Characteristics and Impact of Post-Transplant Interdisciplinary Palliative Care Consultation in Older Allogeneic Hematopoietic Cell Transplant Recipients

Abstract

Context and Objectives: The myriad of benefits of early palliative care (PC) integration in oncology are well established, and emerging evidence suggests that PC improves symptom burden, mood, and quality of life for hematopoietic cell transplant (HCT) recipients. Specific impact of PC consultation on outcomes of older allogeneic HCT (allo-HCT) recipients, a historically high-risk population vulnerable to transplant-related complications and mortality, has not been explored.

Design and Methods: In this single institution, retrospective analysis of 527 first allo-HCT recipients aged ≥60 years, we characterized 75 patients who had received post-HCT PC consultation and its association with geriatric vulnerabilities identified by pre-HCT geriatric assessment. We also examined end-of-life care outcomes among patients who died within one-year of allo-hematopoietic cell transplantation.

Results: In multivariate analysis, higher disease risk, female gender, and, importantly, pre-HCT functional limitation (hazard ratio 2.35, 95% confidence interval, 1.35–4.09, p = 0.003) were associated with post-HCT PC utilization. Within one-year of hematopoietic cell transplantation, 127 patients died; among those, recipients of early PC consultation had significantly higher rates of hospice enrollment (25% vs. 9%, p = 0.019) and lower rates of hospital death (71% vs. 90%, p = 0.013), intensive care unit admission (44% vs. 75%, p = 0.001), and high-intensity medical care in last 30 days of life (46% vs. 77%, p = 0.001).

Conclusions: Our results highlight important pre-HCT risk factors associated with increased PC needs posthematopoietic cell transplantation and benefits of PC involvement for older allo-HCT recipients at the end of life. Prospective studies should examine the optimal timing of PC consultation and its multidimensional benefits for older allo-HCT patients.

Introduction

The integration of primary and subspecialty palliative care (PC) into standard oncologic care has a profoundly positive impact including improved symptom management, mood, quality of life, patient and caregiver satisfaction, cost savings, and possibly survival.^1,2 The American Society of Clinical Oncology recommends incorporating interdisciplinary PC for all patients with advanced cancer and/or high symptom burden and unmet needs.³ PC utilization in hematologic malignancies, however, has been limited by prognostic uncertainty, slow adoption, and transfusion requirements at the end of life.⁴

Hematopoietic cell transplantation is a potentially curative treatment option for patients with advanced hematologic malignancies; its use especially in older adults has increased over the past two decades.^5,6 Landmark studies on PC integration into inpatient HCT care have shown significant benefits, including improved symptom burden, mood, and quality of life, persisting for at least six months posthematopoietic cell transplantation.^7,8 Given PC resource constraints and access barriers, however, it is not surprising that the overall PC utilization in hematopoietic cell transplantation remains low.^9,10

We have previously shown that older acute myeloid leukemia patients who relapsed after allogeneic hematopoietic cell transplantation had extremely poor prognoses and high intensity, low quality end-of-life care.¹¹ However, the impact of subspecialty PC in older allogeneic hematopoietic cell transplantation (allo-HCT) recipients has not been explored in association with their pre-HCT geriatric vulnerabilities. In this study, we examine clinical factors associated with PC utilization and its impact during allo-hematopoietic cell transplantation.

Patients and Methods

Patients aged ≥60 years who underwent first allo-hematopoietic cell transplantation for a hematologic malignancy between 2008 and 2017 at our institution were included. A waiver of authorization for this retrospective review was obtained from the Institutional Review and Privacy Board. The study was conducted in accordance with the Declaration of Helsinki and national ethical regulations. Hematopoietic cell transplantation eligibility criteria, transplant care, and disease monitoring followed standard institutional guidelines. Baseline demographic, clinical, transplant, and survival data were retrieved from our institutional transplant database. Pretransplant geriatric assessment (GA) by an interdisciplinary clinical provider was described previously.¹² GA domains included comorbidity (hematopoietic cell transplant-comorbidity index [HCT-CI]), function (basic and activities of daily living/instrumental activities of daily living [ADL/IADL]), mobility (prior fall), mood (depression), nutrition (weight loss), and medications (potentially inappropriate medication [PIM] use).

Subspecialty PC consultation at our institution was conducted by an interdisciplinary team comprising physicians, nurse practitioners, a social worker, a chaplain, and a clinical pharmacist since 2007. Markers of high-intensity end-of-life care were described previously, including intensive care unit (ICU) admission, intubation/mechanical ventilation, hemodialysis, and cardiopulmonary resuscitation within 30 days of death; and death in the hospital.¹³ Descriptive statistics were used to characterize PC consultation, and comparisons between groups were performed using Fisher's exact test or Wilcoxon rank-sum test where appropriate. The association of baseline demographic, clinical, transplant characteristics, and individual GA domain with PC consultation was examined using the cumulative incidence method and the Gray's test. The multivariate model was built with univariates at p < 0.05. All statistical analyses were performed in R version 3.5.0 (R development core team, Vienna, Austria).

