Lenalidomide performance in the real world

Patterns of use and effectiveness in a Medicare population with myelodysplastic syndromes

Authors


  • The results of this study were presented in part at the American Society of Hematology 54th Annual Meeting, Atlanta, GA, USA, December 2012, and at the 12th International Symposium on Myelodysplastic Syndromes, Berlin, Germany, May, 2013.

  • The opinions expressed in this article are the authors' own and do not reflect the view of the Agency for Healthcare Research and Quality, the Department of Health and Human Services, or the United States government.

Abstract

BACKGROUND

Lenalidomide is approved for the treatment of anemia with transfusion dependence (TD) in patients with lower-risk myelodysplastic syndrome (MDS) with 5q deletion (del5q-MDS), but its “real-life” use and effect on transfusion needs are unclear. In the current study, the authors examined its use in the Medicare population.

METHODS

Patients with MDS who were enrolled in Medicare Parts A, B, and D were identified using International Classification of Diseases 9-Clinical Modification (ICD-9) codes from 100% Medicare claims from 2006 through 2008. Patients were followed until the end of the study or death. Claims were used to determine time to initiation of lenalidomide, daily dose, duration, and other MDS therapies. Transfusion status was defined each week based on transfusion use in rolling 8-week period: TD, required transfusions during 2 weeks, separated by ≥ 3 weeks; transfusion user (TU), 1 transfusion; and transfusion independence (TI), no transfusions.

RESULTS

A total of 753 of 23,855 patients (3.2%) received lenalidomide, including 31% of 470 patients with del5q-MDS. At the time of lenalidomide initiation, 33% of patients were TD, 31% were TU, and 36% were TI. The median time to lenalidomide initiation was shorter for patients with del5q-MDS than for other lower-risk patients (8 weeks vs 20 weeks; P < .01). The percentage of patients with del5q-MDS receiving lenalidomide increased over time. Lenalidomide initiation was found to be negatively associated with older age and baseline diabetes, stroke, and renal disease. During the observation period, 44% of TU/TD patients (53% of the patients with del5q-MDS) achieved reductions in transfusion use; among TD patients receiving ≥ 3 cycles, 77% reduced their transfusion use and 40% achieved TI.

CONCLUSIONS

To the authors' knowledge, the current study is the first report of lenalidomide use in a large Medicare-enrolled population with MDS. Reductions in transfusion rates were overall consistent with data from clinical trials. Response rates were higher when ≥ 3 lenalidomide cycles were received. Cancer 2013;119:3870–3878. © 2013 American Cancer Society.

INTRODUCTION

Anemia that requires transfusions represents a significant problem for patients with myelodysplastic syndromes (MDS). Historically, the primary therapeutic strategy was supportive care with red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs). The addition of 3 new therapies, the DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine and the immunomodulatory agent lenalidomide, to the MDS therapeutic armamentarium has been a major advancement.

Lenalidomide is a potent oral derivative of thalidomide that is active in several hematologic malignancies. Patients with lower-risk (LR) MDS with chromosome 5q deletions (del5q-MDS) are highly responsive to lenalidomide. In clinical trials, lenalidomide induced RBC transfusion independence (TI) in approximately two-thirds of these patients, and complete cytogenetic responses in some patients.[1, 2] Lenalidomide was approved by the US Food and Drug administration in December 2005 for use in patients with transfusion-dependent (TD) anemia due to LR del5q-MDS with or without additional cytogenetic abnormalities.[3-5] Lenalidomide also induced TI in 26% of patients with LR MDS without del5q.[5] Current treatment guidelines recommend consideration of lenalidomide therapy in some patients with TD LR MDS without 5q deletion.[6] A similar percentage of patients with higher-risk (HR) del5q-MDS develop TI, but responses are typically shorter than those among patients with LR del5q-MDS.[3-5]

Despite accumulating evidence supporting the use of lenalidomide therapy in some MDS subtypes, data regarding patterns of use and effectiveness in the “real-world” setting, i.e outside of the context of clinical trials, are to the best of our knowledge scarce.[7, 8] To address this issue, we conducted a retrospective observational study using a large, 100% Medicare-enrolled, claims-based MDS database to characterize lenalidomide use and the effects on RBC transfusion use.

