Frailty and the Management of Hematologic Malignancies Gregory A. Abel and Heidi D. Klepin

25 Pages·2017·0.76 MB·English

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Blood First Edition Paper, prepublished online November 15, 2017; DOI 10.1182/blood-2017-09-746420

Frailty and the Management of Hematologic Malignancies

Gregory A. Abel1 and Heidi D. Klepin2

1Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
2Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC

Corresponding Author:
Gregory A. Abel, MD, MPH
Dana-Farber Cancer Institute
450 Brookline Avenue, Dana 1106
Boston, MA 02215

phone: [phone]
fax: [phone]
email: [email protected]

Running Title: Frailty and Blood Cancers

Conflicts of Interest: There are no conflicts of interest to report.

Word Count: 3973

Abstract: 124
Number of Pages: 23
Figures: 4
Tables: 1
References: 73
Copyright © 2017 American Society of Hematology
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Frailty and Blood Cancers 2
Abstract
The majority of blood cancers occur in the elderly. This fact conspires with an aging population in many
countries to make rigorous assessment for frailty increasingly important for hematologic oncologists. In
this review, we first define frailty and its relevance for patients with hematologic malignancy. Next, we
review current data regarding the impact of domains of frailty on outcomes for blood cancers including
myelodysplastic syndromes (MDS), acute leukemia, non-Hodgkin lymphomas such as chronic
lymphocytic leukemia (CLL), and multiple myeloma. Finally, after presenting assessment and treatment
options for the practicing hematologist, we propose elements of a new research agenda for geriatric
hematology: the exchange of age limits for rigorous frailty screening, development of disease-specific
measures, and inclusion of functional and patient-reported outcomes along with survival.
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Frailty and Blood Cancers 3
Introduction to Frailty
While recent years have seen an explosion in new treatments for hematologic malignancies such
as chronic lymphocytic leukemia (CLL)1 and multiple myeloma,2 including the expansion of age limits
for stem cell transplantation for acute leukemia and myelodysplastic syndromes (MDS),3 there is overall
little specific evidence to guide treatment decisions for older adults. This is largely because they are
under-represented in cancer-related clinical trials;4 indeed, about one-third of hematology trials listed in
the National Institutes of Health registry include age-based exclusions.5 Moreover, even when there are
no age restrictions, older patients who are eligible are most often not representative of the older patients
commonly seen in practice. Hematologists are thus left with great clinical uncertainty, and must either
assume that new treatments will be effective despite data that hails primarily from younger patients, or
avoid such treatments altogether for their older patients.
Like all patients, older patients with blood cancers want to know “What is the optimal treatment
for me?” To answer them, we must consider the features of the malignancy, potential efficacy and
toxicity of treatment, and each patient’s individual characteristics such as life expectancy, personal
values, and presence or absence of frailty. This is a tall order, and the goal of the burgeoning field of
geriatric hematology is to fill this knowledge gap. Integrating frailty assessment (“staging the aging”6)
into routine clinical care, so that current evidence can be better applied to older patients regardless of
chronological age, is part of this agenda. We must also advocate for the inclusion of older patients—
accompanied by rigorous frailty assessment— into clinical trials of new agents, so that there are
directly-applicable data.
Frailty is a “vulnerable state that arises from decreased reserve in multiple organ systems, which
are initiated by disease, lack of activity, inadequate nutritional intake, stress, and/or the physiologic
changes of aging.”7,8 While chronological age, comorbidity, and performance status are relatively easy
to assess, they have only limited utility in capturing the heterogeneity of older patients with blood
cancers;9 indeed, determining biological age requires measures of function. Although frailty is
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Frailty and Blood Cancers 4
associated with comorbid burden,10,11 comorbidity is a distinct concept. Some patients have many
comorbidities that are optimally managed such that they are not frail, while others have limited
comorbidity that is so poorly managed as to make them frail. While scales such as the well-known
Charlson Comorbidity Index (CCI)12 and the Sorror index for hematopoietic cell transplantation (HCT-
CI)13 and its derivatives14 are clinically useful and predict survival for many blood cancers,15,16 in this
review, we will focus on work that specifically relates to the broader concept of frailty.
The implications of frailty vary in different clinical scenarios. For example, a phenotypically
frail older adult may do well with low-intensity therapy for indolent disease but poorly with intensive
therapy for aggressive disease. The goal of frailty screening, or enhanced functional assessment, is to
estimate a patient’s “physiological age” when considering treatment options and goals of care. Such
assessment takes several domains into account, including comorbidity, psychological health, current
quality of life, medication burden, physical health, cognitive function, and social support. Moreover,
many geriatricians do not consider frailty a binomial construct, such that while some patients are clearly
robust and other clearly frail, there is a third category of patients considered “vulnerable,” “unfit,” or
“pre-frail.”
Many frailty assessments are based on Fried’s phenotype model,17 which focuses on items such
as weight loss, poor grip strength, slow gait speed, low physical activity and self-reported exhaustion.
The Rockwood model18 alternatively assesses frailty as the cumulative effect of 30 or more “deficits”
and considers additional factors such as comorbidity and cognition. There are also hybrid models19 and
simple questionnaires,20-22 but screening is best captured through in-person functional examination,
known as geriatric assessment. This approach has been repeatedly shown to detect unrecognized
vulnerabilities in large cohorts of cancer patients, and predict treatment tolerance, survival, and quality
of survivorship.23-29
Frailty has also been associated with poor therapeutic response, increased toxicity, and worse
survival for patients with blood cancers.16,30-33 Because these patients are often at an immunologic and
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Frailty and Blood Cancers 5
hematopoietic disadvantage due to the malignancy itself, chemotherapy can work hand-in-hand with the
blood cancer to intensify frailty. Moreover, a recent review of 19 publications from 15 studies of elderly
patients with hematologic cancers9 found that 75% revealed an association between objective measures
of physical capacity and survival, 67% for nutritional status, and 50% for comorbidity. Indeed, frail
older patients with MDS,16,34 AML,32,35 lymphoma,36,37 and myeloma38,39 have all been shown to have
worse disease-related outcomes when compared to robust counterparts of similar age. We will consider
each of these diseases, reviewing evidence for the utility of geriatric assessment and frailty screening in
decision-making, and building the rationale for routine enhanced functional assessment for patients with
blood cancers. Importantly, the following is not intended to be a meta-analysis or even a systematic
review, which the nascent nature of this field currently precludes.

