- Email: [email protected]
Aging: Treating the Older Patient
Accepted Manuscript Title: Aging, ‘Treating the Older Patient’ Author: Ashley Rosko, Andrew Artz PII: DOI: Reference:
S1083-8791(16)30485-2 http://dx.doi.org/doi: 10.1016/j.bbmt.2016.11.007 YBBMT 54444
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
28-9-2016 4-11-2016
Please cite this article as: Ashley Rosko, Andrew Artz, Aging, ‘Treating the Older Patient’, Biology of Blood and Marrow Transplantation (2016), http://dx.doi.org/doi: 10.1016/j.bbmt.2016.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aging, ‘Treating the Older Patient’
The Older Myeloma Patient: Evaluating Aging and Understanding Fitness for Ashley Rosko, MD Ohio State University
The Older AML Patient: Candidacy and Optimization for Allogeneic Transplant Andrew Artz, MD, MS University of Chicago
Corresponding Author: Andrew S. Artz, MD, MS [email protected] University of Chicago Chicago, IL 60637 Email: [email protected]
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Telephone: 773-702-4400 Highlights Despite greater use of autologous transplant for multiple myeloma and allogeneic transplant for AML, significant underutilization persists Geriatric assessment is a multi-dimensional tool to characterize physiologic age and can identify vulnerabilities or frailty before transplant in older patients Hematopoietic cell transplant outcomes can achieve favorable disease free survival in older adults both in myeloma and AML Keywords: Multiple myeloma; acute myeloid leukemia; transplant; elderly; geriatric assessment; autologous; allogeneic
Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy of older adults. The median age of diagnosis is 69 years, and in the next 15 years myeloma incidence is expected to double in this age demographic.1, 2 Novel therapeutics and routine use of autologous stem cell transplant (ASCT) have led to substantial improvements in overall response rates and durable remissions.3-5 In contrast to younger MM patients, older patients have only modest improvements in overall survival.6-8 MM deaths overall are highest in patients aged 75 years and greater, and early mortality is most common in those 70 years and older.4, 9 The disparity in overall survival for aging adults is multifactorial; secondary to comorbidities, treatment strategy, toxicities, physiologic reserve, and therapy discontinuation. Transplant ‘eligibility’ is an active and important area of MM investigation. ASCT is established in younger populations to improve survival over non-transplant
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therapy10,
11
and has PFS advantages over delayed transplant in the novel era. 12 ASCT is feasible and an efficacious
component of therapy for older patients with MM as well. 13 Older adults mobilize sufficient numbers of stem cells and can tolerate transplant with excellent outcomes resulting in increased numbers of older adults undergoing autologous transplant.14 Nearly half of autologous transplants are done in adults 60 years and greater, this number will only increase as the population ages.15 Referral bias for transplant still exists likely due to historic reports depicting conflicting tolerance, response rates and survival.16 Transplant eligibility Transplant eligibility is matter of estimating a patients’ physiologic reserve for an intensive therapy.17 Identifying and intervening on factors that contribute to vulnerability in pre-transplant myeloma patients is imperative to balance quality of life with an efficacious therapy. One method to identify and resolve occult health factors, is a geriatric assessment. A geriatric assessment (GA) is a global evaluation of the health of older adults; it goes beyond the disease-focused history and aims to identify unrecognized issues to intervene and prevent future complications. GA tools are established metrics to accurately assess risk of morbidity and mortality in cancer populations. 18, 19 The GA consists of a multi-dimensional evaluation of functional status, fall history, social support, cognitive and psychological status, sensory loss, nutritional status, co-morbidities and a polypharmacy evaluation. Table 1 depicts a set of tools often employed in a cancer specific GA. Geriatric assessments have been shown to predict mortality and toxicity, independent of performance status and
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age.20 Traditional metrics, such as Karnofsky performance status (KPS), are often over estimated by clinicians and are a poor indicator of treatment toxicity risk.21 The treatment approach for MM is heterogeneous due to concerns for frailty and tolerance in older adults. Primary dose reductions and therapy discontinuations result in worse outcomes in older adults with MM.22, 23 Although it is known that functional assessments can improve upon outcomes in cancer patients; feasibility, practicality and disease specificity are barriers to implementation. 24-26 Nonetheless, a simple geriatric assessment based on age, comorbidities, cognition, and physical function can predict mortality in the MM population. Frailty assessments in MM patients were predictive of death independent of treatment, cytogenetics, or stage.23
Biomarkers of Physiologic Age Recently novel aging biomarkers are being explored to provide a rapid measure of physiologic fitness. 27-29 Ideally an aging biomarker would capture vulnerability by estimating physiologic reserve and risk for chemotherapy and/or transplant toxicity. Exploring biomarkers of aging in a cancer population is particularly challenging, as many aging biomarkers are evaluated in a community dwelling population without a cancer diagnosis. Despite these challenges many potential biomarkers of aging are being explored to evaluate the relationship among chronologic aging, frailty syndromes and cancer. Candidate biomarkers include molecular markers, inflammatory markers, immunosenescence panels, serum and hematologic parameters, and hormones (Table 2). Each of these biomarkers has various associations with aging and frailty and limited reported relationships with AHST or myeloma. Inflammatory
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markers such as IL-6, CRP, TNF-alpha, D-dimer have reported associations with frailty in oncology studies.30 Inflammatory panels such as the senescence-associated secretory phenotype (SASP) has a well-established relationship with aging, gerontogic conditions and frailty.31 Distinct changes in the immune system are reported with aging 32-34 and are being explored with frailty and have parallels with MM pathophysiology.35, 36 T-cell dysfunction is commonly reported in MM where markers of immunosenscence are associated with relapsed disease.37 Clonal expansions of T-cells are common with aging and are also present with long-term survival in MM38
although the biology of clonal expansions may differ. Aging results in shifts in T-cell compartments,32,
39, 40
proliferative capacity41, and increased cytotoxicity.42 Anemia, inherent to MM, has been independently associated with functional disability in older adults.43 miRNA expression profiles have been shown to correlate with age in healthy populations,44 cardiovascular disease,45,
46
but not frailty in a solid tumor cancer populations.47 NT-BNP has recently been reported to be a useful predictor of
survival, independent of age and performance status in multiple myeloma patients. 48 The molecular biomarker p16INK4a is being explored for risk of chemotherapy toxicity and transplant tolerance. 49, 50 There is considerable evidence that p16INK4A is one of the most robust and validated aging biomarkers. p16 mRNA accumulates in aging tissues and increases with chronologic aging in peripheral blood T-cells, as well as with internal and external stresses.51-55 Over the human lifespan, p16 levels increase more than 16-fold in peripheral blood T-cells.56, 57 Prolonged expression of p16 promotes irreversible cell cycle arrest or cellular senescence. External stressors can trigger p16 expression such as physical inactivity, chemotherapy50,
58
and tobacco exposure. Additionally,
single nucleotide polymorphisms located near the INK4/ARF locus are linked with age-related diseases including cardiovascular disease, diabetes and decreased physical function.52-54 p16 can be quantified in peripheral blood T-cells providing a feasible and
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relatively non-invasive method to monitor expression over time in a clinical setting. Aging biomarkers paired with geriatric metrics may provide a novel method to gauge risk of transplant toxicity in the myeloma population. The need for objective biomarkers of aging is especially important in the field of MM due to the aged population affected, heterogeneity in older adult fitness, and diverse treatment strategies that are available. Ultimately an individualized approach to patient fitness based on geriatric metrics and aging biology can aid the clinician in decision making for myeloma transplant.
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The Older AML Patient: Candidacy and Optimization for Allogeneic Transplant
Overview The potent anti-leukemic effects of allogeneic hematopoietic cell transplantation must be balanced against transplant associated morbidity and mortality, especially for older patients. Reduced intensity allogeneic transplant achieves 30-50% 2 year survival for AML in patients 60 years and older. Emerging data highlight the importance of physiologic reserve beyond chronologic age alone. Multi-dimensional health surveys such as geriatric assessment encompassing comorbidity, function, social support, cognition, nutrition and other domains identify unrecognized and prognostically relevant health impairments. Age-related vulnerabilities may predispose to toxicity due to inherent physiologic stress of transplant. Enrollment on prospective studies is essential to delineate the most effective risk-stratification tools to inform transplant candidacy. Interventions to attenuate transplant risks based on health vulnerabilities in older patients are proposed although prospective studies are mandatory.