MATERIALS AND METHODS

Study Population

Medicare beneficiaries with MDS were selected using 100% Medicare enrollment and claims data from 2006 through 2008. Claims for Medicare Parts A, B, and D included detailed information regarding dates; International Classification of Diseases 9-Clinical Modification (ICD-9-CM) diagnoses; and services provided based on ICD-9-CM procedure codes, Healthcare Common Procedure Coding System (HCPCS) codes, and/or National Drug Codes (NDC). Inclusion required 1 inpatient claim or 2 outpatient claims with a MDS diagnosis within a 12-month span. Patients were observed from the date of their first MDS claim (index date) through death or study end (December 31, 2008). To ensure the observation of the use of all oral therapies, the cohort was also limited to patients continuously enrolled in Medicare Part D from the index date through the end of the study (Fig. 1). All MDS risk groups were included. MDS was identified by a single ICD-9-CM diagnostic code (238.7) until October 2006, when a fifth digit was added that allowed for classification by patient MDS risk status. The ICD-9-CM code 238.72 identified patients with LR MDS, code 238.74 identified patients with del5q-MDS, and code 238.73 was used for patients with HR MDS. Diagnostic codes 238.7 and 238.75 were grouped together as not otherwise specified (NOS).

Figure 1.

Generation of the database and the specific cohort of the study is shown. MDS indicates myelodysplastic syndromes; ICD-9, International Classification of Diseases 9-Clinical Modification; w/o, without; LIS, low-income subsidy.

Studied Variables

Patient characteristics (age at diagnosis, race, and sex) were determined from Medicare enrollment files. Receipt of the Medicare Part D low-income subsidy (LIS) was captured based on monthly enrollment indicators. Sociodemographic factors from the 2000 US Census were linked to the enrollment files by ZIP code of residence.[9]

Baseline Health Status

Baseline comorbidities were defined based on claims during the 12 months before the diagnosis of MDS was made. We included an indicator for poor predicted disability status (DS), a weighted claims-based measure recently described by Davidoff et al.[10]

MDS Therapies

Prescribed treatments were identified from HCPCS or NDC codes in the Medicare Part B claims or Part D event files. We specified lenalidomide treatment episodes as periods of continuous claims with < 6 months between fills. We calculated the duration of lenalidomide use (first to last claim plus days supplied), daily dose, time from MDS diagnosis to the initiation of lenalidomide treatment, and time until discontinuation. Small gaps in therapy were smoothed through a series of logical imputations. For example, when observing monthly fills of 14 or 21 tablets, we assumed that each fill covered a 28-day period and we adjusted days supplied and average daily dose measures accordingly. We also measured use of DNMTi, ESAs, and RBC transfusions.

Transfusion Status and Response

We measured transfusion status weekly based on a rolling 8-week period (current and prior 7 weeks). Patients with ≥ 2 transfusion weeks with a gap of ≥ 2 weeks were designated as TD. Patients with only 1 transfusion episode in the 8 weeks were designated as transfusion users (TU), whereas those who received no transfusions were designated as TI. To measure response to treatment, we selected patients who were TD or TU at the time of lenalidomide initiation, and scanned subsequent weekly transfusion status measures during the first episode of therapy to identify changes from baseline. We categorized responses to parallel International Working Group 2000 for MDS “major” and “minor” erythroid response criteria.[11] Reductions from TD to TI status reflected a “major erythroid response,” whereas reductions from TD to TU or from TU to TI reflected a minor response.

Statistical Analysis

Cohort analyses included univariate, bivariate, and multivariate regression models. Analyses were conducted on the full cohort and on the subcohorts with del5q-MDS and other LR MDS. All analyses were conducted using SAS (version 9.2; SAS Inc, Cary NC) and Stata (version 12; StataCorp, Chicago, IL) statistical software. The study was approved by the University of Maryland Institutional Review Board.

