The burden of managing pleural effusions in patients with chronic myelogenous leukemia post-imatinib failure: A literature-based economic analysis

Abstract

To develop an economic analysis of the management of pleural effusions in patients with imatinib-resistant/intolerant chronic myelogenous leukemia (CML).
A cost of treatment analysis was conducted from the US payer perspective, based on resource utilization data for 48 patients with dasatinib-related pleural effusions at a large US cancer center. Probabilities of various procedures and treatment events were derived from published resource use data, supplemented with expert opinion. Cost data was derived from median reimbursements for relevant CPT codes for outpatient services and medical literature for inpatient services. Sensitivity analyses were conducted for types of procedures used. All costs were adjusted to US dollars (2007 rates).
Sixty percent of pleural effusions were managed medically costing $750 per episode. Forty percent of pleural effusions were more significant (>25% of one lung volume), with half of those requiring invasive procedures. Cost of inpatient procedures was $10,616 for chest tube and $15,170 with pleural catheter. Cost of outpatient procedures was $713 for ultrasound thoracentesis and $4,598 for pleural catheter. The average cost of treating a pleural effusion was $2,062 to >$2,700 for all severity levels and approximately $6,400 to >$9,000 for invasive procedures. Key cost drivers were invasive procedures and recurrence.
This economic analysis using actually observed treatment patterns suggests that the management of pleural effusion adverse events in CML patients is costly, requires intensive resource utilization, and may be an important factor in treatment selection.

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ORIGINAL RESEARCH
The burden of managing pleural effusions in patients
with chronic myelogenous leukemia post-imatinib
failure: A literature-based economic analysis
Jennifer Stephens
Kimbach Tran Carpiuc
Marc Botteman
Pharmerit North America
LLC , Bethesda , MD, USA
Correspondence: Jennifer M Stephens
Clinical Director, Pharmerit North America
LLC, 4350 East-West Highway, Suite 430,
Bethesda, MD 20814, USA
Tel +1 240 821 1290
Fax +1 240 821 1296
Email jstephens@pharmerit.com
Objectives: To develop an economic analysis of the management of pleural effusions in patients
with imatinib-resistant/intolerant chronic myelogenous leukemia (CML).
Methods: A cost of treatment analysis was conducted from the US payer perspective, based
on resource utilization data for 48 patients with dasatinib-related pleural effusions at a large
US cancer center. Probabilities of various procedures and treatment events were derived from
published resource use data, supplemented with expert opinion. Cost data was derived from
median reimbursements for relevant CPT codes for outpatient services and medical literature
for inpatient services. Sensitivity analyses were conducted for types of procedures used.
All costs were adjusted to US dollars (2007 rates).
Results: Sixty percent of pleural effusions were managed medically costing $750 per episode.
Forty percent of pleural effusions were more significant (25% of one lung volume), with
half of those requiring invasive procedures. Cost of inpatient procedures was $10,616 for chest
tube and $15,170 with pleural catheter. Cost of outpatient procedures was $713 for ultrasound
thoracentesis and $4,598 for pleural catheter. The average cost of treating a pleural effusion
was $2,062 to $2,700 for all severity levels and ∼$6,400 to $9,000 for invasive procedures.
Key cost drivers were invasive procedures and recurrence.
Conclusion: This economic analysis using actually observed treatment patterns suggests that
the management of pleural effusion adverse events in CML patients is costly, requires intensive
resource utilization, and may be an important factor in treatment selection.
Keywords: dasatinib, nilotinib, imatinib, adverse events, safety, cost, and cost analysis
Introduction
Imatinib has revolutionized the treatment of chronic myelogenous leukemia (CML) as
targeted therapy acting on the abnormal protein Bcr-Abl produced by the Philadelphia
chromosome. With five-year survival rates of 89% in chronic phase CML (CML-CP),
imatinib is the first-line standard of care for CML-CP treatment.1 However, some CML
patients may become resistant to imatinib or do not tolerate imatinib.