Epidemiology of AML in Older Adults
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Advancing age represents the primary risk factor for acute myeloid leukemia (AML) diagnosis and disease fatality- the median age of diagnosis in western countries is around 67 to 70 years of age and older age strongly associates with worse survival (seer.cancer.gov). 59
Adverse biologic factors inherent to the disease, competing health conditions and less treatment together interfere to limit long-term
success. The biology of older age as a risk for AML and inferior outcomes remains an area of interest although age-related clonal myeloid hematopoiesis appears to predispose to leukemia and possibly chemotherapy resistance clones. 60
A large series of AML patients enrolled on Cancer and Leukemia Group B trials illustrates the influence of age on outcomes. Patients 60 years and older had less frequent favorable risk disease employing the European Leukemia Net criteria and more frequent adverse cytogenetics (31% adverse disease for older vs 22% in patients under 60 years). For the favorable risk group, only 24% of older patients achieved 3 year disease free survival compared to 55% in younger patients. Non-transplant protocol based treatment rarely accomplished leukemia control for intermediate and adverse risk disease- 3 year disease free survival was 11% and 6%, respectively. 61
The large UK AML16 showed of intensive therapy showed similar results with 5 year survival of around 14-15%. 62
Older Age and Allogeneic Transplant for AML
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The historical barrier of older age to allogeneic hematopoietic cell transplant has slowly been lifted over the past 2 decades. The Center for International Blood and Marrow Transplant Registry (CIBMTR) showed 22% of allogeneic transplant recipients were 60 years or older in the 2007 to 2013 period among common malignant conditions.63 Likewise, US allografts for patients 70 years and older have risen 10 fold over the past decade, with AML as the leading indication (Figure 1). 64 Few older AML patients receive allogeneic transplant; a population study of AML 2000 and 2007 showed only 4% of AML patients 65 to 74 years underwent allografts. 65 Swedish data described a marked uptick in transplant use for those 61 to 70 years in recent years yet no transplants for those 70 years and older for AML. 66
Transplant Outcomes for Older AML Patients A review of studies of adults 60 years and older undergoing allogeneic transplant for AML, found among 749 patients in 13 studies overall survival (OS) at 1, 2 and 3 years was 58%, 45%, and 38%.67 Devine published a multi-institutional prospective study of a lowintensity fludarabine-busulfan-ATG regimen using matched related and unrelated donors AML in first remission. 68 Patients 60 to 74 years of age achieved a favorable 2 year survival of 48% and low non-relapse mortality of 14%. Registry data for AML and MDS patients 70 and older utilizing all donor sources and conditioning regimens showed 2 year survival of 38% of and 2 year non-relapse mortality (NRM) of 30%. 64 Haploidentical and umbilical cord graft studies in older AML have been described. 69-71
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Advancing age still confers greater risks of transplant related mortality for AML in first remission.72 However, limiting the comparison to g HLA matched grafts after reduced intensity conditioning show no major influence of age alone.73 74 A report by Versluis derived from prospective AML studies of patients 60 years and older revealed reduced intensity transplant from matched related or unrelated donors improved 5 year overall at 35% versus 26% for other forms of consolidation therapy (HR=0.71 p = .017).75
Provisional Recommendations on Candidacy GA and Risk Categorization No well-designed studies have characterized the morbidity and risks of transplant in older adults of HCT versus non-HCT approaches. Decisions to pursue allogeneic HCT demand individualization and attention to disease status, donor type, regimen, center experience, and patient goals. A Geriatric Assessment (GA) has been the standard tool within Geriatric Oncology to better characterize health in older patients. The GA in table 1 was adopted from the Cancer and Aging Research Group and supplemented by additional medical history which may be relevant to transplant. 76, 77 The extensive resources committed for transplant and appreciable risks may justify this low-risk low-cost evaluation. Table 3 illustrates a schema used at our institution which divides patients into anticipated transplant associated mortality risk into fit (i.e, consider similar to younger patients), vulnerable (higher-risk but transplant risks may be manageable, review optimization strategies) and unfit (avoid transplant due to excessive risks unless on trial or exceptional
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circumstances). This schema has not been tested and should not be considered a guideline. The available data and/or rationale for such criteria are summarized below.
Age The preponderance of data supporting allografting for older AML has been in patients 65 years or less and sparse for 70 years and above. 64, 78 Ideally, patients above 75 years of age would undergo transplant on clinical trials specifically addressing age-related issues. Chronologic age alone between 60 and 75 years will not usually dictate transplant candidacy and complementary evaluation may aide decision making. Patients younger than 60 years may also benefit from a comprehensive health evaluation.
Comorbidity The hematopoietic cell transplantation-comorbidity index (HCT-CI) summates various comorbid conditions extracted from history and objective testing. 79 In adults 60 years and older undergoing non-ablative HLA matched allografts, Sorror showed a borderline significant increase in NRM for intermediate comorbidity of HCT-CI of 1-2 (HR= 1.69, 95% CI 0.91 – 3.14) and 3 or more (HR= 2.0, 95% CI 1.12- 3.6) relative to no comorbidity and inferior survival for those with the higher comorbidity. In a registry validation, 1 year allogeneic transplant NRM was 17%, 21% and 26% for HCT-CI scores of 0, 1 – 2 and 3, respectively (p <.001). 80 NRM did not differ for HCT-CI of 1 – 2 relative to 0 after reduced intensity regimens. High comorbid burden (i.e., HCT-CI of 5 or more) exacted a
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profound effect on NRM (HR=1.77, 95% CI 1.50 – 2.10). Similar effect sizes for NRM and survival have been reported by degree of comorbid burden.81 Comorbidity and age are additive to the prognostic effects on NRM and survival. 80, 82, 83 Thus, older patients entering transplant with HCT-CI scores of 3-5 are vulnerable and at our center we simply avoid for HCT-CI 6 unless exceptional circumstances or trial. Following the scoring guidelines by Sorror will maximize accuracy in tabulating comorbidity and likely prognostic discrimination. 84
Geriatric Assessment and Functional Status Functional Status Low physician rated Karnofsky Performance Status (KPS) (e.g., <60-70%) often exclude patients from allogeneic transplant consideration and among older transplanted patients; KPS of 80% or less may have worse outcomes relative to 90% to 100%. 85
Patient reported and/or performance based function is an essential core element of a multi-dimensional GA. We reported a high frequency of patient reported functional impairments for patients 50 years and older prior to allografting as 40% had at least one limitation in a core functionally tool -The Lawton Instrumental Activities of Daily Living (IADL) encompassing ability to manage medications, finances, meals, grocery shop, telephone, transportation and driving, and housekeeping/chores. 86 Other reports from Houston and San Francisco have likewise demonstrated a high frequency of functional vulnerabilities by GA testing prior to
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transplant. 87, 88 In the Chicago cohort (n=203), the presence of any IADL limitation independently imparted high risks of NRM and inferior survival but not relapse rates. Adverse effects were amplified in patients 60 and older (HR=3.3) relative to patients 50 – 59 (HR= 1.9) although confidence intervals overlapped. Patient function through a self-report quality of life instrument also conveyed worse 1 year survival in a multi-institutional study by Wood et al of all ages supporting the premise of patient reported function for prognostication. 89
Slow 4 meter walk speed also predicted higher mortality in the Chicago series. In studies of adult patients of all ages, cardiopulmonary fitness tools of 6 minute walk distance or cycle ergometry may risk-stratify patients.90, 91 Whether patient reported function, performance based function or both will be optimal is unknown. Other studies in Geriatrics and Geriatric Oncology support IADL to stratify for outcome using this convenient survey tool. 76, 92
Other Health Domains Emotional Health The Houston and Chicago series showed surveys of emotional health uncovered a higher frequency of emotional health impairments than by the HCT-CI alone.87 The Mental Health Inventory-5 demonstrated 36% of patients in the Houston study expressed anxiety or depression. By the short-form 36 (SF-36) quality of life instrument mental composite summary subscale, slightly over half of the
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patients in the Chicago GA indicated mental health at least one standard deviation below population normals. 83 Emotional health and motivation are clearly relevant factors although the attendant risks from these disturbances require additional study.
Cognition The Houston series on GA described a 16% prevalence of mild cognitive impairment prior to transplant. 87 We found in 27 unselected patients 60 years and older before allografting, a 10% rate of cognitive impairment by the mini-mental status examination (verbal communication, Artz and Lacy). A diagnosis of cognitive impairment should not be based on screening tests alone. One approach to establish cognitive impairment is to perform neuropsychologic testing and/or consult Geriatrics. The consequences of allografting in cognitive impairment are unknown although Klepin reported pre-treatment cognitive impairment negatively affected early survival after receipt of AML induction therapy in older adults.93 Therefore, one must exercise caution in pursuing allogeneic transplant should cognitive deficits be uncovered.
Composite Models and Biomarker Data-driven models should be developed to maximally guide candidacy. Multi-dimensional risk scores utilizing comorbidity, function, age if not other markers as utilized in Geriatric Oncology and non-cancer older populations 76, 94 will likely emerge. For example, we found a combination of high comorbidity (i.e., HCT-CI 3 or more) and functional impairment by IADL produced a
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simple 3 level scoring system with appreciable discrimination: 2 year survival exceeded 60% for no risk factors compared to 29% and 0% for those with 1 or 2 risk factors in patients 60 years and older, respectively. Biomarkers such as elevated c-reactive protein and depressed albumin add prognostication discrimination to comorbidity and age.81, 95 Hypoalbuminemia (< 3.5 g/dL) can be applied as a readily available biomarker in light of the established and independent risks of NRM.