RESULTS

Baseline Characteristics and Demographics

The study cohort consisted of 23,855 patients with MDS (Table 1). The MDS risk groups were as follows: del5q-MDS in 480 patients (2%), other LR MDS in 6355 patients (26.6%), and HR MDS in 1277 patients (5.4%), whereas the majority (15,657 patients; 65.6%) were coded as having MDS-NOS. Patients were predominantly white (87.8%) and female (58.1%); 75.3% were aged ≥ 75 years and 18.9% had poor DS. The most prevalent baseline comorbidities included ischemic cardiac disease (41.1%), diabetes (36.3%), congestive heart failure (30.6%), renal (27.9%) and thyroid (25.1%) disease, prior solid tumor malignancy (19.4%), and prior venous thromboembolism (4.2%).

Table 1. Characteristics of the MDS Cohort Overall and by MDS Risk Group at Diagnosis
   MDS Risk Group
 Entire Cohortdel5qOther Lower-RiskUnspecified
 No.%No.%No.%No.%
  1. Abbreviations: de5q-MDS, lower-risk myelodysplastic syndrome with 5q deletion; LIS, low-income subsidy; MDS, myelodysplastic syndromes.

  2. a

    The census regions do not sum to the overall totals due to missing values.

  3. Source: 100% Medicare enrollment and claims for beneficiaries with MDS who were enrolled in Medicare Part D between 2006 and 2008.

Overall23,855100%4802.0635526.615,65765.6
Age at diagnosis        
66–74587924.612025.0153724.2379424.2
75–8411,31347.423348.5318150.1724146.2
≥85666327.912726.5163725.8462229.5
Sex        
Male10,00041.917235.8264241.6651141.6
Female13,85558.130864.2371358.4914658.4
Race        
White20,94687.843590.6553087.013,81688.2
Nonwhite290912.2459.482513.0184111.8
Census regiona        
Northeast484520.37816.3143422.6316120.2
Midwest576524.210922.7123119.4407826.0
South952739.921745.2276743.5594738.0
West364815.37515.690714.3242215.5
Drug coverage        
Continuous Part D (LIS)785632.912025.0192730.3540834.5
Continuos Part D (non-LIS)15,99967.136075.0442869.710,24965.5
Diagnosis period        
2006: first half459719.35912.365110.2374323.9
2006: second half404617.07415.499315.6274117.5
2007: first half497920.911624.2150023.6301919.3
2007: second half346514.58918.5116018.3198612.7
2008: first half414217.49319.4131920.8248015.8
2008: second half262611.04910.273211.5168810.8
Baseline health status        
Predicted poor disability status451018.95812.195415.0330921.1
Diabetes866736.313628.3241738.0565836.1
Thyroid disorder599925.111323.5162425.6394825.2
Congestive heart failure730930.611824.6186429.3501232.0
Ischemic heart disease980441.117636.7261441.1649241.5
Acute myocardial infarction7963.3112.31792.85743.7
Stroke or transient ischemic attack303012.76313.180212.6200512.8
Renal disease665927.911022.9175327.6449828.7
Liver disease10924.6204.22874.57344.7
Venous thromboembolism9984.2224.62273.66984.5
Gastrointestinal bleeding308412.96814.280912.7205313.1
Solid tumor cancer462919.47415.4130020.5299319.1
Cytopenia7033.0153.11993.14172.7
Neutropenia20418.65110.64937.813058.3
Pancytopenia22099.36613.85688.913428.6
Thrombocytopenia430118.08718.195215.0292318.7

Lenalidomide Use

During the 3-year observation period (2006-2008), lenalidomide was prescribed to 753 patients with MDS (3.2%), 19.8% of whom had del5q-MDS and 24.2% of whom had other LR MDS (Table 2); others had HR or unclassified MDS. The percentage of patients with del5q-MDS treated with lenalidomide increased over time (32.2% in first 6 months of 2006 to 37.6% in first 6 months of 2008; rates of use for beneficiaries diagnosed in the latter one-half of 2008 were not reported due to inadequate follow-up to assess use). The median time from diagnosis to the initiation of lenalidomide was 11.5 weeks (range, 0 weeks-132 weeks) for new users; the time to initiation was shorter for patients with del5q-MDS compared with other patients with LR MDS (8 weeks vs 20 weeks; P < .01). Among patients who received lenalidomide, 72.3% had received a prior ESA and 11.7% had received a prior DNMTi. Approximately 56.4% of lenalidomide users received ESA treatment concurrently with lenalidomide, whereas 29.0% received ESAs after discontinuing lenalidomide.