Two new drugs targeted for CML, nilotinib and dasatinib, have been developed as
options for imatinib-resistant and/or -intolerant patients. Although these newer drugs
are effective in obtaining responses in imatinib-resistant/intolerant CML, their target2
and adverse event profiles differ.3,4
Pleural effusion is usually a rare drug-related adverse event, typically resulting in
the need for some type of intervention. Common symptoms of pleural effusion include
significant cough, fatigue, and dyspnea, which may affect the patient’s quality of life.5
Risk of effusions exists with all the tyrosine kinase inhibitors (TKIs) currently indicated
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for CML (imatinib, dasatinib, and nilotinib), but is most
commonly seen with dasatinib. Recent data from imatinib-
resistant patients receiving dasatinib at a large cancer center
show that pleural effusion events occur in up to 35% of
patients, with risk persisting over time.6 Pleural effusion may
emerge unexpectedly and as late as 24 months into therapy
with few predictive factors. These effusions can lead to other
complications and require additional medical resource use
beyond the typical routine care.6,7 The interventions may be
costly and add to the overall economic burden and resource
use of managing CML patients.
Given the published clinical and resource use details
provided for pleural effusion management in dasatinib-treated
patients,6,7 our objective was to develop an economic burden
analysis of treating pleural effusions in CML patients by apply-
ing costs to the published medical resource utilization rates.
Methods
We developed a literature-based cost-of-treatment analy-
sis to determine the economic burden associated with
treating pleural effusions in CML patients with imatinib
resistance/intolerance. The analysis adopted a US third
party payer/insurer perspective including both inpatient
and outpatient direct medical costs. The model provides
cost-of-treatment estimates for managing pleural effusion
adverse events, from initiation of therapy to two years of
follow-up. The primary clinical input data were derived
from the observed medical resource utilization reported for
48 patients with dasatinib-related pleural effusions at one
large cancer center.6,7
Table 1 summarizes the treatment patterns and rates
of resource utilization associated with dasatinib-related
pleural effusions from MD Anderson Cancer Center:6,7 38%
received an echocardiogram (ECHO); 71% received a course
of diuretics; 29% had recurrent effusions; 30% received
steroids; 19% required a median of 3 (range 1–12) thora-
centesis outpatient procedures (or outpatient pleural catheter
placement) due to dyspnea grade 3 with median volume
withdrawn per thoracentesis of 1.5 L [range 0.5–2 L]); 4%
were managed with inpatient chest tube or pleural catheter
Table 1 Clinical and resource use management of pleural effusions in CML6,7
Severity Reported management of dasatinib pleural effusion
All Levels – Physician evaluation
– ECHO (38%); and some CT scans (% not specied)
– Chest X-ray (100%)
– Dose interruptions in 83% for median of 27 days (range 4–113 days), with more than
one interruption in 29% for recurrence
– Dose reduction in 71% (n = 34)
Level 1–2
(up to 25% of one lung volume)
– All episodes resolved upon
*dasatinib continuation (28%)
*loop diuretics (14%)
*both loop diuretics and discontinuation (55%)
– A short course of oral prednisone (40 mg/day × 4) was required in 24% of low-grade
effusion patients, which resulted in disappearance of effusion in 72 hours
– Invasive procedures in 7% (both level 2)
Level 3
(26%–50% of one lung volume)
– 81% interrupted dasatinib and received loop diuretics (the others continued dasatinib
due to advanced disease)
– 44% received a short course of oral prednisone
– Invasive procedures in 25%
Level 4–5
(51 to 75% of one lung volume)
– All interrupted dasatinib and required invasive procedures for management
Invasive procedures – 19% of all patients with pleural effusions required a median of three thoracenteses
(range 1–12 thoracenteses per patient due to dyspnea grade 3; median volume
withdrawn per thoracentesis was 1.5 L [range 0.5–2 L])
– 4% of all patients required placement of chest tube
– 4% of all patients required placement of a Denver peritoneovenous shunt
– 2% of patients received a pericardial window
Notes: Treatment categorized by level of effusion (not NCI grade) and based on volume of lung involved.

