Biol Blood Marrow Transplant 25 (2019) 1659
1665

Biology of Blood and

Marrow Transplantation
journal homepage: www.bbmt.org

Analysis

Healthcare Utilization is High in Adult Patients Relapsing after

Allogeneic Hematopoietic Cell Transplantation
Jessica A. Langston1,2,*, Vandana Sundaram3, Vyjeyanthi S. Periyakoil1,2, Lori Muffly4
1
Division of Primary Care and Population Health, Department of Medicine, Stanford University, Stanford, California
2
VA Palo Alto Health Care System, Palo Alto, California
3
Quantitative Sciences Unit, Stanford University, Stanford, California
4
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, California

Article history: A B S T R A C T
Received 8 December 2018 Disease relapse is the leading cause of death for patients with acute leukemia (AL) and myelodysplastic syndrome
Accepted 1 April 2019 (MDS) who undergo allogeneic hematopoietic cell transplantation (HCT). Relapse post-HCT is associated with poor
prognosis; however, inpatient healthcare utilization of this population is unknown. Here we describe survival,
Keywords: intensity of healthcare utilization, and characteristics associated with high resource use at the end of life (EOL). Adult
End-of-life care patients with AL/MDS who underwent HCT at a large regional referral center with subsequent relapse between 2005
Intensity of healthcare and 2015 were included in this retrospective study. We compared the distribution of demographic and clinical charac-
utilization teristics of patients as well as healthcare utilization over 2 years postrelapse and at EOL by postrelapse disease-directed
Myelodysplastic syndrome
therapeutic interventions. We created a composite score for EOL healthcare utilization intensity by summing the pres-
Acute leukemia
ence of any of the following criteria: death in the hospital, use of chemotherapy, emergency department, hospitaliza-
Relapse
Advance care planning
tion, intensive care unit, intubation, cardiopulmonary resuscitation, or hemodialysis in the last month of life. Higher
scores indicate more intense healthcare use at EOL. Multivariable linear regression analysis was used to determine var-
iables (demographic characteristics, postrelapse treatment group, advance directives documentation, palliative care
referral, time to relapse) associated with EOL healthcare utilization intensity. One hundred fifty-four patients were
included; median age at relapse was 56 years (interquartile range [IQR], 39 to 63), 55% were men, 79% had AL, and
median time from HCT to relapse was 6 months (IQR, 3 to 10). After relapse, 28% received supportive care only, 50%
received chemotherapy only, and 22% received chemotherapy plus cell therapy (either donor lymphocyte infusion,
second HCT, or donor lymphocyte infusion plus second HCT). With the exception of time until relapse and Karnofsky
Performance Status, baseline characteristics (gender, age, race, graft-versus-host disease, year of treatment) did not
significantly differ by postrelapse treatment group. One hundred thirty-six patients (88%) died within 2 years of
relapse; survival differed significantly by postrelapse treatment group, with those receiving disease-directed treatment
showing lower risk of death. Healthcare use in AL/MDS patients after post-HCT relapse was high overall, with 44% vis-
iting the emergency department at least once (22% at least 2 times), 93% hospitalized (55% at least 2 times, 16% at least
5 times), and 38% using the intensive care unit (median length of stay 5, days; IQR, 3 to 10). Use was high even among
those receiving only supportive care. For those patients who died, the mean intensity score for EOL healthcare use was
1.8 (standard deviation, 1.8). Most patients (70%) had a marker of high-intensity healthcare utilization at the EOL or
died in hospital. In multivariable analysis, an increase in age (estimate -.03 (95% CI, -.06 to -.003) and having AL versus
MDS were significantly associated with a decreased EOL healthcare intensity score; no other variables were associated
with intensity of EOL healthcare use. Healthcare utilization after post-HCT relapse is associated with receipt of dis-
ease-directed therapy but remains high across all groups despite known poor prognosis. Interventions are needed to
minimize nonbeneficial treatments and promote goal-concordant EOL care in this seriously ill patient population.
© 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