Table 2. Patterns of Lenalidomide Initiation, Use of Other MDS Therapies, Duration, and Dose, Overall and for del5q-MDS and Other Lower-Risk MDS Types
    MDS Risk Group
  Overalldel5q-MDSOther Lower-Risk
  No.%No.%No.%
  1. Abbreviations: de5q-MDS, lower-risk myelodysplastic syndrome with 5q deletion; DNMTi, DNA methyltransferase inhibitors; ESA, erythropoiesis-stimulating agents; LEN, lenalidomide; MDS, myelodysplastic syndromes; SE, standard error.

  2. a

    Differences between del5q and other lower-risk MDS were significant at P < .01.

  3. b

    Restricted to Medicare beneficiaries with continuous Part A/B/D coverage who first received lenalidomide at the time of or after the incident MDS diagnosis between 2006 and 2008, first episode of lenalidomide.

  4. c

    Suppressed due to small sample size.

  5. Source: 100% Medicare enrollment and claims for beneficiaries with MDS who were enrolled in Medicare Part D between 2006 and 2008.

Cohort no., % of total 23,855100.04802.0635526.6
Any LEN use, % of total 753100.014919.818224.2
Percent of cohort receiving LENa  3.2 31.0 2.9
LEN use by MDS diagnosis period
2006: first halfa 1433.11932.2213.2
2006: second halfa 1443.62635.1323.2
2007: first halfa 1653.33025.9463.1
2007: second halfa 1093.23236.0322.8
2008: first halfa 1233.03537.6332.5
LEN use only after MDS diagnosisa6902.914129.41692.7
Time to LEN initiation from diagnosis of MDS, wkb
Mediana11.5 8 20 
Minimum0 0 0 
Maximum132 89 125 
Meana23.7 14.8 27.7 
SE1.0 1.5 2.0 
Use of ESAs and DNMTi Among LEN Usersb
Any useESAa54579.010574.514887.6
 DNMTia14921.61712.15029.6
Prior to LEN initiationESAa49972.39164.514384.6
 DNMTia8111.7c c 
Concurrent with LEN useESAa38956.48661.09858.0
 DNMTia304.3c c 
After LEN discontinuationESA20029.03625.55834.3
 DNMTi7611.0c c 
Duration, adherence of LEN use, no. of 28-d cycles supplied
Mean (SE) 4.10.185.10.474.20.34
Median 2 3 2 
Maximum 29.8 29.8 26 
Received >3 cycles, % 34.3 44.7 36.7 
Average daily dose, mgb
< 3.8 304.3c c 
3.8–4.9 578.31712.1127.1
5.0–7.5 28641.46948.96639.1
7.6–9.9 436.2117.8137.7
10.0–15.0 23634.23424.15834.3
>15.0 385.5c c 

Prior use of other MDS therapies tended to be lower for patients with del5q-MDS compared with those with other LR MDS, which is consistent with a shorter time to the initiation of lenalidomide. The mean number of 4-week cycles for all patients was 4.1 (median, 2 cycles; range 0.4 cycles-29.8 cycles), with 34.3% of patients receiving > 3 cycles. In contrast, patients with del5q-MDS received a mean of 5.1 treatments with 4-week lenalidomide cycles (median, 3 treatments; range, 1 treatment-29.8 treatments), with 44.7% of patients receiving > 3 cycles. The median starting daily dose of lenalidomide was 7.5 mg (mean, 8.1 mg; mode, 10 mg). Doses tended to be lower in patients with del5q-MDS compared with other patients with LR MDS, but small sample sizes precluded statistical comparisons. There was a trend toward lower doses in the last, compared with first, treatment periods for individual patients, which is consistent with dose reductions with longer lenalidomide use (data not shown). Reduction in doses with longer therapy could reflect dose adjustment for side effects or a reduction to lower effective doses.