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Economic burden of pleural effusions in CML
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placement; 4% required Denver shunts as inpatients for
recurrent effusions; and 2% required an inpatient pericardial
window (for pericardial effusion coexisting with the pleural
effusion).
Clinical expert input was used only to supplement the
literature related to assumptions of frequency of office
visits and chest X-rays. For this economic analysis, we
assumed all patients would incur two additional physician
office visits for diagnosis and follow-up of pleural effu-
sion, and that two chest X-rays (one at each visit) would
be performed. This was done to account for a real-world
practice pattern that was not reflected in dasatinib pleural
effusion management at the cancer center, given that the
patient follow-up visits were protocol driven during the
study.
Standard costs for relevant CPT codes and median reim-
bursement fees for outpatient procedures and office visits
were retrieved from the Ingenix National Fee Analyzer.8,9
The CPT code for placement of a Denver peritoneovenous
shunt (used for a recurrent effusion) was not available. The
estimated cost for this procedure was based on the CPT code
49425, insertion of a peritoneal venous shunt, and added costs
for associated care: two days of general ward hospital stay,
and two days of physician inpatient visits.
The cost of inpatient management of pleural effusions
with chest tube placement and other invasive procedures were
obtained from the medical literature.10,11 The cost of inpatient
chest tube placement was $10,616, while an inpatient pleural
catheter placement was $15,170 based on details provided by
Putnam and colleagues.10 The cost of an inpatient pericardial
window was $15,344 based on details provided by Girardi
and colleagues.11
Drug costs for medical management with diuretics
(furosemide 40 mg daily for 10 days) and steroids (oral
prednisone 40 mg daily for four days) were based on
generic cost data from the Redbook.12 In addition to the
drug acquisition costs of less than one dollar for a course
of either generic furosemide or prednisone, we included a
standard $7 dispensing fee to more accurately reflect the
true cost of having the medication filled in an outpatient
pharmacy.
Table 2 lists the CPT code, drug, and literature costs that
were included in our analysis, along with associated prob-
abilities used in calculating the cost of pleural effusions.
Table 2 Results of economic analysis presenting average cost for treatment of a pleural effusion in CML
Health care resource use Unit cost per
events
Number
of units
Probability Invasive
procedure
subgroup
probabilities
Estimated avg
cost of treatment
per CML patient
across all effusions
Estimated avg cost
of treatment per
patient requiring
invasive procedures
Course of diuretics $8 1.29 0.68 1.00 $7 $10
Short course of steroids $8 1.29 0.29 0.58 $3 $6
Chest X-ray (2 views; CPT 71020) $100 2.58 1.00 1.00 $258 $258
ECHO (CPT 93307) $484 1 0.38 1.00 $182 $484
Physician ofce visits (CPT 99214) $117 2.58 1.00 1.00 $301 $301
Outpatient ultrasound thoracentesis $713 3 0.19 0.75 $406 $1,604
(CPT 32000) or or
Outpatient pleural catheter placement10 $4,598 1 0.19 0.75 $874 $3,449
Inpatient chest tube placement10 $10,616 1 0.04 0.17 $446 $1,805
or or
Inpatient pleural catheter placement10 $15,170 1 0.04 0.17 $637 $2,579
Denver shunt placement* $3,807 1 0.04 0.17 $152 $647
Inpatient pericardial window11 $15,344 1 0.02 0.08 $307 $1,279
Average per patient cost without
pleural catheter:
$2,062 $6,394
Average per patient cost with
pleural catheter:
$2,717 $9,013
Notes: Costs in US dollars (2007 rates). *Cost estimate was based on the CPT code 49425, insertion of peritoneal venous shunt. Assumptions included a two-day length
of stay in general ward at $725/day and two days of physician inpatient visits (CPT 99222 and CPT 99232). Unit costs: Ingenix for CPT codes,8,9 Putnam and colleagues for
inpatient chest tube and pleural catheter,10 Girardi and colleagues for inpatient pericardial window,11 and Red Book for drug costs.12

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We determined the unit cost per health care resource utilized
and calculated the average per patient cost of pleural effu-
sion with dasatinib. The average per patient cost of treating
pleural effusions in this patient population was estimated
by multiplying the number of units of health care resource
use consumed by the probability of each event occurring.
