Aging and Hematologic Disorders

Anemia

Anemia in older and younger adults is defined by the World Health Organization (WHO) as hemoglobin less than 13 g/dL for men and less than 12 g/dL for women. For adults aged 65 years and older, the prevalence of anemia is approximately 10% to 11% and increases to 20% to 25% for those aged 85 years and older, and to 50% for those in nursing homes. Common causes of anemia in the older age group include iron deficiency/bleeding, chronic disease/inflammation, renal insufficiency, and hematologic malignancies. Approximately 30% to 40% of older adults with anemia lack a discernible cause despite a thorough investigation. Unexplained anemia has been associated with acquired somatic mutations in genes associated with myeloid malignancies as detected by whole-exome sequencing (see Chapter 19 ).

The work-up of anemia should include history taking (symptoms and their effect on daily activities and duration), physical examination, and laboratory testing (complete blood count with differential, renal function, and peripheral smear; depending on the white blood cell differential other testing may include reticulocyte count, iron indices, folate, B ₁₂ , copper, and zinc levels, thyroid function studies, haptoglobin, liver function test and enzymes, fecal occult blood). If primary bone marrow disorders or anemia is unexplained (especially when patients are symptomatic requiring transfusion), a bone marrow aspirate/biopsy is recommended. It is important to consider age-related vulnerabilities in the work-up of anemia. If patients are frail and/or work-up likely will not change management, periodic monitoring may be considered as an alternative to an invasive bone marrow aspirate/biopsy.

General Principles in Older Adults with Hematologic Malignancies

Chronological age alone does not determine underlying fitness due to heterogeneity in underlying health status. A geriatric assessment encompasses the use of validated tools to assess age-related vulnerabilities, including functional status and physical performance, cognition, nutrition, psychological health, comorbidities, social support, and medications ( Table 157.1 ). Age-related vulnerabilities assessed as part of the geriatric assessment predict both morbidity and mortality in several hematologic malignancies.

Geriatric assessment complements standard oncologic assessments and can be used (1) to uncover vulnerabilities in older adults that would not otherwise be captured during routine visits, (2) to predict treatment tolerance and prognosticate, (3) to assign treatment, and (4) to guide supportive care interventions. Studies have shown that geriatric assessment-guided care improves patient and caregiver satisfaction, increases discussion of age-related vulnerabilities, reduces treatment toxicity without worsening survival, improves treatment tolerance, improves quality of life (QOL), and reduces healthcare utilization.

Two specific tools based on the geriatric assessment have been developed to predict chemotherapy toxicity—the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and the Cancer Aging and Research Group (CARG) calculators. The CARG toxicity calculator was developed and validated among older patients with solid tumors, whereas the CRASH toxicity calculator was developed and validated in older patients with a variety of cancers, including hematological malignancies. Specific age-related vulnerabilities incorporated in the CRASH toxicity calculator included Instrumental Activities of Daily Living (IADL), Eastern Cooperative Group (ECOG) Performance Status, Mini-Mental State Examination, and Mini-Nutritional Assessment. The risk of both hematologic and nonhematologic toxicities can be estimated using this tool (see Table 157.2 for a case example).

Studies of the use of geriatric assessment for treatment assignment, although limited, have been done in several hematologic malignancies. Geriatric assessment may prevent both undertreatment (providing less than recommended therapy, thereby leading to worse outcomes) and overtreatment (providing intensive treatment where the harms outweigh the benefits or providing intensive treatment for a cancer that is not expected to affect an older adult in his or her remaining lifetime). Based on geriatric assessment, patients are generally classified as fit, vulnerable, or frail. Alternatively, they can be classified as fit or unfit. It is important to note that these classifications are context- and treatment-specific. For example, an older adult may be fit to receive lower-intensive treatment but unfit to receive high-intensity treatment.

Age-related vulnerabilities are dynamic, and an unfit patient may become fit during the disease trajectory or vice versa. Therefore geriatric assessment may guide supportive care interventions to reverse these vulnerabilities. For example, functional impairment is associated with chemotherapy toxicity and poor survival. For these patients, geriatric assessment may inform the need for interventions such as exercise and physical therapy to improve functional status, therefore improving treatment tolerability and prognosis.