Factors Associated With Lenalidomide Prescription

Table 3 presents multivariate logistic regression estimates for factors associated with lenalidomide use. Lenalidomide initiation was found to be negatively associated with older age (age ≥ 85 years; odds ratio [OR], 0.58 [95% confidence interval (95% CI), 0.46-0.74]), poor DS (OR, 0.56; 95% CI, 0.41-0.75), baseline diabetes (OR, 0.83; 95% CI, 0.69-0.99), renal disease (OR, 0.72; 95% CI, 0.58-0.88), and prior stroke (OR, 0.68; 95% CI, 0.51-0.91). As expected, the del5q-MDS subtype was found to be the strongest factor associated with lenalidomide prescription (OR, 15.4; 95% CI, 11.8-20.0 relative to the reference category of other LR MDS). HR MDS also was found to be associated with an increased use of lenalidomide (OR, 1.70; 95% CI, 1.26-2.29), whereas the MDS-NOS subtype was associated with lower rates of use (OR, 0.73; 95% CI, 0.60-0.89). Baseline pancytopenia and thrombocytopenia and high local rates of difficulty in speaking English also were found to be positively correlated with the prescription of lenalidomide. In contrast, LIS receipt, sex, ethnicity, area-level education, median household income, urbanicity, and region of residence were not found to be associated with lenalidomide prescription.

Table 3. Association Between Patient Characteristics and Lenalidomide Use Among Medicare Beneficiaries With MDSa
 Overall (n = 22,399) 
Independent VariablesORLower LimitUpper LimitP
  1. Abbreviations: de5q-MDS, lower-risk myelodysplastic syndrome with 5q deletion; LIS, low-income subsidy; MDS, myelodysplastic syndromes.

  2. a

    Restricted to Medicare beneficiaries with continuous Part A/B/D coverage; excluded beneficiaries who first received lenalidomide prior to the incident MDS diagnosis between 2006 and 2008.

  3. Source: 100% Medicare enrollment and claims for beneficiaries with MDS who were enrolled in Medicare Part D between 2006 and 2008.

Age at diagnosis    
66–74 (reference)    
75–840.870.721.05.148
≥850.580.460.74<.0001
Sex    
Male (reference)    
Female0.900.761.07.240
Race    
White (reference)    
Black0.910.621.34.638
Hispanic1.130.651.95.669
Other0.850.531.37.506
Percentage with < high school education0.810.341.92.627
Percentage with English language difficulty2.191.393.46.001
Median household income    
First quartile (reference)    
Second quartile1.271.001.61.050
Third quartile1.110.851.45.442
Fourth quartile1.050.791.41.726
Urbanicity    
Large urban (reference)    
Other urban/rural0.940.751.18.600
Census region    
Midwest (reference)    
Northeast0.900.691.16.407
South1.090.881.34.440
West0.900.681.19.450
Drug coverage    
Continuous Part D, non-LIS (reference)    
Continuous Part D, LIS0.990.811.23.956
MDS risk group    
Lower-risk (238.72) (reference)    
Unspecified (238.7 and 238.75)0.730.600.89.002
del5q-MDS (238.74)15.411.820.0<.0001
Higher-risk (238.73)1.701.262.29.001
Disability status    
Good (reference)    
Poor0.560.410.75<.0001
Comorbidities    
Diabetes0.830.690.99.043
Thyroid disorder1.090.901.32.371
Acute myocardial infarction0.630.351.15.130
Congestive heart failure1.030.831.28.771
Ischemic heart disease1.070.891.28.491
Stroke or transient ischemic attack0.680.510.91.009
Cardiac conduction disorder0.960.791.17.715
Renal disease0.720.580.88.002
Liver disease0.690.451.07.101
Venous thromboembolism1.420.982.06.068
Gastrointestinal bleed1.190.931.51.173
Solid tumor1.100.901.34.357
Cytopenia0.830.511.35.452
Neutropenia1.260.981.62.078
Pancytopenia1.561.212.02.001
Thrombocytopenia1.261.031.54.026
Diagnosis period    
2006: first half (reference)    
2006: second half0.990.771.28.958
2007: first half0.770.601.00.047
2007: second half0.700.520.93.014
2008: first half0.680.510.90.007
2008: second half0.650.460.90.009