For example, in Table 2 the cost of a course of diuretics
was estimated at $8. The number of units was assumed to
be 1.29, taking into account the first occurrence and a 29%
rate of recurrence of pleural effusion that would require
additional treatment. The probability that a patient would
require diuretic therapy was 68%, as based on the literature.
Therefore, the expected cost of diuretic treatment per patient
was ∼$7 ($8 cost of drug × 1.29 units × 0.68 probability).
The expected costs for each health care resource use that
may have occurred for all patients were calculated, as well
as the average per patient cost considering all health care
resources consumed. All grades of pleural effusion were
considered in our analysis.
Sensitivity analyses were conducted to test the assump-
tions and impact on overall costs. All costs are presented in
US dollars (2007 rates) to reflect year of clinical/resource
data reported by the cancer center.
Results
Pleural effusion occurred in 35% of dasatinib-treated
patients.6,7 Sixty percent of pleural effusions reported at
the cancer center involved 25% of one lung volume and
were managed medically including diuretics and steroids.6,7
Costs for this medically managed group were $750 per
episode, including physician visits, ECHO, chest X-rays
and medications.
Forty percent of pleural effusions were more significant,
involving 26% to 75% of one lung volume, with half of
those patients requiring invasive procedures. Forty-eight
percent of all pleural effusions were characterized as NCI
grade 3 or 4 based on symptoms. Inpatient procedures
for placement of a chest tube or a pleural catheter had
estimated costs of $10,616 and $15,170, respectively. The
cost of invasive outpatient management of pleural effusions
ranged from $713 for ultrasound thoracentesis to $4,598 for
placement of a pleural catheter (see Table 2). Other costs of
invasive procedures ranged from $3,807 for placement of a
Denver shunt (due to recurrent pleural effusions), to $15,344
for patients who required a pericardial window (due to
co-existing pericardial effusion with pleural effusion). Table 2
summarizes the unit cost per health care resource utilization
associated with the treatment of pleural effusions.
The average per patient cost for treatment of pleural
effusion was $2,062. If patients were to have placement
of a pleural catheter instead of thoracentesis or chest tube
placement, the average per patient cost would increase to
$2,717. The average total cost of invasive procedure treat-
ment for patients without a pleural catheter was $6,394;
this increased to $9,013 in patients with a pleural catheter
(Table 2).
In sensitivity analyses, alternating assumptions indicated
that the analysis was robust. Costs of treatment of pleural
effusions were changed based on Medicare reimbursement
rates for various CPT codes, instead of median fees for
private payers. Using Medicare reimbursements, the average
cost per event decreased by only 6%–12% relative to the
base case results. Assuming no recurrence of pleural effusion
reduced total average costs by ∼20%, while placement of a
pleural catheter instead of repeated thoracentesis or chest
tube placement increased the cost by ∼30%. Additionally,
excluding the cost for ultrasound-guided thoracentesis
would only minimally decrease the average per patient costs
of treating pleural effusions.
Discussion
This economic analysis based on observed treatment patterns
suggests that the management of pleural effusions in CML
requires medical intervention and is costly, particularly for
those requiring invasive procedures. The total average cost
per patient across all pleural effusions is about $2,000 to
$2,700 depending on the type of intervention, while the
total average cost per patient for those requiring invasive
procedures is estimated to be $6,400 to $9,000. The rate of
recurrence of pleural effusions was a major cost driver in
this analysis. Each successive treatment of recurrent pleural
effusion adds to the costs of therapy, with increased costs
due to additional hospital stays, increased laboratory and
radiology costs, increased personnel costs for procedures, and
increased pharmacy costs. The rate of recurrence of pleural
effusion was 29%, based on the real-world rates reported in
the literature.6
The cost of pleural effusion adverse events should be
considered in the context of the total cost of treating the CML
patient, of which the primary driver is currently the drug
cost of tyrosine kinase inhibitor (TKI) therapy. Considering
that the cost of the newer TKIs may be $150 per day, the
cost of pleural effusions alone, averaged across the CML
population, is not a major cost driver of the total cost of
care. However, for the physician managing an individual
patient with a significant pleural effusion requiring inpatient

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procedures, the pleural effusion may represent 25% of the
cost of treating their CML.