Evidence for the Impact of Frailty among Specific Blood Cancers
AML and MDS
In patients with AML, geriatric assessment has been demonstrated to add information to the
standard oncology assessment based on Eastern Cooperative Oncology Group (ECOG) performance
status.40 In one prospective study,41 50 patients 60 years or older underwent geriatric assessment by a
nurse within five days of initial hospitalization and 63% were found to be impaired in more than one
functional domain (depression, distress, impairment of activities of daily living, physical function,
cognitive impairment or comorbidity). Moreover, participants with good ECOG performance status
were often impaired: for example, more than 50% with cognitive impairment had ECOG performance
≤
status 1. Another study of patients with blood cancers (including AML) had subjects assess their own
ECOG performance status and compared it to physician assessment. Agreement was only fair/moderate
κ
(weighted =0.41[0.37, 0.44]),42 arguing that enhanced functional assessment is worthwhile.
Frail patients with AML have been demonstrated to have worse survival. In a retrospective study
of 101 patients 65 or older,35 in addition to increased comorbidity, difficulty with strenuous activity (HR
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Frailty and Blood Cancers 6
= 2.2 [1.2, 4.0]), and reports of pain (HR = 2.2 [1.2, 4.0] were independent prognostic factors in a
multivariable model including cytogenetic risk group. These remained independent predictors even for
≤
patients with ECOG performance status 1. In another prospective study of patients with AML (n=74;
median age 70), pre-treatment geriatric assessment included evaluation of cognition, depression,
distress, physical function, and comorbidity.32 Adjusting for age and disease risk, impaired cognition
and physical function were independently associated with worse survival (Figure 1). Baseline clinical
characteristics (age, risk group, performance status, hemoglobin, and creatinine) explained 20% of
variation in survival, and comorbidity another 1%. Impaired physical and cognitive functioning
explained an additional 5% and 6% respectively.
Frailty has also been associated with poor survival in MDS. For example, a retrospective study
(n=114) demonstrated that low serum albumin (a marker of poor nutrition) and poor physical function
both added prognostic information to the International Prognostic Scoring System (IPSS).34 Moreover, a
large prospective study (n=445) characterized the impact of frailty among older patients with MDS
(median age 73).8 Using the Clinical Frailty Scale (CFS),43 in a multivariate analysis that included age-
adjusted revised IPSS (IPSS-R)44 and comorbidity score, frailty independently predicted survival
(Hazard Ratio [HR] 2.7 [1.7, 4.2]), and was more predictive than comorbidity as measured by the CCI
(HR 1.8 [1.1, 2.8]). Integration of frailty significantly improved prognostication of the IPSS-R in all but
the highest risk group.
A multi-site European study of 195 older patients (median age 71 years) with MDS (n=63) and
AML (n=132)45 similarly measured frailty domains. These included impairments in activities of daily
living and poor quality of life/fatigue. In a multivariable analysis of patients treated non-intensively,
both pre-treatment impairment in activities of daily living (HR 2.60 [1.37, 5.46]) and poor quality of
life/fatigue (HR 1.82 [1.02, 3.23]) were associated with worse survival.
Finally, it is critically important to assess the robustness of older patients with MDS or AML
being considered for HCT. In a small prospective study, investigators screened 50 older patients (mean
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Frailty and Blood Cancers 7
age 65 years) eligible for allogenic HCT (70% had either MDS or AML).46 The assessment included the
following domains: comorbidity, polypharmacy, nutritional status, physical performance, functional
status, social support, psychological status, and cognition. In the total cohort, 66% of patients had an
abnormal assessment, and about one in five (22%) were ultimately considered frail. The authors
concluded that older HCT candidates should undergo formal frailty screening.
Lymphoma and CLL
Several small studies, some prospective and some retrospective, have demonstrated the impact of
frailty on outcomes for non-Hodgkin lymphoma (NHL), including ability to complete chemotherapy and
≥
poor overall survival.47-50 For example, an analysis from the Netherlands47 recruited 44 patients 70
years, most with diffuse large B-cell lymphoma (DLBCL; 91%) for geriatric assessment. The
assessment included the Groningen Frailty Indicator (GFI),22 a 15-item questionnaire that assesses
physical, cognitive, social, and psychological domains of frailty. In multivariable analyses, abnormal
GFI was associated with early termination of chemotherapy (Odds Ratio [OR] 9.2 [1.5, 55.8]) as well as
worse overall survival (HR 2.6 [1.1, 6.1]). In another analysis,50 143 German patients with
lymphoproliferative malignancies were recruited for geriatric assessment—median age was 63 years.
Advanced age, poor performance status, dependence in activities of daily living (ADL; patients needed
help with simple daily activities such as dressing), dependence in instrumental activities of daily living
(IADL; patients needed help with more complex skills correlating with ability to live alone), and
presence of severe comorbidity were all significantly associated with shorter survival. In multivariable
analysis, impaired IADL and comorbidity were both independently associated with survival.
In contrast to AML/MDS, several studies have also assessed specific chemotherapy agents for
frail older patients with NHL. For example, there are data for vinorelbine and prednisone for frail