Older adults and their caregivers often overestimate chance of cure. When appropriate, geriatric assessment may provide an opportunity for hematologists to guide older adults and caregivers toward end-of-life choices that are consistent with their values and preferences. Studies have shown that geriatric assessment-guided care increases discussion of patient goals, healthcare proxy, and advance directive wishes, as well as improves completion of advances directives. This may in turn encourage early referral to palliative care, which in the context of AML, has been shown to improve QOL, improve psychological health, and decrease use of chemotherapy in the last 30 days of life.

In the next few sections, the use of geriatric assessment in lymphoma, AML, myelodysplastic syndrome (MDS), multiple myeloma, and hematopoietic stem cell transplantation (HSCT) is described.

Lymphoma in Older Adults

Lymphomas primarily occur in older adults, with at least half of lymphoma cases occurring in patients who are 65 and older. Choosing a treatment regimen for older patients can be challenging because many older patients may not be able to tolerate standard of care regimens due to their comorbidities, functional status, and increased risk for toxicities. This is especially relevant for older patients with aggressive non-Hodgkin lymphomas, which are often treated with intensive, curative anthracycline-containing regimens. While there is no precise definition of frailty to identify those who are unfit for curative treatment, geriatric assessment can be an important guide.

For patients with aggressive lymphomas, a geriatric assessment may help with treatment assignment. In a randomized controlled trial of 224 older patients with diffuse large B-cell lymphoma (DLBCL), a geriatric assessment was used to assign treatment to either standard-dose rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or the less-intensive rituximab plus cyclophosphamide, etoposide, vincristine, and prednisone (R-miniCEOP). The outcomes were similar between the two groups. However, patients who were older than 72 and had low-risk disease appeared to have a better outcome when treated with R-miniCEOP ( P = .011). In a systematic review on the use of the geriatric assessment for older patients with DLBCL, four prospective observational studies showed that independent of the treatment regimen, geriatric assessment could predict overall response rates, overall survival, and therapy-related toxicities. Choice of the regimen to be used was left to the discretion of the treating oncologist rather than based on a geriatric assessment. Although there have been other studies investigating less-intensive chemotherapy regimens, geriatric assessment was not used for treatment assignment. When curative treatment is considered for aggressive lymphoma, older adults without impairment on geriatric assessment should be strongly considered for standard treatments regardless of age. Older patients with vulnerabilities may benefit from modified treatment plans.

Components of a geriatric assessment can independently assist with prognostication. In older patients with CLL, physical performance was the best predictor of outcome when compared with comorbidities, cognition, and functional status. Seventy-five patients, out of 97 enrolled in a clinical trial of the German CLL Study Group, underwent a geriatric assessment before initiation of low-dose fludarabine. Components of a geriatric assessment in this study included the cumulative illness rating scale (CIRS) to measure comorbidities, timed up-and-go (TUG) to measure objective physical function also called “physical performance,” the dementia detection (DEMTECT) test, and IADL for self-reported functional status. Although there was little correlation between the CIRS, TUG, DEMTECT, and IADL results with treatment toxicity, decreased performance in TUG (i.e., slower speed) or DEMTECT test was strongly associated with decreased survival. Overall survival was remarkably poor in patients who underperformed in either TUG or DEMTECT test (median overall survival 53.8 vs. 40.5 vs. 18.2 months for TUG test ≤10 s vs. 11 to 19 s vs. ≥20 s; median overall survival 53.8 vs. 57.8 vs. 17.0 months for DEMTECT test >12 vs. 9 to 12 vs. < 9 points, respectively, P <.05). The differences were significant after adjusting for age and disease-specific factors that are known to be of use in determining prognosis. These results are supported by a recent study in 448 patients with hematologic malignancies that showed that for every 0.1-m/s decrease in measured usual gait speed, there was an associated higher mortality, odds of unplanned hospitalizations, and emergency department visits. Therefore gait speed should be routinely used to assess frailty in older adults with blood cancers.

In summary, geriatric assessment is an important tool in the prognostication and assignment of treatment for patients with lymphoma and CLL. Geriatric assessment is underutilized in clinical practice because of its perceived complexity. Additional prospective, randomized studies are warranted to validate the use of geriatric assessment in determining treatment approaches and uncovering vulnerabilities.