Lenalidomide and Transfusion Status

Despite the approved indication for lenalidomide in patients with LR MDS with del5q with TD anemia, 36% of patients were transfusion-naive (TN; no prior history of RBC) or TI at the time of lenalidomide initiation, whereas 31% were TU and 33% were TD (Fig. 2 Top). Point estimates indicated that 44% of the patients who were either TU or TD at the time of lenalidomide initiation (53% of patients with del5q-MDS) experienced a transfusion response. Among those who were TD at the time of lenalidomide initiation, 45% experienced a reduction in transfusion use during the observation period, with 15% achieving TI (Fig. 2 Top). Moreover, 43% of patients who were TU at the time of lenalidomide initiation (55% of patients with del5q-MDS) achieved TI status (Fig. 2 Top). When analysis was limited to patients who received ≥ 3 cycles of lenalidomide, 71% of patients who were TU or TD at the time of lenalidomide initiation (83% of patients with del5q-MDS) experienced a transfusion response (Fig. 2 Bottom). Among TD patients who received ≥ 3 lenalidomide cycles, 77% experienced a transfusion response and 40% achieved TI (Fig. 2 Bottom). Among these more extensively treated patients who were TU at time of lenalidomide initiation, 67% became TI (Fig. 2 Bottom). Small sample sizes provided inadequate power to detect differences between MDS risk groups.

Figure 2.

Change in transfusion status with lenalidomide therapy is shown. The bar in the middle represents the distribution of patients by transfusion status at the time of the initiation of lenalidomide therapy, whereas the pie charts represent the change in transfusion status during the observation period (Top) for all patients and (Bottom) for patients who received ≥ 3 cycles of lenalidomide. TI, transfusion independence; TD, transfusion dependence; TU, transfusion user; TN, transfusion-naive.

DISCUSSION

To the best of our knowledge, the current study represents the first report of lenalidomide use for patients with MDS in a large population of Part D-enrolled Medicare beneficiaries with newly diagnosed MDS. We are not aware of other large “real-life” analyses evaluating changes in transfusion status in patients with MDS patients who received lenalidomide therapy or, in particular, any reports of patients not enrolled in Medicare. We evaluated patterns of lenalidomide use and associated changes in RBC transfusion status in a “real-world” setting during the first 3 years after lenalidomide was approved for the treatment of MDS (2006-2008). As expected, rates of use were highest among patients with del5q-MDS and the time to lenalidomide initiation was shorter for patients with del5q-MDS versus those with other LR MDS. These observations suggest general increased awareness of the selective activity of lenalidomide for patients with del5q-MDS on the part of prescribing physicians. Reports of hematologic response in patients with LR MDS without del5q[5, 12] might account in part for the current study finding that the majority of patients with MDS (80%) who received lenalidomide were not coded as having del5q-MDS. However, this finding, as well as our observation that patients with del5q-MDS constituted an increasing percentage of lenalidomide users, may be an artifact of the change in ICD-9-CM coding that occurred 10 months into our observation period.

The findings of the current study with regard to rates of lenalidomide use are in contrast with estimates from a survey of 101 hematology and medical oncology providers that was completed between June 2005 and January 2007.[7] In that study, which spanned the first year after lenalidomide was approved for the treatment of MDS, providers reported that 8% of recently diagnosed and 1% to 9% of established patients with MDS received lenalidomide. However, the study cohort was not limited to Medicare beneficiaries, and did not provide information regarding risk status, karyotype, or other patient characteristics among lenalidomide users and nonusers.[7]

In contrast to the labeled indication for TD patients, approximately one-third of patients with MDS (including a similar percentage of patients with del5q-MDS) initiated lenalidomide treatment while TI. This apparent inconsistency with treatment guidelines was also found in our previous study examining guideline adherence with regard to ESA use in patients with MDS.[13] It is possible that physicians were privy to clinical parameters suggesting a need for RBC transfusion, and chose to preempt transfusions by initiating lenalidomide therapy. Absent clinical measures in our claims data, we are unable to assess this scenario more definitively.