patients with intermediate-high grade NHL,51 and another study demonstrated that R-CVP (rituximab,
cyclophosphamide, vincristine, prednisone) is active in frail patients aged 80 or over with DLBCL
(although not without substantial toxicity).52 Another large study aimed to tailor initial treatment of
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Frailty and Blood Cancers 8
older patients with DLBCL through geriatric assessment.53 Following 334 assessments from 2003 to
2006, 99 patients were identified as frail (median age 78). Robust patients were enrolled in a randomized
trial comparing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R-mini
CEOP (rituximab, cyclophosphamide, epirubicin, vinblastine, prednisone); frail patients were treated at
physician discretion. Compared to the robust, frail patients had worse overall survival (HR 3.1 [2.2,
4.3]), but did a bit better when treated with rituximab-containing chemotherapy (HR 2.4 [1.5, 3.9]).
As older patients with aggressive lymphoma may present with curable disease, it is important to
determine if they should be treated with curative intent. An Italian multicenter study54 aimed to assess if
geriatric assessment could identify elderly patients who were neither robust nor frail but “unfit,” such
that they might still benefit from curative treatment. In total, 173 patients aged 70 or older were treated
by clinical judgement (curative intent was rigorously defined by regimen), and later grouped according
to geriatric assessment into fit (46%), unfit (16%) and frail (38%) categories. Treatment with curative
intent improved overall survival in unfit (75% vs. 45%) but not in frail patients (44% vs. 39%), arguing
that enhanced functional assessment can identify patients who are not robust but may still benefit from a
curative approach.
Hodgkin lymphoma less often affects the elderly, but is difficult to treat when it does, especially
for the frail. A phase II study of first-line brentuximab for patients 60 or older (n=27)55 found 81% were
impaired in at least one geriatric domain. Treatment yielded a 92% response rate, with 73% achieving
complete remission. The authors concluded that brentuximab is reasonable for frail older patients.
Finally, given its predilection for older patients, understanding the contribution of frailty to
outcomes for chronic lymphocytic leukemia (CLL) seems especially important. Frailty results from the
CLL9 trial of the German CLL study group were recently published, in which 75 of 97 patients
underwent geriatric assessment (median age 75) prior to treatment with low-dose fludarabine +/- an
erythropoiesis-stimulating agent.36 The study evaluated a geriatric assessment that included the Timed
Up and Go test (TUG)56 for physical function and the dementia detection test (DEMTECT)57 for
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Frailty and Blood Cancers 9
cognition, finding 61% were impaired in either physical or cognitive functioning. Poor performance on
either was associated with worse survival (p=0.005 and 0.007 respectively), prompting the authors to
conclude that these tools should be integrated into both future trials and routine management of CLL.58
Multiple Myeloma
Perhaps because of its relatively long natural history, treatment trajectory, and associated
comorbid diagnoses such as renal failure and bone disease, efforts to assess fitness for patients with
myeloma have been the most concerted. The effort began with the initial and revised myeloma-specific
comorbidity index (R-MCI),59-61 but has more recently focused on the creation and validation of the
International Myeloma Working Group (IMWG) frailty score. Following a pooled analysis of 869
newly-diagnosed elderly patients from three multi-center randomized trials, the IMWG developed a
frailty score and assessed its impact on clinical outcome and toxicity.39 Importantly, the associated trials
were for patients who were deemed ineligible for autologous HCT.
The European Myeloma Network (EMN) and Gruppo Italiano Malattie Ematologiche
dell’Adulto (GIMEMA) conducted baseline geriatric assessments in these trials using the Katz ADL,62
Lawton IADL,63 and CCI12 instruments. The median age was 74 years, and median follow-up was 18
months. The most frequent comorbidities were diabetes without organ damage (13%), cardiopulmonary
disease (10%), and mild renal failure (7%). The most prevalent abnormal ADL were independence in
bathing, transferring, and dressing. Among IADL, transportation, housekeeping, shopping, and laundry
were most often abnormal. Using weights derived from survival analysis that adjusted for disease factors
to create a scoring system—including age category as well as performance on ADL, IADL and CCI—
three risk groups were ultimately identified: “fit” (39% of the cohort), “intermediate fit” (31%), and
“frail” (30%).
The resulting IMWG frailty score predicted both survival and risk of toxicity (Figure 2). For
example, the 3-year overall survival was 84% among the fit, 76% among the intermediate-fit, and 57%
≥
among the frail. Moreover, the cumulative incidence of grade 3 nonhematologic adverse events at one
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Frailty and Blood Cancers 10
year in these groups was 22%, 26% and 34% respectively. The IMWG score has since been
prospectively assessed in an external cohort of 125 newly-diagnosed patients who were not part of a
clinical trial.38 In that cohort, multivariate analysis confirmed that cytogenetics, ADL, IADL, and CCI
added to risk for poor outcomes. Three-year overall was 91% for the fit, 77% for the intermediate-fit,
and 47% for the frail, suggesting the IMWG score is useful in the “real-world” of clinical practice.