INTRODUCTION
Allogeneic hematopoietic cell transplant (HCT) is a main-
Financial disclosure: See Acknowledgments on page 1664. stay of curative therapy for adults with acute leukemia (AL)
* Correspondence and reprint requests: Jessica Langston, Stanford Univer-
sity, Department of Palliative and Hospice Medicine, 300 Pasteur Drive, Room
and myelodysplastic syndrome (MDS). Advances in the man-
HC005, M/C 5277, Stanford, CA 94305. agement of HCT complications and reduced-intensity trans-
E-mail address: [email protected] (J.A. Langston). plant approaches have expanded HCT to a broader cohort of

https://doi.org/10.1016/j.bbmt.2019.04.001
1083-8791/© 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
1660 J.A. Langston et al. / Biol Blood Marrow Transplant 25 (2019) 1659
1665

patients, including those with impaired functional status or risk of death after relapse, adjusting for age at HCT, sex, race/ethnicity, pri-
advanced age. However, post-HCT disease relapse continues to mary diagnosis, graft-versus-host disease (none versus any), comorbidity
(none versus any), year of HCT, months from HCT to relapse (<6 months ver-
be a significant issue and remains the leading cause of death
sus
6 months), and Karnofsky Performance Status score (<90 versus
90).
after HCT for adults with hematologic malignancies. Approxi- Time to death was calculated as the days from relapse until death; patients
mately 30% to 40% of adults with AL/MDS will relapse after were censored at 2 years postrelapse or at the last follow-up date.
HCT; these patients have a poor prognosis with median sur- We also conducted multivariable linear regression analysis to determine
if any variables were associated with EOL intensity of healthcare use. In addi-
vival generally estimated at 6 months or less [1-10].
tion to the variables included in the multivariable Cox proportional hazards
Relative to solid tumor cancers, hematologic malignancies regression model, we included presence of advanced directive documenta-
are generally associated with underuse of palliative and hos- tion and referral to palliative care clinic or consultation service.
pice services and overuse of high-intensity treatments near
the end of life (EOL) [11-16]. Rationales for this EOL pattern of
care have been proposed, including the unpredictable pattern RESULTS
of clinical decline in patients with hematologic malignancies, Between 2005 and 2015, 349 of 1249 adult patients (29%)
clinicians’ bias toward offering all possible treatments for these with AL/MDS experienced relapse after their first allogeneic
patients, and the small but finite possibility of cure for select HCT. One hundred fifty-four of these patients continued to
patients [17]. Studies have similarly demonstrated that adults receive their hematologic or supportive care within the Stan-
undergoing allogeneic HCT for hematologic malignancies use ford healthcare system and were included in our analytic
high levels of healthcare resources at EOL [18-22]. However, cohort. Patient and HCT demographics are characterized in
despite the exceedingly high risk of mortality in AL/MDS Table 1, stratified based on postrelapse disease-directed thera-
patients who relapse after allogeneic HCT, little data exist spe- peutic interventions (none/supportive care only, chemother-
cifically examining the intensity of healthcare utilization apy only, chemotherapy plus additional cellular therapy).
broadly and at the EOL in this patient population, with the few Median age at HCT was 55 years (interquartile range [IQR], 38
existing studies reporting qualitative or limited data on small to 62), and median age at relapse was 56 years (IQR, 39 to 63).
patient samples [23,24]. This retrospective observational study Fifty-five percent were men, 79% had AL, and median time
aims to fill this gap in the literature by analyzing healthcare from HCT to relapse was 6 months (IQR, 3 to 10). After post-
utilization over time in AL/MDS patients who relapsed after HCT disease relapse, 28% did not receive any further disease-
allogeneic HCT in a large referral center in Northern California. directed treatment, 50% received chemotherapy only, and 22%
received chemotherapy plus additional cellular therapy (either
METHODS donor lymphocyte infusion, n = 28; second HCT, n = 5; or donor
Study Design
All adult patients (age
18 years at time of HCT) with acute myeloid leu- lymphocyte infusion plus second HCT, n = 1). With the excep-
kemia (AML), acute lymphoblastic leukemia, or MDS who underwent first tion of time until relapse and Karnofsky Performance Status
allogeneic HCT at Stanford University and subsequently experienced disease score (P < .01), there were no significant differences in demo-