Results and Discussion

This analysis included 527 patients. Baseline patient, transplant, and geriatric characteristics are given in Table 1. Most patients had a myeloid malignancy (69%), and 27% had high/very high disease risk index. Approximately half had HCT-CI ≥3 or Karnofsky Performance Status (KPS) <90. As in our previous study, we found a wide range of pre-HCT geriatric deficits, including limitations in ADL/IADL (13%), depression (17%), impaired mobility (prior fall, 18%), malnutrition (weight loss, 17%), and the regular use of PIMs (44%).^11,12 This indicated a high-risk population for mortality and morbidity of allogeneic hematopoietic cell transplantation.

Table 1.

Baseline Demographic and Clinical Characteristics

	Total cohort (N = 527), n (%)	Died within one-year of transplant (N = 127), n (%)
Age, years (median, range)	65.5 (60–78.4)	65.5 (60–75.2)
Gender
Female	213 (40)	55 (43)
Male	314 (60)	72 (57)
Race/ethnicity
Caucasian	484 (92)	114 (90)
Non-Caucasian	43 (8)	13 (10)
Marital status
Married/partnered	430 (82)	106 (83)
Single/divorced	97 (18)	21 (17)
Diagnosis
Myeloid	366 (69)	88 (69)
Lymphoid	161 (31)	39 (31)
Comorbidity
HCT-CI 0–2	240 (46)	43 (34)
HCT-CI ≥3	287 (54)	84 (66)
KPS at transplant
<90	247 (47)	54 (43)
≥90	273 (53)	72 (57)
Missing	7	1
Disease risk index
Low/intermediate	383 (73)	80 (63)
High/very high	144 (27)	47 (37)
Conditioning intensity
RIC/NMA	218 (41)	51 (40)
Myeloablative	309 (59)	76 (60)
Donor
Matched	402 (76)	87 (69)
Alternative	125 (24)	40 (31)
ADL/IADL
Normal	368 (87)	80 (78)
Impaired	55 (13)	23 (22)
Missing	104	24
PIM user
No	297 (56)	60 (47)
Yes	230 (44)	67 (53)
Depression
No	439 (83)	106 (83)
Yes	88 (17)	21 (17)
Prior fall
No	431 (82)	103 (81)
Yes	96 (18)	24 (19)
Weight loss
No	439 (83)	99 (78)
Yes	88 (17)	28 (22)

ADL, activities of daily living; HCT-CI, hematopoietic cell transplantation-comorbidity index; IADL, instrumental activities of daily living; KPS, Karnofsky Performance Status; PIM, potentially inappropriate medication; RIC/NMA, reduced-intensity/nonmyeloablative conditioning.

Seventy-five patients received PC consultation within six months after allogeneic hematopoietic cell transplantation and before relapse/disease progression (cumulative incidence 14%; 95% confidence interval [CI], 11–17). We chose six months because previous studies had demonstrated lasting benefits of PC consultation for this duration.^7,8 Over the years, both the absolute number and the percentage of older allo-HCT recipients who received PC consultations increased, culminating in 28% in 2017 (n = 23). This rate of PC consultation is much higher than the national average, likely due to our large hospital size and resource availability.^9,10 Not surprisingly, most consults were requested by the HCT team (87%) and occurred in hospital (92%). The most common consult reasons were for pain management (60%), end-of-life care (20%), assistance with goals-of-care discussions (16%), and management of other symptoms (4%). The median number of visits was 5 (range 1–26). These results were consistent with significant often unmet PC needs during acute hematopoietic cell transplantation care,^9,10 and the high mortality risk in older allo-HCT recipients.⁶

Univariate and multivariate analyses of pretransplant factors associated with post-HCT PC consultation are given in Table 2, which demonstrated increased consultation rates among patients with high/very high disease risk (hazard ratio [HR] = 1.88; 95% CI, 1.16–3.06; p = 0.01) and lower rates among males (HR = 0.53; 95% CI, 0.33–0.86; p = 0.009). Most importantly, PC consultation rates were substantially higher for patients with impaired ADL and/or IADL prehematopoietic cell transplantation (HR = 2.35; 95% CI, 1.35–4.09; p = 0.003), but not for patients with multimorbidity (HCT-CI ≥3), suggesting that older patients with functional limitation may have increased PC needs. Mechanistically, functional limitation could lead to higher symptom burden, as shown for solid tumor patients,¹⁴ or lead to the development of geriatric syndromes such as delirium and fall.¹² Overall worse prognosis from the provider/patient perspectives could also contribute to this increase in PC consultation.^6,14 These findings highlight important roles of pre-HCT GA, in combination with disease risk assessment, in anticipating post-HCT PC need and advanced-care planning for high-risk recipients.¹⁵ Our results also provide a starting point to examine appropriate PC consultation triggers in allo-HCT care (i.e., prognosis-based vs. needs-based),¹⁶ and potential referral bias among individual HCT providers.