The negative correlation of advanced age, comorbidities, and poor DS with prescription of lenalidomide that was observed in our multivariate analysis is discouraging, because one of the goals of introducing nonintensive therapies is to allow more frail elderly patients with MDS with comorbidities to receive active therapy that can be better tolerated. These findings are consistent with a recent report of patterns of use of DNMTi among elderly Medicare beneficiaries with MDS who were followed through 2007.[14] In this study, only 11% of patients with MDS received DNMTi therapy, and older patients and those with more comorbidities were found to be less likely to receive DNMTi. The additional burden of physician office visits or hospitalization for their administration may explain the low rates of DNMTi use but, as an oral agent, lenalidomide should not be subject to these constraints. Instead, the lower rate of lenalidomide use observed in vulnerable patient populations might reflect a more cautious approach with a newly approved agent, and rates of use may increase with improved familiarity.

Contrary to expectations, we did not find strong evidence that socioeconomic status, including LIS receipt, influenced the initiation of lenalidomide. Lenalidomide is an expensive oral medication, and therefore beneficiaries without the LIS are subject to very large initial out-of-pocket payments and continued large payments even when reaching the catastrophic coverage phase. In contrast, those with the LIS pay minimal amounts toward their initial prescription, and pay nothing once they reach the catastrophic phase. The lack of an observed effect of LIS receipt on lenalidomide treatment may suggest that patients are not price-sensitive. Decreased price response has been demonstrated in other studies for patients with cancer,[15, 16] and the perceived benefits of lenalidomide may be sufficiently large to justify the payment from the patient's perspective. However, patients may face income constraints that either discourage the initiation of lenalidomide or encourage its early discontinuation. Our ZIP code-level income measure may not adequately correlate with person-specific income, and consequently may not capture an association between income and treatment.

Although the transfusion response rates for the full cohort in the current study reflected a mix of risk groups and a relatively short duration of therapy for many patients, overall they are consistent with data in previously published clinical trials. In the registration study by List et al, patients with TD anemia due to MDS with 5q deletions irrespective of karyotype complexity received lenalidomide at a dose of 10 mg daily for 21 days or 28 days of a 28-day cycle,[1] with TI or a reduction in the need for transfusions noted in 67% and 76% of patients, respectively.[1] The randomized phase 3 MDS004 trial suggested a dose-dependent effect of lenalidomide: with the 10-mg dose (taken for 21 of 28 days), 56.1% and 50% of patients, respectively, achieved TI for ≥ 26 weeks and cytogenetic response compared with 42.6% and 25%, respectively, with the 5-mg dose (taken for 28 of 28 days).[2] Lenalidomide has limited activity in patients with LR MDS without 5q deletions (TI, 26%; median duration, 41 weeks) and HR MDS with 5q deletions (TI, 25.5%; median duration, 26 weeks), with responses typically less frequent and shorter in duration than those noted in patients with LR MDS with 5q deletions.[3-5]

Relative to these trial data, we observed that 44% of all patients with MDS and 53% of patients with del5q-MDS who were either TU or TD at the time of lenalidomide initiation experienced a reduction in transfusion use. For patients who were TD at the time of lenalidomide initiation (all risk groups), 45% experienced a reduction in RBC transfusions, including 15% who achieved TI (Fig. 2 Top). When we restricted the analysis to patients who received ≥ 3 cycles of lenalidomide, 71% of patients who were TU or TD at the time of lenalidomide initiation (all risk groups, including 83% of patients with del5q-MDS) experienced a reduction in transfusion use. The patients who were TD at the time of lenalidomide initiation (all risk groups) and subsequently received ≥ 3 cycles of therapy had an augmented benefit; 77% had reductions in transfusions, including 40% who achieved TI (Fig. 2 Bottom). Small sample sizes provided inadequate power with which to detect differences between MDS risk subgroups (including those with del5q-MDS vs other LR MDS) or to compare differences based on lenalidomide dose.