relapse between January 1, 2005 and December 31, 2015 were identified for
inclusion. Stanford serves as a large-volume regional HCT referral center cov-
graphic characteristics between postrelapse treatment groups;
ering AL/MDS patients across a large swath of Northern California. those receiving either chemotherapy or chemotherapy plus
Patients who did not receive any postrelapse care at Stanford were additional cellular therapy tended to have experienced a lon-
excluded. Demographic and HCT characteristics were abstracted from an ger disease-free survival after initial HCT (P < .01).
existing institutional research database maintained by the Stanford Blood &
One hundred thirty-six patients (88%) died within 2 years
Marrow Transplant Program. All other variables were collected by detailed
chart review of the electronic medical record, including electronically linked of post-HCT disease relapse; among these patients, median
and scanned records from affiliated hospitals. Postrelapse therapies and hos- survival from the time of disease relapse was 4 months (IQR, 1
pital and emergency department (ED) admissions were evaluated over a to 9). Two-year survival after relapse differed significantly by
2-year time period after disease relapse. All included patients consented for
postrelapse treatment group (Figure 1), with patients who
Stanford Institutional Review Board
approved observational data collection
and monitoring. received treatment having a lower risk of death compared
with patients who did not receive postrelapse treatment. Spe-
EOL Intensity Composite Score cifically, patients receiving treatment had an 81% less risk of
In the subset of patients who died, we created an EOL intensity score death (hazard ratio, .19; 95% confidence interval, .11-.31) com-
using a composite of measures for defining the intensity of healthcare utiliza-
tion at the EOL. No single validated intensity scoring system has yet been
pared with patients receiving no disease-directed treatment.
defined for EOL care in the blood cancer population; therefore, we used an Healthcare utilization in AL/MDS patients after post-HCT
approach similar to that utilized in prior work on EOL intensity in cancer relapse is shown in Table 2. Overall use was high, with 68
patients [25-28]. One point was given for the presence of each of the follow- patients (44%) visiting the ED at least once (34 [22%] at least
ing occurring within 30 days of death: use of chemotherapy, more than 1 hos-
2 times, 9 [6%] at least 5 times), 141 patients (93%) hospitalized
pitalization, more than 14 days of hospitalization, more than 1 ED visit,
intensive care unit (ICU) admission, mechanical intubation, cardiopulmonary (85 [55%] at least 2 times, 24 [16%] at least 5 times), and 58
resuscitation, initiation of hemodialysis, or death in hospital. The total num- patients (38%) admitted to the ICU at least once (median length
ber of points was summed for an intensity score ranging from 0 to 9. A higher of ICU stay, 5 days; IQR, 3 to 10). Use of the ED and hospitaliza-
intensity score indicated greater usage of high-intensity treatment measures
tion were significantly higher in those receiving postrelapse
at EOL.
treatment rather than supportive care only (P < .001), whereas
Statistical Analysis ICU utilization was not associated with postrelapse treatment
We compared the distribution of demographic and clinical characteristics (P = .16).
of patients by postrelapse disease-directed therapeutic interventions. Cate- Among the patients who died, the median intensity score
gorical variables were compared using chi-square or Fisher’s exact tests; con-
tinuous variables were compared using the Kruskal-Wallis test. To compare
for EOL healthcare use was 1 (IQR, 0 to 3), and the mean inten-
healthcare use over 2 years postrelapse and at EOL, we grouped patients sity score was 1.8 (standard deviation, 1.8) (Figure 2). Most
based on postrelapse disease-directed therapeutic interventions into 2 patients (70%) had some high-intensity healthcare utilization
groups: those who received no treatment/supportive care and those who toward the EOL. Over half of the patients (52%) died in a hospi-
received any treatment (chemotherapy only or chemotherapy plus cell ther-
apy). We compared the overall survival over 2 years postrelapse, by none/
tal setting, with 39% having a length of stay of at least 14 days
supportive care versus treatment, using Kaplan-Meier curves and conducted in the last month of life. In multivariable regression analysis,
a multivariable Cox proportional hazards regression analysis to estimate the an increase in age (estimate,
.03; 95% confidence interval,
 J.A. Langston et al. / Biol Blood Marrow Transplant 25 (2019) 1659
1665 1661

