	No
6	MM	25	22	0.03		No	2	Yes
7	MM	25	1	0.04		No	1	No
8	MDS	25	5	7.35		No	0.5	No
9	MM	25	13	8.00	0.49	Yes (normal)	5	Yes
10	MDSc	10	5	26.5		No	5	No

The majority of patients on lenalidomide (72%) had an evaluation of thyroid function at some point in their medical records before starting treatment. The median time of TSH measurement before start of lenalidomide was 6 months. Thyroid function evaluation, as indicated by laboratory testing for TSH, occurred more frequently near the onset of treatment and occurred more infrequently as time on lenalidomide therapy elapsed. Few patients had any recorded TFTs after 1 year of treatment.

Patients in the three groups with normal TFTs, lenalidomide-induced, and preexisting TFT abnormalities, respectively, were on lenalidomide for 8, 5, and 10 months. Three percent, 10%, and 11% of them, respectively, received four or more tests of thyroid function during their time on lenalidomide. Among 20 patients in the sample without any check of thyroid function either before or during their treatment with lenalidomide, four reported feeling new or significantly increased fatigue, three reported new cold-intolerance, and three reported new-onset constipation after starting the drug.

Eighteen patients (11%) had preexisting thyroid abnormalities that changed either directly before or during lenalidomide treatment, see Table III. Fourteen of these had previous definite thyroid diagnoses, such as goiter or primary hypothyroidism. Of those with documented preexisting thyroid disease and abnormal thyroid function tests at the onset of lenalidomide treatment, three showed further significant changes in TFTs during lenalidomide therapy, see Table III. Only 6 of 18 in this group had a follow-up TSH to determine if thyroid function had returned to normal. In patients with preexisting thyroid abnormalities, additional thyroid abnormalities were more common, when checked, than in those with normal baseline function before starting lenalidomide (P < 0.001).

Table III. Patients with Previous Hypothyroidism and Hyperthyroidism Started on Lenalidomide

Hypothyroidism
Patient	First TSH abnormality	Second TSH abnormality	Other testinga Yes/No	Thyroid function rechecked Yes/No	Previous thalidomide
Normal TSH values of Hypothyroidism −0.3 to 5.0. Normal TSH values of Hypothyroidism −0.3 to 5.5. a Thyroglobulin and other immunological work up. b Abnormal before lenalidomide. c Borderline value with elevated free T4 on levothyroxine.
1	8.16		No	Yes	Yes
2	5.44b	8.16	No	Yes	Yes
3	6.66b		No	No	Yes
4	6.74b		No	Yes	No
5	6.40b		No	No	No
6	5.55b		No	No	Yes
7	5.85b		No	No	No
8	12.0b		Yes (abnormal)	No	Yes
9	5.67b		No	Yes	No
10	5.75b		Yes (normal)	Yes	No
11	11.9b	17.3	No	Yes	Yes
Hyperthyroidism
1	23.4b	0.59c	No	Yes	Yes
2	0.02b		No	Yes	No
3	0.014b		No	No	Yes
4	0.05		No	No	Yes
5	0.05b		No	No	Yes
6	0.28b		Yes (normal)	Yes	No
7	0.04b		No	Yes	No

Discussion

Lenalidomide has been associated with adverse side effects including fatigue, constipation, neutropenia, thrombocytopenia, anemia, and diarrhea [16, 17]. In this case series, we found that 10 of 170 patients had new-onset thyroid function abnormalities, six with hypothyroidism, and four with hyperthyroidism. These were not associated with any other drug or prior history. In addition, 18 patients, most with preexisting thyroid disease, were found to have biochemical evidence of abnormal thyroid function either before or during lenalidomide treatment. In patients who underwent thyroid function testing before the initiation of lenalidomide, the 6-month time interval between the first check and the start of treatment suggests that initial measurements of thyroid function often occurred long before the beginning of therapy and were not performed as baseline surveillance before beginning lenalidomide.

Nearly one-half of patients with preexisting abnormalities had no follow up of thyroid function test abnormalities. We therefore cannot know whether the abnormalities persisted or abated. In addition, because TFTs were inconsistently checked, the hyperthyroid values could represent one phase of clinical thyroiditis. Lastly, of 20 patients who did not undergo any thyroid biochemical testing either before or during their treatment with lenalidomide, one third had symptoms suggestive of hypothyroidism including fatigue, constipation, and cold intolerance.

Fatigue is a common symptom experienced by cancer patients; for this reason, the causes of it are not often investigated. It occurs both as a result of the cancer itself and as a side effect of cancer treatment [18]. Cancer-related fatigue can increase physical and psychological stress. When fatigue is a result of cancer treatment, it can lower the quality of life for patients who are sometimes at the end of their life. Cancer-related constipation is also common and is an important detractor from patient quality of life [19]. Despite its clinical importance, constipation has not been well studied. Hyperthyroidism as a result of cancer therapy is even less well described. The weakness, palpitations, agitation, or sleep disturbance that can accompany hyperthyroidism may also impact the quality of life of cancer patients.

Several antineoplastic agents have been known to cause hypothyroidism, most prominently the tyrosine kinase inhibitor class [20]. The importance of thyroid dysfunction with lenalidomide is less well documented. In this case series report, we found a prevalence of thyroid abnormalities close to that reported in the literature of 5% [17]. However, four cases were of hyperthyroidism. Equally important was our observation that 11% of patients undergoing this treatment had preexisting thyroid abnormalities. However, this preexisting disease was inadequately reevaluated and could be related to symptoms of hyperthyroidism or hypothyroidism. While many patients in our sample had nonspecific symptoms of fatigue or weakness at some time during their treatment, no definite correlation can be made with their thyroid function abnormalities since the hematology clinic notes did not address most of the TSH abnormalities recorded in the chart.

In our study, 33% of patients who had no thyroid function evaluation recorded developed one or more symptoms associated with hypothyroidism after starting lenalidomide. While survivors of hematological diseases after allogeneic bone marrow transplantation or total body irradiation have a 47% prevalence of thyroid dysfunction after treatment [21], we found only one such patient in our sample.

Given that symptoms of hypothyroidism can overlap those of cancer, erroneously leading to lenalidomide dose adjustments or decreased quality of life, checking TSH at regular intervals during treatment with lenalidomide is valuable [22]. We recommend that thyroid function evaluation be routinely performed before treatment and regularly after starting treatment with lenalidomide. Because of the high prevalence of fatigue, constipation, and weakness in this population, we also recommend that any change in symptoms commonly associated with hypothyroidism or hyperthyroidism should prompt hematologists to evaluate thyroid function at any time during lenalidomide administration [23].

Our retrospective analysis has several limitations including a lack of corroboration between patient reports and the documented clinical evaluation. The major limitation of the retrospective chart review method is that it relies on an administrative method of data collection. Inadequate documentation, missing clinical information or a misinterpretation of the chart can all contribute to inaccuracies in the data. Furthermore, this method is descriptive and cannot offer any insights into cause-and-effect relationships except through the establishment of a timeline. Lastly, as patients had outside providers, we do not have data on additional thyroid function tests occurring outside our institution.

In summary, lenalidomide is used in induction and relapse of multiple myeloma with great effect but can cause significant thyroid abnormalities which merit routine monitoring. This is particularly important before the start and early in treatment, when clinical symptoms suggestive of thyroid dysfunction develop, or when patients have known preexisting thyroid disease. Treatment of symptomatic thyroid dysfunction can improve the quality of life for patients undergoing cancer treatment.