Regimen Intensity The decision of regimen and graft sources is beyond the scope of this review, yet risk-stratification must account for the intended regimen and graft source. Unfortunately, a low-intensity regimen may not necessarily improve outcomes for older adults due to heightened risks of relapse. The preliminary data of a benefit in relapse free survival of myeloablative chemotherapy for AML and MDS in patients up to the age of 65 years of age with low comorbidity suggest one may consider an ablative regimen for older fit AML patients.96
Transplant Optimization Rationale
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Multi-disciplinary optimization strategies to reduce transplant morbidity are attractive when considering the substantial risks associated with specific vulnerabilities and rapid transplant growth in patients 70 years and older. The promise has not been prospectively tested.
Standard Platform Team Approach Our center has attempted to leverage vulnerabilities detected by GA by assembling an interdisciplinary team to develop targeted interventions as outlined in Table 4. The team consists of a dietician, social worker, Geriatric Oncologist, transplant physician (often separate from the primary transplant physician), transplant nurse, transplant advanced practice provider, physical therapist, and a data or clinical coordinator. Most team members exist in transplant programs. Other team members which may be considered include a pharmacist, psychologist, and patient advocate. Cultivating relationships with medical subspecialists for prevalent comorbid conditions such as cardiac and pulmonary dysfunction promotes a mindset of optimal monitoring and management and away from clearance alone.
Specific Interventions
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Randomized transplant studies of exercise during and after transplant have shown only modest benefits and primarily data was derived in younger adults at lower risk of functional disability.97 Structured exercise may be preferred over low intensity education based on the reduction in disability in non-transplant older adults.98 Starting prior to transplant (pre-habilitation) will likely maximize yield although extended time for pre-habilitation in AML patients may not be feasible. The conditioning regimen of transplant may still be an opportunity to gain strength and endurance and can be married to pre-habilitation. Medication avoidance can follow the updated “Beers Criteria” and requires diligence.99
Augmented social support can facilitate patient monitoring, adherence, and optimization across domains. Older adults often rely on older spouses or siblings who may have their own health issues. A family meeting of all potential caregivers may combat patient reluctance to enlist children or other social support. We routinely request a back-up caregiver should the primary caregiver become ill and inquire about the health of the primary caregiver. During anticipated cytopenia and toxicities from conditioning therapy (when such a regimen is used), a fortified caregiver presence (i.e., 24/7 available) is a consideration.
Geriatric Assessment guided interventions
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Based on the GA, specific vulnerabilities often emerge for which individualized therapy can be directed often by non-physician team members (e.g., dietician, physical therapist, social worker). For example, dentures may prompt regular dietician input and modified nutritional recommendations. Subtle or mild cognitive impairment justify greater attention to medication avoidance, focus on sleep hygiene, and consideration of serial monitoring for delirium (including caregiver education ) when hospitalized and/or Geriatrics consultation. Weakness in a specific arm may guide placement of central venous catheters, modified exercises, initiation of an assist device (e.g., cane, walker) and special instructions on rising from a bed or chair.
Timing Time to transplant may be one of the most modifiable factors and key reasons to characterize fitness for transplant. The high-rates of relapse and short-disease free survival in older adults justifies moving quickly to allogeneic transplant for appropriate candidates. A common clinical dilemma for the vulnerable older AML patient is the tendency toward a sluggish pursuit of transplant due to uncertainty about the harms and benefits of transplant. Here the decision making process for transplant may be as important as the criteria employed. 100, 101
Future Directions
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Transplant studies must ensure adequate representation of older adults and compare results to non-transplanted treatment strategies. Large prospective studies incorporating multi-dimensional tools such as geriatric assessments will be required to better inform transplant candidacy. Finally, optimization strategies should be tested to reduce transplant associated morbidity and perhaps extend transplant to older and more vulnerable AML patients.
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References:
1.
Surveillance E, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database.
2.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of Cancer Incidence in the United States: Burdens Upon an Aging, Changing Nation. J. Clin. Oncol. 2009;27:2758-2765.
3.
Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J. Clin. Oncol. 2010;28:4621-4629.
4.
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122-1128.
5.
Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.
6.
Pulte D, Gondos A, Brenner H. Improvement in survival of older adults with multiple myeloma: results of an updated period analysis of SEER data. Oncologist. 2011;16:1600-1603.
7.
Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521-2526.
20
Page 20 of 36
8.
Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic. Mayo Clin. Proc. 2010;85:225-230.
9.
Warren JL, Harlan LC, Stevens J, Little RF, Abel GA. Multiple myeloma treatment transformed: a population-based study of changes in initial management approaches in the United States. J. Clin. Oncol. 2013;31:1984-1989.
10.
Attal M, Blaise D, Marit G, et al. Consolidation Treatment of Adult Acute Lymphoblastic-Leukemia - a Prospective, Randomized Trial Comparing Allogeneic Versus Autologous Bone-Marrow Transplantation and Testing the Impact of Recombinant Interleukin-2 after Autologous Bone-Marrow Transplantation. Blood. 1995;86:1619-1628.
11.
Cavo M PA, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). Abstract #8000. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 3, 2016.
12.
Attal M, Lauwers-Cances V, Hulin C, et al. Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Blood. 2015;126.
13.
Wildes TM, Finney JD, Fiala M, et al. High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma. Bone Marrow Transplant. 2015;50:1075-1082.
14.
Wildes TM, Finney JD, Fiala M, et al. High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma. Bone marrow transplantation. 2015;50:1075-1082.
15.
Pasquini MC ZXCuaoohsctCSS, 2015. Available at: http://www.cibmtr.org.
16.
Offidani M, Leoni P, Corvatta L, et al. ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myeloma. Eur. J. Haematol. 2010;84:474-483.
21
Page 21 of 36
17.
Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J. Clin. Oncol. 2014;32:587-600.
18.
Pal SK, Katheria V, Hurria A. Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. CA Cancer J. Clin. 2010;60:120-132.
19.
Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J. Clin. Oncol. 2007;25:1936-1944.
20.
Hamaker ME, Prins MC, Stauder R. The relevance of a geriatric assessment for elderly patients with a haematological malignancy--a systematic review. Leukemia research. 2014;38:275-283.
21.
Hurria A, Togawa K, Mohile S, et al. Predicting Chemotherapy Toxicity in Older Adults and the Importance of Geriatric Assessment Reply. J. Clin. Oncol. 2012;30:561-562.
22.
Bringhen S, Mateos MV, Zweegman S, et al. Age and organ damage correlate with poor survival in myeloma patients: metaanalysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98:980-987.
23.
Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-2074.
24.
Karnakis T, Gattas-Vernaglia IF, Saraiva MD, Gil-Junior LA, Kanaji AL, Jacob-Filho W. The geriatrician's perspective on practical aspects of the multidisciplinary care of older adults with cancer. J. Geriatr. Oncol. 2016.
25.
Caillet P, Paillaud E, Dupuis J. [6/7. Malignant hematological diseases in the elderly]. Soins Gerontol. 2011:45-46.
26.
Hurria A, Cirrincione CT, Muss HB, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:12901296.
22
Page 22 of 36
27.
Hubbard JM, Cohen HJ, Muss HB. Incorporating biomarkers into cancer and aging research. J. Clin. Oncol. 2014;32:26112616.
28.
Walston JD. Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability. Nestle Nutrition Institute workshop series. 2015;83:1-10.
29.
Pustavoitau A, Barodka V, Sharpless NE, et al. Role of senescence marker p16 INK4a measured in peripheral blood Tlymphocytes in predicting length of hospital stay after coronary artery bypass surgery in older adults. Exp. Gerontol. 2016;74:29-36.
30.
Hubbard JM, Jatoi A. Incorporating Biomarkers of Frailty and Senescence in Cancer Therapeutic Trials. J. Gerontol. A Biol. Sci. Med. Sci. 2014.
31.
LeBrasseur NK, Tchkonia T, Kirkland JL. Cellular Senescence and the Biology of Aging, Disease, and Frailty. Nestle Nutrition Institute workshop series. 2015;83:11-18.
32.
Czesnikiewicz-Guzik M, Lee WW, Cui D, et al. T cell subset-specific susceptibility to aging. Clin. Immunol. 2008;127:107-118.
33.
Haynes L, Swain SL. Why aging T cells fail: implications for vaccination. Immunity. 2006;24:663-666.
34.
Effros RB. The role of CD8 T cell replicative senescence in human aging. Discov. Med. 2005;5:293-297.
35.
Lu Y, Tan CT, Nyunt MS, et al. Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies. Oncotarget. 2016.
36.