Table 1
Demographic and Clinical Characteristics

Treatment after Relapse

Characteristic All Patients None Chemotherapy Only Chemotherapy Plus Cell Therapy*
(N = 154) (n = 43) (n = 77) (n = 34)
Age at HCT, yr, median (IQR) 55 (38-62) 57 (48-63) 53 (38-62) 50 (27-61)
Age at relapse, yr, median (IQR) 56 (39-63) 57 (48-64) 54 (39-63) 52 (30-63)
Sex
Male 85 (55.2) 22 (51.2) 43 (55.8) 20 (58.8)
Female 69 (44.8) 21 (48.8) 34 (44.2) 14 (41.2)
Race/ethnicity
Hispanic 21 (13.6) 4 (9.3) 13 (16.9) 4 (11.8)
White 99 (64.3) 29 (67.4) 48 (62.3) 22 (64.7)
Asian 23 (14.9) 5 (11.6) 12 (15.6) 6 (17.7)
Black 2 (1.3) 2 (4.7) 0 0
Unknown/other 9 (8.8) 3 (7.0) 4 (5.2) 2 (5.9)
Primary diagnosis
AML 89 (57.8) 26 (60.5) 41 (53.3) 22 (64.7)
Acute lymphoblastic leukemia 32 (20.8) 4 (9.3) 21 (27.3) 7 (20.6)
MDS 33 (21.4) 13 (30.2) 15 (19.5) 5 (14.7)
GVHD
None 111 (72.1) 35 (81.4) 56 (72.7) 20 (58.8)
Limited 9 (5.8) 1 (2.3) 6 (7.8) 2 (5.9)
Extensive 34 (22.1) 7 (16.3) 15 (19.5) 12 (35.3)
Acute GVHD 47 (30.5) 14 (32.6) 27 (35.1) 6 (17.7)
Comorbidity index, mean (SD) 0.84 (1.3) 1.02 (1.6) 0.75 (1.1) 0.79 (1.4)
Karnofsky Performance Status score
<90 28 (18.2) 10 (23.3) 17 (22.1) 1 (2.9)

90 114 (74.0) 29 (67.4) 54 (70.1) 31 (91.2)
Unknown 12 (7.8) 4 (9.3) 6 (7.8) 2 (5.9)
Year of HCT
1999-2007 31 (20) 14 (33) 11 (14) 6 (18)
2008-2011 70 (45) 13 (30) 40 (52) 17 (50)
2012-2015 53 (34) 16 (37) 26 (34) 11 (32)
Months from HCT to relapse, median (IQR) 6 (3-10) 3 (1-6) 6 (3-11) 8 (5-24)
Time from HCT to relapse
<6 mo 74 (48.0) 31 (72.1) 34 (44.2) 9 (26.5)

6 mo 80 (52.0) 12 (27.9) 43 (55.8) 25 (73.5)
Died 140 (90.9) 43 (100) 72 (93.5) 25 (73.5)
Months from relapse to death, median (IQR) 5 (1-9) 1 (1-2) 5 (2-9) 10 (7-13)
Location of deathy
Hospital 73 (52.1) 23 (53.4) 34 (47.2) 16 (64.0)
Hospice 42 (30.0) 14 (32.6) 23 (31.9) 5 (20.0)
Home w/o hospice 4 (2.9) 1 (2.3) 2 (2.8) 1 (4.0)
Unknown 21 (15.0) 5 (11.6) 13 (18.1) 3 (12.0)
Values are n (%) unless otherwise defined. GVHD indicates graft-versus host disease; SD, standard deviation.
* Chemotherapy plus cell therapy group: In addition to chemotherapy, 1 patient had both repeat HSCT and donor lymphocyte infusions, 5 had only repeat HCT,
and 28 had only donor lymphocyte infusions.
y
Percent based on number who died.