Frailty Assessment and Management in Practice: Opportunities and Challenges
Feasibility of Screening
Routine geriatric assessment of older adults with blood cancers is feasible. Most assessments
include a self-administered questionnaire with an administered component (cognitive, physical
performance) typically performed by a nurse or another trained professional. In the study of elderly
AML inpatients mentioned above, of 54 patients approached for bedside geriatric assessment, 50 (93%)
completed it.41 Another group demonstrated that over a one-year period, 85% of new blood cancer
patients 75 or older agreed to a brief geriatric screening, and that scores correlated with intensity of
subsequent treatment decisions.64 In another study, community and tertiary patients with cancer 65 or
older from North Carolina (n=1088) underwent frailty assessment including tests for cognitive function,
TUG,56 and a questionnaire.65 The median time to complete the assessment was 23 minutes in the
tertiary center and 30 minutes in the community (31% of the sample). The authors concluded that
routine geriatric assessment could be brief and effective, even in community settings.
Multi-Disciplinary Care Models
Several models have been created to enhance assessment and management of frailty in older
adults with cancer. In a recent review,66 Dale and colleagues discuss four that have emerged in the
United States. The first, the “primary provider model” utilizes formally-trained geriatric oncologists who
perform an initial comprehensive assessment and manage all geriatric and oncology needs.
Unfortunately, this model is limited due to the small number of geriatric oncologists available, even at