Fahey JL, Schnelle JF, Boscardin J, et al. Distinct categories of immunologic changes in frail elderly. Mech. Ageing Dev. 2000;115:1-20.
23
Page 23 of 36
37.
Chung DJ, Pronschinske KB, Shyer JA, et al. T Cell Exhaustion/Senescence in Relapsed Multiple Myeloma after Autologous Stem Cell Transplantation. Blood. 2015;126.
38.
Bryant C, Suen H, Brown R, et al. Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood Cancer Journal. 2013;3.
39.
Chen GB, Lustig A, Weng NP. T cell aging: a review of the transcriptional changes determined from genome-wide analysis. Front. Immunol. 2013;4.
40.
Moro-Garcia MA, Alonso-Arias R, Lopez-Larrea C. When aging reaches CD4+T-cells: phenotypic and functional changes. Front. Immunol. 2013;4.
41.
Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30:306-312.
42.
Cao JN, Gollapudi S, Sharman EH, Jia Z, Gupta S. Age-related alterations of gene expression patterns in human CD8+ T cells. Aging cell. 2010;9:19-31.
43.
Owusu C, Cohen HJ, Feng T, et al. Anemia and Functional Disability in Older Adults With Cancer. J. Natl. Compr. Canc. Netw. 2015;13:1233-1239.
44.
Zhang HY, Yang H, Zhang CN, et al. Investigation of MicroRNA Expression in Human Serum During the Aging Process. J Gerontol a-Biol. 2015;70:102-109.
45.
Jazbutyte V, Fiedler J, Kneitz S, et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age. 2013;35:747-762.
46.
Boon RA, Iekushi K, Lechner S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495:107-110.
24
Page 24 of 36
47.
Hatse S, Brouwers B, Dalmasso B, et al. Circulating MicroRNAs as easy-to-measure aging biomarkers in older breast cancer patients: correlation with chronological age but not with fitness/frailty status. PLoS One. 2014;9:e110644.
48.
Milani P, Rajkumar SV, Merlini G, et al. N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma. Am. J. Hematol. 2016.
49.
Rosko AE, Hofmeister CC, Benson D, Efebera YA, Huang Y, Burd C. T-Cell p16(INK4A) Expression Increases PostTransplant in Patients with Multiple Myeloma. Blood. 2014;124.
50.
Sanoff HK, Deal AM, Krishnamurthy J, et al. Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer. Jnci-J Natl Cancer I. 2014;106.
51.
Liu Y, Johnson SM, Fedoriw Y, et al. Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes. Blood. 2011;117:3257-3267.
52.
Melzer D, Frayling TM, Murray A, et al. A common variant of the p16(INK4a) genetic region is associated with physical function in older people. Mech. Ageing Dev. 2007;128:370-377.
53.
Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-1341.
54.
Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491-1493.
55.
Liu Y, Sanoff HK, Cho H, et al. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging cell. 2009;8:439-448.
56.
Zindy F, Soares H, Herzog KH, Morgan J, Sherr CJ, Roussel MF. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ. 1997;8:1139-1150.
25
Page 25 of 36
57.
Ressler S, Bartkova J, Niederegger H, et al. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging cell. 2006;5:379-389.
58.
Rosko A, Hofmeister C, Benson D, et al. Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma. Bone Marrow Transplant. 2015;50:1379-1381.
59.
Juliusson G, Lazarevic V, Horstedt AS, Hagberg O, Hoglund M, Swedish Acute Leukemia Registry G. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119:3890-3899.
60.
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014;371:2488-2498.
61.
Mrozek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J. Clin. Oncol. 2012;30:4515-4523.
62.
Burnett AK, Russell NH, Hills RK, et al. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2016.
63.
Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation2015.
64.
Muffly L, Pasquini MC, Martens M, et al. Increasing Use of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients Age 70 Years and Older: A CIBMTR Study of Trends and Outcomes. Biology of Blood and Marrow Transplant.22:S68-S69.
65.
Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97:1916-1924.
66.
Bower H, Andersson TM, Bjorkholm M, Dickman PW, Lambert PC, Derolf AR. Continued improvement in survival of acute myeloid leukemia patients: an application of the loss in expectation of life. Blood Cancer J. 2016;6:e390.
26
Page 26 of 36
67.
Rashidi A, Ebadi M, Colditz GA, DiPersio JF. Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol. Blood Marrow Transplant. 2016;22:651-657.
68.
Devine SM, Owzar K, Blum W, et al. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J. Clin. Oncol. 2015.
69.
Blaise D, Furst S, Crocchiolo R, et al. Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor. Biol. Blood Marrow Transplant. 2016;22:119-124.
70.
Kasamon YL, Bolanos-Meade J, Prince GT, et al. Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J. Clin. Oncol. 2015;33:3152-3161.
71.
Sandhu KS, Brunstein C, DeFor T, et al. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged >/=70 Years. Biol. Blood Marrow Transplant. 2016;22:390-393.
72.
Horan JT, Logan BR, Agovi-Johnson MA, et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J. Clin. Oncol. 2011;29:805-813.
73.
McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28:1878-1887.
74.
Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874-1883.
27
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75.
Versluis J, Hazenberg CL, Passweg JR, et al. Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis. Lancet Haematol. 2015;2:e427-436.
76.
Hurria A, Mohile S, Gajra A, et al. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer. J. Clin. Oncol. 2016;34:2366-2371.
77.
Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:3457-3465.
78.
Brunner AM, Kim HT, Coughlin E, et al. Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Biol. Blood Marrow Transplant. 2013;19:1374-1380.
79.
Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919.
80.
Sorror ML, Logan BR, Zhu X, et al. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol. Blood Marrow Transplant. 2015;21:1479-1487.
81.
Vaughn JE, Storer BE, Armand P, et al. Design and Validation of an Augmented Hematopoietic Cell TransplantationComorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation. Biol. Blood Marrow Transplant. 2015;21:1418-1424.
82.
Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J. Clin. Oncol. 2014;32:3249-3256.
83.
Muffly LS, Kocherginsky M, Stock W, et al. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. Haematologica. 2014;99:1373-1379.
84.
Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121:2854-2863.
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85.
Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood. 2013;121:2567-2573.
86.
Muffly LS, Boulukos M, Swanson K, et al. Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients. Biol. Blood Marrow Transplant. 2013;19:429434.
87.
Holmes HM, Des Bordes JK, Kebriaei P, et al. Optimal screening for geriatric assessment in older allogeneic hematopoietic cell transplantation candidates. J. Geriatr. Oncol. 2014;5:422-430.
88.
Olin RL, Andreadis C, Martin TG, et al. Comprehensive Geriatric Assessment Identifies Significant Functional Impairments in Older Hematopoietic Cell Transplant Recipients. Biology of Blood and Marrow Transplant.20:S65-S66.
89.
Wood WA, Le-Rademacher J, Syrjala KL, et al. Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer. 2016;122:91-98.
90.
Wood WA, Deal AM, Reeve BB, et al. Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study. Bone Marrow Transplant. 2013;48:1342-1349.
91.
Jones LW, Devlin SM, Maloy MA, et al. Prognostic Importance of Pretransplant Functional Capacity After Allogeneic Hematopoietic Cell Transplantation. Oncologist. 2015;20:1290-1297.
92.
Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J. Clin. Oncol. 2002;20:494-502.
93.
Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121:4287-4294.
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94.
Cruz M, Covinsky K, Widera EW, Stijacic-Cenzer I, Lee SJ. Predicting 10-year mortality for older adults. JAMA. 2013;309:874-876.
95.
Artz AS, Logan BR, Zhu X, et al. Pre-Transplant C-Reactive Protein (CRP), Ferritin and Albumin As Biomarkers to Predict Transplant Related Mortality (TRM) after Allogeneic Hematopoietic Cell Transplant (HCT). Blood. 2014;124:422-422.
96.
Pasquini MC, Logan B, Wu J, et al. Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Blood. 2015;126:LBA-8LBA-8.
97.
Persoon S, Kersten MJ, van der Weiden K, et al. Effects of exercise in patients treated with stem cell transplantation for a hematologic malignancy: a systematic review and meta-analysis. Cancer Treat. Rev. 2013;39:682-690.
98.
Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311:2387-2396.
99.
By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J. Am. Geriatr. Soc. 2015;63:2227-2246.
100.
Randall J, Keven K, Atli T, Ustun C. Process of allogeneic hematopoietic cell transplantation decision making for older adults. Bone Marrow Transplant. 2016;51:623-628.
101.
Artz AS, Chow S. Hematopoietic cell transplantation in older adults: deciding or decision-making? Bone Marrow Transplant. 2016.
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Figure 1. Allogeneic Transplant Malignant Indications and Change Over Time in the United States Reported to the Center for International Blood and Marrow Transplantation Registry.