.06 to
.003) and having acute lymphoblastic leukemia or after first HCT and higher Karnofsky Performance Status score,
AML versus MDS were significantly associated with a which may in general confer a modestly more favorable prog-
decreased EOL healthcare intensity score (Table 3). nosis after post-HCT relapse [10] and may justify a more
aggressive treatment course. In our population, there was in
DISCUSSION fact a survival advantage after receipt of further disease-
The poor survival for our study population of AL/MDS directed therapy, although 2-year survival was still limited to
patients relapsing after allogeneic HCT is similar to that identi- 16% in patients receiving disease-directed treatment after
fied in prior work in the field of allogeneic HCT [5-10]. Our relapse (chemotherapy § additional cellular therapy).
study adds to the existing literature by detailing healthcare uti- Despite overall limited survival outcomes in this population
lization and EOL healthcare intensity in this particularly vul- relapsing after allogeneic HCT, healthcare utilization after dis-
nerable patient population. In our cohort, patients who ease relapse was high, with 44% visiting the ED, 92% hospital-
received additional therapies (chemotherapy and/or additional ized, and 38% spending hospital days in the ICU. These rates
cellular therapies) tended to have a longer disease-free interval were particularly elevated among patients receiving postrelapse
1662 J.A. Langston et al. / Biol Blood Marrow Transplant 25 (2019) 1659
1665

Figure 1. Survival probability by postrelapse treatment group.

Table 2
Healthcare Utilization after Relapse

Disease-Directed Treatment after Relapse

All Patients None Any Treatment P
(N = 154) (n = 43) (n = 111)
ED visits
0 86 (56) 38 (88) 48 (43) <.001*
1 34 (22) 5 (12) 29 (26)

2 34 (22) 0 34 (31)
Hospitalizations
0 13 (8) 8 (19) 5 (5) <.001*
1 56 (36) 28 (65) 28 (25)

2 85 (55) 7 (16) 78 (70)
Length of stay, days
Median (IQR) 28 (10-55) 6 (5-14) 36 (20-70) <.001y
ICU stays
0 96 (62) 32 (74) 64 (58) .16*
1 43 (28) 9 (21) 34 (31)

2 15 (10) 2 (5) 13 (12)
Length of stay, days
Median (IQR) 5 (3-10) 6 (3-9) 4.5 (3-10) 1.0y
Intubation 20 (13) 7 (16) 13 (12) .44*
Cardiopulmonary resuscitation 7 (5) 3 (7) 4 (4) .40*
Hemodialysis 8 (5) 1 (2) 7 (6) .44*
Advance directives 82 (53) 26 (60) 56 (50) .74z
Palliative care consult 75 (49) 20 (47) 55 (50) .12z
Values are n (%) unless otherwise defined.
* Fisher’s exact test.
y
Wilcoxon rank-sum test.
z
Chi-square statistic.
 J.A. Langston et al. / Biol Blood Marrow Transplant 25 (2019) 1659
1665 1663