Development of pleural effusions with dasatinib poses a
significant challenge to physicians as the risk persists over
time, onset is unpredictable, and management may require
repeat invasive procedures and possible complications.6,7
For example, twelve percent of dasatinib patients with
CML-CP experience pleural effusions as late as 24 months
into treatment.7 Over time, risk of all grade (and grade 3/4)
pleural effusions increases to 29% (12% grade 3/4) in chronic
phase and 50% (28% grade 3/4) in accelerated phase. The
true incidence of dasatinib-related pleural effusions in CML
patients is not yet known because it is a relatively new treat-
ment. However, the incidence of pleural effusion does differ
based on the dosing regimen of dasatinib. Recent six-month
phase III trial data published for the 100 mg daily dose of
dasatinib in CML-CP patients indicate lower rates of pleural
effusion than the 140 mg daily dose (7%–10% vs 18%–20%,
respectively).13
While pleural effusion rates have been reduced with a
100 mg daily dose of dasatinib, pleural effusion in CML
remains a significant adverse event regardless of the dose
and may be a clinically important factor in treatment selec-
tion. A frequent intervention in the management of pleural
effusion is temporary interruption of therapy, which was
required in 83% of dasatinib patients with a pleural effusion
for a median of 27 days, after which the dose was reduced
in 71%.6,7 Almost one-third of patients required treatment
interruptions on more than one occasion for recurrent pleural
effusion; a total of 6% of patients were permanently discon-
tinued from dasatinib for recurrent effusions.7 These patients
may then be at risk for disease progression while the drug is
being held or discontinued, and the broader socioeconomic
cost of not effectively controlling CML during these pleural
effusion events was not considered in the current analysis.
Potential limitations were addressed when possible
through conservative approaches to the assumptions and
conducting sensitivity analyses to assess main drivers of
cost. While health care resource utilization data were based
on pleural effusions occurring at one major US cancer center,
the costs applied to the resources were general reimburse-
ments or literature-based costs and not specific to that cancer
center. Thus, because patient demographics and treatment
patterns may differ among institutions, costs of treating
pleural effusions may also vary. For example, we attempted
to account for differences in treatment patterns by includ-
ing the cost of both inpatient and outpatient pleural catheter
placement in the analysis.10 We also used the median fees
for various outpatient procedures, thus the cost estimates for
half of the payers could be higher. Additionally, as a sensi-
tivity analysis, a Medicare reimbursement perspective was
considered and average cost of pleural effusion treatment
decreased only somewhat, suggesting that regardless of type
of reimbursement structure, treatment of pleural effusions
remains costly. The most sensitive cost driver in the analysis
was the type of invasive procedure selected for managing the
more significant pleural effusions. If the physician is able
to anticipate early on that multiple thoracentesis procedures
will be required for a patient, use of an outpatient pleural
catheter could reduce total cost of management by up to 30%.
Finally, due to gaps in the literature and variations in expert
opinion, our analysis included conservative assumptions for
additional office visits and X-rays, and did not include the
cost of platelet transfusions that may be needed to perform
thoracentesis or the cost of follow-up diagnostics/scans.
Thus, while we present a conservative analysis, the results
provide an initial estimate of the costs of treating pleural
effusions in CML patients.
Conclusions
This economic analysis, based on observed treatment and
resource use patterns, suggests that the management of
pleural effusions in CML patients is costly and requires
intensive resource utilization. Understanding of the clinical
management and economic burden of treatment-related
adverse events for patients with CML is essential in an era
of tightening health care budgets. CML therapies without
significant risk of pleural effusion may provide cost offsets
related to adverse event management.
Disclosure
This research was funded by Novartis Pharmaceuticals.
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