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Table 1: Geriatric Evaluation For Older AML Candidacy For Allogeneic Domains Common Tools Comorbidity Hematopoietic cell transplantation-comorbidity index Function
Instrumental activities of daily living Timed up and go, grip strength, 4 meter walk
Social Support and Function
Illness specific subscales of social support (ISSS) Center specific tool Min-mental state examination or Montreal cognitive assessment
Cognition
Psychological
Geriatric depression scale Mental health inventory 17
Nutritional status
Weight loss, body mass index
Polypharmacy
>5 medications
32
Transplant Additional Geriatric Questions Remote cancer, urinary problems, visual or hearing impairment, diastolic dysfunction, prior renal impairment, osteoporosis Arthritis, falls, maximum ability for physical activity, exercise, balance Back-up caregiver, alcohol use, stairs at home , person preparing meals, power of attorney Prior confusion, memory impairment and duration Assess retention of information without family member interjection Sleep problems, motivation for transplant, coping skills, preparation for setbacks, life goals (e.g., specific event) Last dental evaluation, dentures, use of supplements, effect of prior therapy on nutrition and weight over the counter medications, side effects from prior medication, clarify remote allergies
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Table 2. Aging and Frailty Assessments Molecular Markers
Immune Dysregulation Heme Parameters Serum markers
Clinical Tools
Aging Frailty X
INK4A
p16
Leukocyte Telomere Length DNA Methylation miRNA Immunosenescence
x
x
x
SASP Anemia IL-6 CRP NT-proBNP Albumin D-dimer TNF sICAM-1 Geriatric Assessment Metrics
x x x x x x
x x x x x x x
x
x x
33
Transplant x
Myeloma
x x
x x
x
x x
x
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Table 3: Provisional Framework for Allogeneic Hematopoietic Cell Transplant Eligibility Criteria for Acute Myeloid Leukemia Patients 60 years and Older with Adequate Disease Control Factor Fit Vulnerable Usually Exclude or Trial (All of the below) (Any of the below) (Any of the below) Age < 66 years 66-75 >75 Comorbidity HCT-CI 0-2 HCT-CI 3-5 6+ or severe organ dysfunction KPS (%) Function IADL Performance*
90-100
70-80
<70
Normal No impairment
Any limitation Impaired
Limitations and HCT-CI 4+ Severely limited
Cognitive
No impairment
Other Factors
Normal
Mild cognitive impairment, prior confusion Weight loss, single or limited caregiver, falls, albumin <3.5 g/dL, limited motivation
Moderate cognitive impairment Weight loss, single or limited caregiver, falls, albumin <3.5 g/dL, limited motivation + others
*Performance is measured by timed up and go, 4 meter walk, and grip strength. 6 minute walk used for pre-habilitation baseline HCT-CI, hematopoietic cell transplantion-comorbidity index/sorror index; KPS, Karnofsky performance score; IADL, Lawton instrumental activities of daily living (omitting ability to do laundry)
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Table 4: Standard Optimization Platform For Older Allogeneic Transplant Recipients Utilized at University of Chicago Health Area Standard Optimization Recommendations Geriatric Assessment (GA) Interventions individualized based on GA detected limitations in table 2. Multi-disciplinary team meeting and written optimization plan before transplant. Comorbid conditions Cultivate preferred subspecialists and request post-transplant follow-up. Referral to Geriatrics or Geriatric Oncology for geriatric syndromes (e.g., falls, incontinence) Function Structured pre-habilitation based on baseline activity and limitations. Home safety assessment (fall risk, stairs, proximity of bathroom) Social Support Pre-transplant family meeting, caregiver present during cytopenia and “on-call” if issues. Request secondary caregivers. Enlist caregivers in optimization plan. Cognition Delirium awareness and precautions, medication avoidance, encourage presence of caregivers, add written material to verbal instructions, call patient to reinforce education. Emotional health Offer cognitive therapy and support group to avoid additional medications unless required Nutrition Develop nutritional plan prior to transplant included preferred supplements if used. Medications Reduce unnecessary medications. Re-evaluate day 30 to 100 post-transplant. Other Infection mitigation plan for grand-children, evaluate remote drug allergies (e.g., penicillin allergy in childhood), more frequent followup, smooth survivorship transition from transplant center.
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Figure 1.
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S1083-8791(16)30485-2 http://dx.doi.org/doi: 10.1016/j.bbmt.2016.11.007 YBBMT 54444
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
28-9-2016 4-11-2016
Please cite this article as: Ashley Rosko, Andrew Artz, Aging, ‘Treating the Older Patient’, Biology of Blood and Marrow Transplantation (2016), http://dx.doi.org/doi: 10.1016/j.bbmt.2016.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aging, ‘Treating the Older Patient’
The Older Myeloma Patient: Evaluating Aging and Understanding Fitness for Ashley Rosko, MD Ohio State University
The Older AML Patient: Candidacy and Optimization for Allogeneic Transplant Andrew Artz, MD, MS University of Chicago
Corresponding Author: Andrew S. Artz, MD, MS [email protected] University of Chicago Chicago, IL 60637 Email: [email protected]
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Telephone: 773-702-4400 Highlights Despite greater use of autologous transplant for multiple myeloma and allogeneic transplant for AML, significant underutilization persists Geriatric assessment is a multi-dimensional tool to characterize physiologic age and can identify vulnerabilities or frailty before transplant in older patients Hematopoietic cell transplant outcomes can achieve favorable disease free survival in older adults both in myeloma and AML Keywords: Multiple myeloma; acute myeloid leukemia; transplant; elderly; geriatric assessment; autologous; allogeneic
Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy of older adults. The median age of diagnosis is 69 years, and in the next 15 years myeloma incidence is expected to double in this age demographic.1, 2 Novel therapeutics and routine use of autologous stem cell transplant (ASCT) have led to substantial improvements in overall response rates and durable remissions.3-5 In contrast to younger MM patients, older patients have only modest improvements in overall survival.6-8 MM deaths overall are highest in patients aged 75 years and greater, and early mortality is most common in those 70 years and older.4, 9 The disparity in overall survival for aging adults is multifactorial; secondary to comorbidities, treatment strategy, toxicities, physiologic reserve, and therapy discontinuation. Transplant ‘eligibility’ is an active and important area of MM investigation. ASCT is established in younger populations to improve survival over non-transplant
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therapy10,
11
and has PFS advantages over delayed transplant in the novel era. 12 ASCT is feasible and an efficacious
component of therapy for older patients with MM as well. 13 Older adults mobilize sufficient numbers of stem cells and can tolerate transplant with excellent outcomes resulting in increased numbers of older adults undergoing autologous transplant.14 Nearly half of autologous transplants are done in adults 60 years and greater, this number will only increase as the population ages.15 Referral bias for transplant still exists likely due to historic reports depicting conflicting tolerance, response rates and survival.16 Transplant eligibility Transplant eligibility is matter of estimating a patients’ physiologic reserve for an intensive therapy.17 Identifying and intervening on factors that contribute to vulnerability in pre-transplant myeloma patients is imperative to balance quality of life with an efficacious therapy. One method to identify and resolve occult health factors, is a geriatric assessment. A geriatric assessment (GA) is a global evaluation of the health of older adults; it goes beyond the disease-focused history and aims to identify unrecognized issues to intervene and prevent future complications. GA tools are established metrics to accurately assess risk of morbidity and mortality in cancer populations. 18, 19 The GA consists of a multi-dimensional evaluation of functional status, fall history, social support, cognitive and psychological status, sensory loss, nutritional status, co-morbidities and a polypharmacy evaluation. Table 1 depicts a set of tools often employed in a cancer specific GA. Geriatric assessments have been shown to predict mortality and toxicity, independent of performance status and
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age.20 Traditional metrics, such as Karnofsky performance status (KPS), are often over estimated by clinicians and are a poor indicator of treatment toxicity risk.21 The treatment approach for MM is heterogeneous due to concerns for frailty and tolerance in older adults. Primary dose reductions and therapy discontinuations result in worse outcomes in older adults with MM.22, 23 Although it is known that functional assessments can improve upon outcomes in cancer patients; feasibility, practicality and disease specificity are barriers to implementation. 24-26 Nonetheless, a simple geriatric assessment based on age, comorbidities, cognition, and physical function can predict mortality in the MM population. Frailty assessments in MM patients were predictive of death independent of treatment, cytogenetics, or stage.23
Biomarkers of Physiologic Age Recently novel aging biomarkers are being explored to provide a rapid measure of physiologic fitness. 27-29 Ideally an aging biomarker would capture vulnerability by estimating physiologic reserve and risk for chemotherapy and/or transplant toxicity. Exploring biomarkers of aging in a cancer population is particularly challenging, as many aging biomarkers are evaluated in a community dwelling population without a cancer diagnosis. Despite these challenges many potential biomarkers of aging are being explored to evaluate the relationship among chronologic aging, frailty syndromes and cancer. Candidate biomarkers include molecular markers, inflammatory markers, immunosenescence panels, serum and hematologic parameters, and hormones (Table 2). Each of these biomarkers has various associations with aging and frailty and limited reported relationships with AHST or myeloma. Inflammatory
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markers such as IL-6, CRP, TNF-alpha, D-dimer have reported associations with frailty in oncology studies.30 Inflammatory panels such as the senescence-associated secretory phenotype (SASP) has a well-established relationship with aging, gerontogic conditions and frailty.31 Distinct changes in the immune system are reported with aging 32-34 and are being explored with frailty and have parallels with MM pathophysiology.35, 36 T-cell dysfunction is commonly reported in MM where markers of immunosenscence are associated with relapsed disease.37 Clonal expansions of T-cells are common with aging and are also present with long-term survival in MM38
although the biology of clonal expansions may differ. Aging results in shifts in T-cell compartments,32,
39, 40
proliferative capacity41, and increased cytotoxicity.42 Anemia, inherent to MM, has been independently associated with functional disability in older adults.43 miRNA expression profiles have been shown to correlate with age in healthy populations,44 cardiovascular disease,45,
46
but not frailty in a solid tumor cancer populations.47 NT-BNP has recently been reported to be a useful predictor of
survival, independent of age and performance status in multiple myeloma patients. 48 The molecular biomarker p16INK4a is being explored for risk of chemotherapy toxicity and transplant tolerance. 49, 50 There is considerable evidence that p16INK4A is one of the most robust and validated aging biomarkers. p16 mRNA accumulates in aging tissues and increases with chronologic aging in peripheral blood T-cells, as well as with internal and external stresses.51-55 Over the human lifespan, p16 levels increase more than 16-fold in peripheral blood T-cells.56, 57 Prolonged expression of p16 promotes irreversible cell cycle arrest or cellular senescence. External stressors can trigger p16 expression such as physical inactivity, chemotherapy50,
58
and tobacco exposure. Additionally,
single nucleotide polymorphisms located near the INK4/ARF locus are linked with age-related diseases including cardiovascular disease, diabetes and decreased physical function.52-54 p16 can be quantified in peripheral blood T-cells providing a feasible and
5
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relatively non-invasive method to monitor expression over time in a clinical setting. Aging biomarkers paired with geriatric metrics may provide a novel method to gauge risk of transplant toxicity in the myeloma population. The need for objective biomarkers of aging is especially important in the field of MM due to the aged population affected, heterogeneity in older adult fitness, and diverse treatment strategies that are available. Ultimately an individualized approach to patient fitness based on geriatric metrics and aging biology can aid the clinician in decision making for myeloma transplant.