patient populations as well as a reduced willingness on the

part of the patient or physicians to tolerate substantial treat-
ment toxicity even in the hopes of achieving a durable remis-
sion or cure.
Our findings beg the question of what may be done to tem-
per the use of nonbeneficial and expensive healthcare services
among patients with exceedingly high morbidity and short life
expectancy. Although we did not find that advance care plan-
ning or palliative care consultation independently impacted
EOL healthcare intensity, others have demonstrated a multi-
tude of benefits associated with palliative care consultation
and advance care planning both near the EOL and concurrent
with disease-directed treatment in both solid tumor and
hematologic malignancy patients [18,20,33-40]. Various mod-
els have been proposed for integrating palliative care into the
bone marrow transplant setting, particularly in pediatric popu-
lations [41]. Further investigation is warranted to determine if
Figure 2. EOL healthcare utilization intensity composite score distribution. the timing, location, or content of palliative intervention mod-
ulates the effect on EOL care for this population.
disease-directed therapies; however, even among patients Our study details the outcomes and healthcare utilization
receiving supportive care alone, the rates of healthcare use among AL/MDS patients relapsing at a single academic institu-
were high. The ICU usage among this population of relapsed tion, which may not be generalizable to populations on a
patients (26% admitted to the ICU with a median of 6 ICU days) national scale or in other healthcare contexts. Patients who did
is particularly concerning, as this likely represents nonbeneficial not pursue postrelapse care at Stanford institutions were
care for this population with 100% mortality by 14 months and excluded from analysis because of a lack of accessibility of
median survival postrelapse of only 1 month. medical records. A substantial percentage of these patients
Studies in solid tumor cancer patients reveal that health- (140 [72%] excluded for this reason) were a part of the Kaiser
care intensity at the EOL is high overall, albeit lower than that Permanente Healthcare System. Local norms are known to
seen in our population, particularly relating to death in the affect intensity of healthcare utilization at the EOL; therefore,
hospital [29-32]. We observed that patients used a median of 1 the postrelapse and EOL course of those patients may differ
high-intensity healthcare service within 30 days of death. This from that presented here [42]. Our medical record abstraction
usage was associated with age and underlying diagnosis, with of EOL care does not easily allow us to identify the intent of the
patients of advancing age and those with acute lymphoblastic care provided, which in some cases may have been palliative
leukemia/AML versus MDS having decreased EOL care inten- (eg, poorly controlled symptoms requiring ED visitation and
sity. In the case of age, this trend may be a reflection of an hospital admission). We are aware that the care delivered to
enhanced awareness of EOL processes and wishes in older these patients at the EOL was provided without the benefit of

Table 3
Multivariable Regression Analysis of Characteristics Associated with Intensity of Healthcare Utilization at EOL (n = 128)

Estimate Standard Error 95% Confidence Interval P

Age (128)*
.03 .01
.06 to
.003 .03
Sex: female (54) vs. male (74)
.04 .36
.76 to .68 .92
Race/ethnicity (vs. other/unknown (8))
White non-Hispanic (79)
.69 .73
2.13 to .76 .91
Black non-Hispanic (2)
1.06 1.54 -4.11 to 1.99
Hispanic (18)
.54 .81
2.14 to 1.06
Asian (21)
.67 .80
2.26 to .91
Diagnosis (vs. MDS (26))
Acute lymphoblastic leukemia (27)
1.57 .62
2.80 to
.33 .02
AML (75)
1.18 .44
2.05 to
.30
GVHD: none (94) vs. any (34) .51 .42
.32 to 1.34 .23
Comorbidity (vs. 3+ (18))
0 (74) .46 .52
.58 to 1.49 .65
1-2 (36) .47 .56
.64 to 1.58
Karnofsky Performance Status score (<90 (27) vs.
90 (101)) .17 .43
.69 to 1.03 .69
Year of HCT (vs. 2012 (47))
1999-2007 (19)
.41 .60
1.59 to .78 .79
2008-2011 (62)
.12 .38
.88 to .63
Months from HCT to relapse: <6 months (63) (vs.
6 months (65)) .14 .37
.60 to .87 .72
No postrelapse disease-directed treatment (38) (vs. any treatment (90))
.70 .38
1.46 to .05 .07
Had palliative care consultation (74) .46 .38
.31 to 1.22 .24
Had advance care documentation (68)
.16 .35
.85 to .53 .65
* Values in parenthesis represent number of patients for each strata for the variable listed.
1664 J.A. Langston et al. / Biol Blood Marrow Transplant 25 (2019) 1659
1665

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