The greater frequency in the reduction of transfusions needed for patients who received ≥ 3 cycles of lenalidomide indicates that, in line with current guidelines,[6] the therapeutic potential of the drug might require ≥ 3 months to be fully achieved in some patients. Conversely, patients with a longer treatment duration may be enriched with early responders, which could explain some of our findings. The current descriptive analysis does not account for this potential pattern; further research on the effect of therapy duration on outcomes is warranted.

The main limitations of the current study relate to the use of claims data to select patient cohorts and to construct valid measures of treatment exposures and transfusion status. MDS risk group was assigned based on ICD-9- diagnostic codes on claims, yet many in the cohort did not have a specific risk group designated. This might be due to cytogenetic evaluation not being performed in routine-care settings or, if performed, the results not being reflected in the coding. As a result, the number of patients identified as carrying del5q is relatively small, and we recognize that some percentage of those patients designated as having other LR MDS or MDS-NOS may actually harbor the del5q abnormality. Although we report lenalidomide use patterns stratified by del5q and other LR MDS, the sample size was not sufficient in either group to test for differences in treatments or outcomes.

Our measures of lenalidomide and other MDS therapies were based on claims. For oral medications in particular we had to presume that the medication was consumed by the patient. Our measure of erythroid response was based on changes in transfusion status, which in turn were based on observed weekly transfusion receipt. Although we modeled this approach on the International Working Group 2000 definitions of major and minor responses, we could not fully operationalize them, absent data on hemoglobin levels.

In addition, our analysis of changes in transfusion response should be considered descriptive and not causal. Although it is possible to use observational data to examine causal relations between lenalidomide and a variety of outcomes, including survival, progression to acute myeloid leukemia (AML), secondary solid tumor malignancies, and venous thromboembolism, reporting such outcomes without adequate controls for other therapies received and without use of an analytic strategy that addresses patient selection would be inadequate and possibly misleading. This type of analysis was outside the scope of the current study, but is clearly warranted in the future.

In summary, the data from the current study suggest that in the first 3 years after the approval of lenalidomide for its MDS indication, prescribing patterns were only partly consistent with clinical guidelines and the drug label.[6, 17] Major deviations were the high percentage of patients who were TI when the drug was prescribed, high rates of the concomitant use of lenalidomide with ESAs and other MDS therapies, and the short duration of treatment episodes for a large percentage of patients. Consistency of prescribing patterns across socioeconomic strata, including in patients who may incur significant copayments, suggests that MDS-associated anemia presents a significant clinical problem for patients with MDS. For those patients who were TD at the time of the initiation of lenalidomide, therapy appears to have had a positive impact on transfusion rates, particularly for those receiving at least 3 cycles. This experience suggests that stronger adherence to treatment guidelines would result in further improvements in outcomes.

FUNDING SUPPORT

Funding was provided by Celgene. Dr. Gore, Ms. McNally, Dr. Baer, Mr. Hendrick, and Dr. Davidoff received partial funding from National Institutes of Health/National Cancer Institute grant RC1 CA145831 (Dr. Davidoff, Principal Investigator).

CONFLICT OF INTEREST DISCLOSURES

Dr. Gore received research support from Celgene and owned stock in the company until December 2010. Dr. Baer received research support from Celgene. Mr. Hendrick received a contract from Celgene to support research and dissemination at conferences and publication. Mrs. Mahmoud is employed by Celgene and owns Celgene stock options. Dr. Davidoff received a contract from Celgene to support research and dissemination at conferences and publication; receives a salary from her current employer, the Agency for Healthcare Research and Quality; owned stock in Celgene until December of 2010 (no relation to the current research and no compensation received from Celgene); and received research funding from Celgene, GlaxoSmithKline, and Novartis until September 2012. In addition, a portion of this research was undertaken while Dr. Davidoff was employed by the University of Maryland School of Pharmacy.

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