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The Older AML Patient: Candidacy and Optimization for Allogeneic Transplant
Overview The potent anti-leukemic effects of allogeneic hematopoietic cell transplantation must be balanced against transplant associated morbidity and mortality, especially for older patients. Reduced intensity allogeneic transplant achieves 30-50% 2 year survival for AML in patients 60 years and older. Emerging data highlight the importance of physiologic reserve beyond chronologic age alone. Multi-dimensional health surveys such as geriatric assessment encompassing comorbidity, function, social support, cognition, nutrition and other domains identify unrecognized and prognostically relevant health impairments. Age-related vulnerabilities may predispose to toxicity due to inherent physiologic stress of transplant. Enrollment on prospective studies is essential to delineate the most effective risk-stratification tools to inform transplant candidacy. Interventions to attenuate transplant risks based on health vulnerabilities in older patients are proposed although prospective studies are mandatory.
Epidemiology of AML in Older Adults
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Advancing age represents the primary risk factor for acute myeloid leukemia (AML) diagnosis and disease fatality- the median age of diagnosis in western countries is around 67 to 70 years of age and older age strongly associates with worse survival (seer.cancer.gov). 59
Adverse biologic factors inherent to the disease, competing health conditions and less treatment together interfere to limit long-term
success. The biology of older age as a risk for AML and inferior outcomes remains an area of interest although age-related clonal myeloid hematopoiesis appears to predispose to leukemia and possibly chemotherapy resistance clones. 60
A large series of AML patients enrolled on Cancer and Leukemia Group B trials illustrates the influence of age on outcomes. Patients 60 years and older had less frequent favorable risk disease employing the European Leukemia Net criteria and more frequent adverse cytogenetics (31% adverse disease for older vs 22% in patients under 60 years). For the favorable risk group, only 24% of older patients achieved 3 year disease free survival compared to 55% in younger patients. Non-transplant protocol based treatment rarely accomplished leukemia control for intermediate and adverse risk disease- 3 year disease free survival was 11% and 6%, respectively. 61
The large UK AML16 showed of intensive therapy showed similar results with 5 year survival of around 14-15%. 62
Older Age and Allogeneic Transplant for AML
8
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The historical barrier of older age to allogeneic hematopoietic cell transplant has slowly been lifted over the past 2 decades. The Center for International Blood and Marrow Transplant Registry (CIBMTR) showed 22% of allogeneic transplant recipients were 60 years or older in the 2007 to 2013 period among common malignant conditions.63 Likewise, US allografts for patients 70 years and older have risen 10 fold over the past decade, with AML as the leading indication (Figure 1). 64 Few older AML patients receive allogeneic transplant; a population study of AML 2000 and 2007 showed only 4% of AML patients 65 to 74 years underwent allografts. 65 Swedish data described a marked uptick in transplant use for those 61 to 70 years in recent years yet no transplants for those 70 years and older for AML. 66
Transplant Outcomes for Older AML Patients A review of studies of adults 60 years and older undergoing allogeneic transplant for AML, found among 749 patients in 13 studies overall survival (OS) at 1, 2 and 3 years was 58%, 45%, and 38%.67 Devine published a multi-institutional prospective study of a lowintensity fludarabine-busulfan-ATG regimen using matched related and unrelated donors AML in first remission. 68 Patients 60 to 74 years of age achieved a favorable 2 year survival of 48% and low non-relapse mortality of 14%. Registry data for AML and MDS patients 70 and older utilizing all donor sources and conditioning regimens showed 2 year survival of 38% of and 2 year non-relapse mortality (NRM) of 30%. 64 Haploidentical and umbilical cord graft studies in older AML have been described. 69-71
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Advancing age still confers greater risks of transplant related mortality for AML in first remission.72 However, limiting the comparison to g HLA matched grafts after reduced intensity conditioning show no major influence of age alone.73 74 A report by Versluis derived from prospective AML studies of patients 60 years and older revealed reduced intensity transplant from matched related or unrelated donors improved 5 year overall at 35% versus 26% for other forms of consolidation therapy (HR=0.71 p = .017).75
Provisional Recommendations on Candidacy GA and Risk Categorization No well-designed studies have characterized the morbidity and risks of transplant in older adults of HCT versus non-HCT approaches. Decisions to pursue allogeneic HCT demand individualization and attention to disease status, donor type, regimen, center experience, and patient goals. A Geriatric Assessment (GA) has been the standard tool within Geriatric Oncology to better characterize health in older patients. The GA in table 1 was adopted from the Cancer and Aging Research Group and supplemented by additional medical history which may be relevant to transplant. 76, 77 The extensive resources committed for transplant and appreciable risks may justify this low-risk low-cost evaluation. Table 3 illustrates a schema used at our institution which divides patients into anticipated transplant associated mortality risk into fit (i.e, consider similar to younger patients), vulnerable (higher-risk but transplant risks may be manageable, review optimization strategies) and unfit (avoid transplant due to excessive risks unless on trial or exceptional
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circumstances). This schema has not been tested and should not be considered a guideline. The available data and/or rationale for such criteria are summarized below.
Age The preponderance of data supporting allografting for older AML has been in patients 65 years or less and sparse for 70 years and above. 64, 78 Ideally, patients above 75 years of age would undergo transplant on clinical trials specifically addressing age-related issues. Chronologic age alone between 60 and 75 years will not usually dictate transplant candidacy and complementary evaluation may aide decision making. Patients younger than 60 years may also benefit from a comprehensive health evaluation.