Table 2.

Univariable and Multivariable Analyses of Pre-HCT Factors Associated with Post-HCT Palliative Care Consultation

	Univariable analysis		Multivariable analysis
	HR (95% CI)	p	HR (95% CI)	p
Gender		0.004		0.009
Female	Reference		Reference
Male	0.51 (0.33–0.81)		0.53 (0.33–0.86)
KPS at transplant		0.034		0.265
<90	Reference		Reference
≥90	0.61 (0.38–0.96)		0.76 (0.47–1.23)
Disease risk index		0.002		0.01
Low/intermediate	Reference		Reference
High/very high	2.05 (1.3–3.25)		1.88 (1.16–3.06)
Conditioning intensity		0.02		0.058
RIC/NMA	Reference		Reference
Myeloablative	0.58 (0.37–0.92)		0.63 (0.4–1.02)
ADL/IADL		<0.001		0.003
Normal	Reference		Reference
Impaired	2.65 (1.55–4.52)		2.35 (1.35–4.09)

Bold indicates significance at p < 0.05.

CI, confidence interval; HCT, hematopoietic cell transplant; HR, hazard ratio.

Importantly, we examined how PC consultation affected the quality and the intensity of end-of-life care among 127 patients who had died within one-year of allogeneic hematopoietic cell transplantation, using established care quality indicators.^13,17,18 Among those patients, 49 had received a PC consultation within six-month of hematopoietic cell transplantation while 78 did not. Patient characteristics of these two groups were similar except for more females in the PC group (Supplementary Table S1). As shown in Figure 1, PC utilization correlated significantly with a decrease in death in the hospital (p = 0.013), ICU admission (p = 0.001), or any marker of high-intensity medical care (p = 0.001) in the last 30 days of life. The rate of hospice utilization was also increased from 9% to 25% (p = 0.019). In addition, the median time from do-not-resuscitate order to death increased from 2 to 6 days (p < 0.001). These results provide evidence that in older allo-HCT recipients, early interdisciplinary PC consultation may improve the quality and reduce the intensity of end-of-life care compared with no PC consultation. Our results are consistent with findings in the pediatric HCT population wherein early PC integration leads to improved quality and reduced intensity of end-of-life care.¹⁹ Mechanistically, as demonstrated in previous studies of solid tumor patients, improved end-of-life care was likely the result of enhanced prognostic communication, expert symptom management, and timely advanced care planning provided by interdisciplinary PC consultants.^2,3

FIG. 1.

Comparisons of end-of-life care intensities among patients who died within one-year of transplant. Bars show percentages of patients who did (light gray bar) or did not (dark gray bar) receive a PC consultation. p values in parentheses. DNR, do-not-resuscitate; ICU, intensive care unit; PC, palliative care.

In summary, we demonstrate for the first time that for older allo-HCT recipients, higher disease risk and pre-existing functional limitation are associated with increased interdisciplinary subspecialty PC consultation posthematopoietic cell transplantation. Such PC consultation correlates with both reduced intensity and improved quality of end-of-life care. These results add another dimension to the growing impact of interdisciplinary PC on HCT care and identify an ideal target patient population where limited PC resources are best directed.^7,8

Our findings have several limitations. First, this is a single-institution retrospective analysis that lacks patient-reported outcomes, an essential outcome of PC consultation. Second, we lack information on referral patterns or comfort levels for PC consultation by different HCT providers (physicians vs. advanced practice providers) or any specific PC triggers. Finally, we lack direct comparisons of PC outcomes between older versus younger HCT recipients. Despite these limitations, our findings support that an interdisciplinary PC team could effectively seamlessly connect pre-HCT GA, HCT care, symptom burden, mood, quality of life, and end-of-life care to improve outcomes for older vulnerable allo-HCT patients. Future studies should prospectively assess the impact of interdisciplinary PC consultation on survival and patient-reported outcomes,²⁰ examine the best timing for PC involvement including prehematopoietic cell transplantation for high-risk patients,²¹ and explore barriers to system-wide implementation such as transfusion requirements and physician perceptions.^22,23

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information

This research was supported, in part, by the NIH/NHLBI Project Program Grant (P01 CA23766) and the NIH/NCI Cancer Center Support Grant (P30 CA008748). R.J.L. acknowledges research support from Elsa U. Pardee Foundation for Cancer Research, New York State Empire Clinical Research Investigator Program (ECRIP), and Parker Institute for Cancer Immunotherapy (PICI) at MSK.

Author Disclosure Statement

No competing financial interests exist.

Supplementary Material

Supplementary Table S1