Comorbidity The hematopoietic cell transplantation-comorbidity index (HCT-CI) summates various comorbid conditions extracted from history and objective testing. 79 In adults 60 years and older undergoing non-ablative HLA matched allografts, Sorror showed a borderline significant increase in NRM for intermediate comorbidity of HCT-CI of 1-2 (HR= 1.69, 95% CI 0.91 – 3.14) and 3 or more (HR= 2.0, 95% CI 1.12- 3.6) relative to no comorbidity and inferior survival for those with the higher comorbidity. In a registry validation, 1 year allogeneic transplant NRM was 17%, 21% and 26% for HCT-CI scores of 0, 1 – 2 and 3, respectively (p <.001). 80 NRM did not differ for HCT-CI of 1 – 2 relative to 0 after reduced intensity regimens. High comorbid burden (i.e., HCT-CI of 5 or more) exacted a
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profound effect on NRM (HR=1.77, 95% CI 1.50 – 2.10). Similar effect sizes for NRM and survival have been reported by degree of comorbid burden.81 Comorbidity and age are additive to the prognostic effects on NRM and survival. 80, 82, 83 Thus, older patients entering transplant with HCT-CI scores of 3-5 are vulnerable and at our center we simply avoid for HCT-CI 6 unless exceptional circumstances or trial. Following the scoring guidelines by Sorror will maximize accuracy in tabulating comorbidity and likely prognostic discrimination. 84
Geriatric Assessment and Functional Status Functional Status Low physician rated Karnofsky Performance Status (KPS) (e.g., <60-70%) often exclude patients from allogeneic transplant consideration and among older transplanted patients; KPS of 80% or less may have worse outcomes relative to 90% to 100%. 85
Patient reported and/or performance based function is an essential core element of a multi-dimensional GA. We reported a high frequency of patient reported functional impairments for patients 50 years and older prior to allografting as 40% had at least one limitation in a core functionally tool -The Lawton Instrumental Activities of Daily Living (IADL) encompassing ability to manage medications, finances, meals, grocery shop, telephone, transportation and driving, and housekeeping/chores. 86 Other reports from Houston and San Francisco have likewise demonstrated a high frequency of functional vulnerabilities by GA testing prior to
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transplant. 87, 88 In the Chicago cohort (n=203), the presence of any IADL limitation independently imparted high risks of NRM and inferior survival but not relapse rates. Adverse effects were amplified in patients 60 and older (HR=3.3) relative to patients 50 – 59 (HR= 1.9) although confidence intervals overlapped. Patient function through a self-report quality of life instrument also conveyed worse 1 year survival in a multi-institutional study by Wood et al of all ages supporting the premise of patient reported function for prognostication. 89
Slow 4 meter walk speed also predicted higher mortality in the Chicago series. In studies of adult patients of all ages, cardiopulmonary fitness tools of 6 minute walk distance or cycle ergometry may risk-stratify patients.90, 91 Whether patient reported function, performance based function or both will be optimal is unknown. Other studies in Geriatrics and Geriatric Oncology support IADL to stratify for outcome using this convenient survey tool. 76, 92
Other Health Domains Emotional Health The Houston and Chicago series showed surveys of emotional health uncovered a higher frequency of emotional health impairments than by the HCT-CI alone.87 The Mental Health Inventory-5 demonstrated 36% of patients in the Houston study expressed anxiety or depression. By the short-form 36 (SF-36) quality of life instrument mental composite summary subscale, slightly over half of the
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patients in the Chicago GA indicated mental health at least one standard deviation below population normals. 83 Emotional health and motivation are clearly relevant factors although the attendant risks from these disturbances require additional study.
Cognition The Houston series on GA described a 16% prevalence of mild cognitive impairment prior to transplant. 87 We found in 27 unselected patients 60 years and older before allografting, a 10% rate of cognitive impairment by the mini-mental status examination (verbal communication, Artz and Lacy). A diagnosis of cognitive impairment should not be based on screening tests alone. One approach to establish cognitive impairment is to perform neuropsychologic testing and/or consult Geriatrics. The consequences of allografting in cognitive impairment are unknown although Klepin reported pre-treatment cognitive impairment negatively affected early survival after receipt of AML induction therapy in older adults.93 Therefore, one must exercise caution in pursuing allogeneic transplant should cognitive deficits be uncovered.
Composite Models and Biomarker Data-driven models should be developed to maximally guide candidacy. Multi-dimensional risk scores utilizing comorbidity, function, age if not other markers as utilized in Geriatric Oncology and non-cancer older populations 76, 94 will likely emerge. For example, we found a combination of high comorbidity (i.e., HCT-CI 3 or more) and functional impairment by IADL produced a
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simple 3 level scoring system with appreciable discrimination: 2 year survival exceeded 60% for no risk factors compared to 29% and 0% for those with 1 or 2 risk factors in patients 60 years and older, respectively. Biomarkers such as elevated c-reactive protein and depressed albumin add prognostication discrimination to comorbidity and age.81, 95 Hypoalbuminemia (< 3.5 g/dL) can be applied as a readily available biomarker in light of the established and independent risks of NRM.
Regimen Intensity The decision of regimen and graft sources is beyond the scope of this review, yet risk-stratification must account for the intended regimen and graft source. Unfortunately, a low-intensity regimen may not necessarily improve outcomes for older adults due to heightened risks of relapse. The preliminary data of a benefit in relapse free survival of myeloablative chemotherapy for AML and MDS in patients up to the age of 65 years of age with low comorbidity suggest one may consider an ablative regimen for older fit AML patients.96
Transplant Optimization Rationale
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Multi-disciplinary optimization strategies to reduce transplant morbidity are attractive when considering the substantial risks associated with specific vulnerabilities and rapid transplant growth in patients 70 years and older. The promise has not been prospectively tested.
Standard Platform Team Approach Our center has attempted to leverage vulnerabilities detected by GA by assembling an interdisciplinary team to develop targeted interventions as outlined in Table 4. The team consists of a dietician, social worker, Geriatric Oncologist, transplant physician (often separate from the primary transplant physician), transplant nurse, transplant advanced practice provider, physical therapist, and a data or clinical coordinator. Most team members exist in transplant programs. Other team members which may be considered include a pharmacist, psychologist, and patient advocate. Cultivating relationships with medical subspecialists for prevalent comorbid conditions such as cardiac and pulmonary dysfunction promotes a mindset of optimal monitoring and management and away from clearance alone.
Specific Interventions
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Randomized transplant studies of exercise during and after transplant have shown only modest benefits and primarily data was derived in younger adults at lower risk of functional disability.97 Structured exercise may be preferred over low intensity education based on the reduction in disability in non-transplant older adults.98 Starting prior to transplant (pre-habilitation) will likely maximize yield although extended time for pre-habilitation in AML patients may not be feasible. The conditioning regimen of transplant may still be an opportunity to gain strength and endurance and can be married to pre-habilitation. Medication avoidance can follow the updated “Beers Criteria” and requires diligence.99
Augmented social support can facilitate patient monitoring, adherence, and optimization across domains. Older adults often rely on older spouses or siblings who may have their own health issues. A family meeting of all potential caregivers may combat patient reluctance to enlist children or other social support. We routinely request a back-up caregiver should the primary caregiver become ill and inquire about the health of the primary caregiver. During anticipated cytopenia and toxicities from conditioning therapy (when such a regimen is used), a fortified caregiver presence (i.e., 24/7 available) is a consideration.
Geriatric Assessment guided interventions
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Based on the GA, specific vulnerabilities often emerge for which individualized therapy can be directed often by non-physician team members (e.g., dietician, physical therapist, social worker). For example, dentures may prompt regular dietician input and modified nutritional recommendations. Subtle or mild cognitive impairment justify greater attention to medication avoidance, focus on sleep hygiene, and consideration of serial monitoring for delirium (including caregiver education ) when hospitalized and/or Geriatrics consultation. Weakness in a specific arm may guide placement of central venous catheters, modified exercises, initiation of an assist device (e.g., cane, walker) and special instructions on rising from a bed or chair.
Timing Time to transplant may be one of the most modifiable factors and key reasons to characterize fitness for transplant. The high-rates of relapse and short-disease free survival in older adults justifies moving quickly to allogeneic transplant for appropriate candidates. A common clinical dilemma for the vulnerable older AML patient is the tendency toward a sluggish pursuit of transplant due to uncertainty about the harms and benefits of transplant. Here the decision making process for transplant may be as important as the criteria employed. 100, 101
Future Directions
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Transplant studies must ensure adequate representation of older adults and compare results to non-transplanted treatment strategies. Large prospective studies incorporating multi-dimensional tools such as geriatric assessments will be required to better inform transplant candidacy. Finally, optimization strategies should be tested to reduce transplant associated morbidity and perhaps extend transplant to older and more vulnerable AML patients.
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References:
1.
Surveillance E, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database.
2.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of Cancer Incidence in the United States: Burdens Upon an Aging, Changing Nation. J. Clin. Oncol. 2009;27:2758-2765.
3.
Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J. Clin. Oncol. 2010;28:4621-4629.
4.
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122-1128.
5.
Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.
6.
Pulte D, Gondos A, Brenner H. Improvement in survival of older adults with multiple myeloma: results of an updated period analysis of SEER data. Oncologist. 2011;16:1600-1603.
7.
Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521-2526.
20
Page 20 of 36
8.
Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic. Mayo Clin. Proc. 2010;85:225-230.
9.
Warren JL, Harlan LC, Stevens J, Little RF, Abel GA. Multiple myeloma treatment transformed: a population-based study of changes in initial management approaches in the United States. J. Clin. Oncol. 2013;31:1984-1989.
10.
Attal M, Blaise D, Marit G, et al. Consolidation Treatment of Adult Acute Lymphoblastic-Leukemia - a Prospective, Randomized Trial Comparing Allogeneic Versus Autologous Bone-Marrow Transplantation and Testing the Impact of Recombinant Interleukin-2 after Autologous Bone-Marrow Transplantation. Blood. 1995;86:1619-1628.
11.
Cavo M PA, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). Abstract #8000. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 3, 2016.
12.
Attal M, Lauwers-Cances V, Hulin C, et al. Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Blood. 2015;126.
13.
Wildes TM, Finney JD, Fiala M, et al. High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma. Bone Marrow Transplant. 2015;50:1075-1082.
14.
Wildes TM, Finney JD, Fiala M, et al. High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma. Bone marrow transplantation. 2015;50:1075-1082.
15.
Pasquini MC ZXCuaoohsctCSS, 2015. Available at: http://www.cibmtr.org.
16.
Offidani M, Leoni P, Corvatta L, et al. ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myeloma. Eur. J. Haematol. 2010;84:474-483.
21
Page 21 of 36
17.
Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J. Clin. Oncol. 2014;32:587-600.
18.
Pal SK, Katheria V, Hurria A. Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. CA Cancer J. Clin. 2010;60:120-132.
19.
Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J. Clin. Oncol. 2007;25:1936-1944.
20.
Hamaker ME, Prins MC, Stauder R. The relevance of a geriatric assessment for elderly patients with a haematological malignancy--a systematic review. Leukemia research. 2014;38:275-283.
21.
Hurria A, Togawa K, Mohile S, et al. Predicting Chemotherapy Toxicity in Older Adults and the Importance of Geriatric Assessment Reply. J. Clin. Oncol. 2012;30:561-562.
22.
Bringhen S, Mateos MV, Zweegman S, et al. Age and organ damage correlate with poor survival in myeloma patients: metaanalysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98:980-987.
23.
Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-2074.
24.
Karnakis T, Gattas-Vernaglia IF, Saraiva MD, Gil-Junior LA, Kanaji AL, Jacob-Filho W. The geriatrician's perspective on practical aspects of the multidisciplinary care of older adults with cancer. J. Geriatr. Oncol. 2016.
25.
Caillet P, Paillaud E, Dupuis J. [6/7. Malignant hematological diseases in the elderly]. Soins Gerontol. 2011:45-46.
26.
Hurria A, Cirrincione CT, Muss HB, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:12901296.
22
Page 22 of 36
27.
Hubbard JM, Cohen HJ, Muss HB. Incorporating biomarkers into cancer and aging research. J. Clin. Oncol. 2014;32:26112616.
28.
Walston JD. Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability. Nestle Nutrition Institute workshop series. 2015;83:1-10.
29.
Pustavoitau A, Barodka V, Sharpless NE, et al. Role of senescence marker p16 INK4a measured in peripheral blood Tlymphocytes in predicting length of hospital stay after coronary artery bypass surgery in older adults. Exp. Gerontol. 2016;74:29-36.
30.
Hubbard JM, Jatoi A. Incorporating Biomarkers of Frailty and Senescence in Cancer Therapeutic Trials. J. Gerontol. A Biol. Sci. Med. Sci. 2014.
31.
LeBrasseur NK, Tchkonia T, Kirkland JL. Cellular Senescence and the Biology of Aging, Disease, and Frailty. Nestle Nutrition Institute workshop series. 2015;83:11-18.
32.
Czesnikiewicz-Guzik M, Lee WW, Cui D, et al. T cell subset-specific susceptibility to aging. Clin. Immunol. 2008;127:107-118.
33.
Haynes L, Swain SL. Why aging T cells fail: implications for vaccination. Immunity. 2006;24:663-666.
34.
Effros RB. The role of CD8 T cell replicative senescence in human aging. Discov. Med. 2005;5:293-297.
35.
Lu Y, Tan CT, Nyunt MS, et al. Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies. Oncotarget. 2016.
36.
Fahey JL, Schnelle JF, Boscardin J, et al. Distinct categories of immunologic changes in frail elderly. Mech. Ageing Dev. 2000;115:1-20.
23
Page 23 of 36
37.
Chung DJ, Pronschinske KB, Shyer JA, et al. T Cell Exhaustion/Senescence in Relapsed Multiple Myeloma after Autologous Stem Cell Transplantation. Blood. 2015;126.
38.
Bryant C, Suen H, Brown R, et al. Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood Cancer Journal. 2013;3.
39.
Chen GB, Lustig A, Weng NP. T cell aging: a review of the transcriptional changes determined from genome-wide analysis. Front. Immunol. 2013;4.
40.
Moro-Garcia MA, Alonso-Arias R, Lopez-Larrea C. When aging reaches CD4+T-cells: phenotypic and functional changes. Front. Immunol. 2013;4.
41.
Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30:306-312.
42.
Cao JN, Gollapudi S, Sharman EH, Jia Z, Gupta S. Age-related alterations of gene expression patterns in human CD8+ T cells. Aging cell. 2010;9:19-31.
43.
Owusu C, Cohen HJ, Feng T, et al. Anemia and Functional Disability in Older Adults With Cancer. J. Natl. Compr. Canc. Netw. 2015;13:1233-1239.
44.
Zhang HY, Yang H, Zhang CN, et al. Investigation of MicroRNA Expression in Human Serum During the Aging Process. J Gerontol a-Biol. 2015;70:102-109.
45.
Jazbutyte V, Fiedler J, Kneitz S, et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age. 2013;35:747-762.
46.
Boon RA, Iekushi K, Lechner S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495:107-110.
24
Page 24 of 36
47.
Hatse S, Brouwers B, Dalmasso B, et al. Circulating MicroRNAs as easy-to-measure aging biomarkers in older breast cancer patients: correlation with chronological age but not with fitness/frailty status. PLoS One. 2014;9:e110644.
48.
Milani P, Rajkumar SV, Merlini G, et al. N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma. Am. J. Hematol. 2016.
49.
Rosko AE, Hofmeister CC, Benson D, Efebera YA, Huang Y, Burd C. T-Cell p16(INK4A) Expression Increases PostTransplant in Patients with Multiple Myeloma. Blood. 2014;124.
50.
Sanoff HK, Deal AM, Krishnamurthy J, et al. Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer. Jnci-J Natl Cancer I. 2014;106.
51.
Liu Y, Johnson SM, Fedoriw Y, et al. Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes. Blood. 2011;117:3257-3267.
52.
Melzer D, Frayling TM, Murray A, et al. A common variant of the p16(INK4a) genetic region is associated with physical function in older people. Mech. Ageing Dev. 2007;128:370-377.
53.
Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-1341.
54.
Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491-1493.
55.
Liu Y, Sanoff HK, Cho H, et al. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging cell. 2009;8:439-448.
56.
Zindy F, Soares H, Herzog KH, Morgan J, Sherr CJ, Roussel MF. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ. 1997;8:1139-1150.
25
Page 25 of 36
57.
Ressler S, Bartkova J, Niederegger H, et al. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging cell. 2006;5:379-389.
58.
Rosko A, Hofmeister C, Benson D, et al. Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma. Bone Marrow Transplant. 2015;50:1379-1381.
59.
Juliusson G, Lazarevic V, Horstedt AS, Hagberg O, Hoglund M, Swedish Acute Leukemia Registry G. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119:3890-3899.
60.
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014;371:2488-2498.
61.
Mrozek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J. Clin. Oncol. 2012;30:4515-4523.
62.
Burnett AK, Russell NH, Hills RK, et al. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2016.
63.
Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation2015.
64.
Muffly L, Pasquini MC, Martens M, et al. Increasing Use of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients Age 70 Years and Older: A CIBMTR Study of Trends and Outcomes. Biology of Blood and Marrow Transplant.22:S68-S69.
65.
Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97:1916-1924.
66.
Bower H, Andersson TM, Bjorkholm M, Dickman PW, Lambert PC, Derolf AR. Continued improvement in survival of acute myeloid leukemia patients: an application of the loss in expectation of life. Blood Cancer J. 2016;6:e390.
26
Page 26 of 36
67.
Rashidi A, Ebadi M, Colditz GA, DiPersio JF. Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol. Blood Marrow Transplant. 2016;22:651-657.
68.
Devine SM, Owzar K, Blum W, et al. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J. Clin. Oncol. 2015.
69.
Blaise D, Furst S, Crocchiolo R, et al. Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor. Biol. Blood Marrow Transplant. 2016;22:119-124.
70.
Kasamon YL, Bolanos-Meade J, Prince GT, et al. Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J. Clin. Oncol. 2015;33:3152-3161.
71.
Sandhu KS, Brunstein C, DeFor T, et al. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged >/=70 Years. Biol. Blood Marrow Transplant. 2016;22:390-393.
72.
Horan JT, Logan BR, Agovi-Johnson MA, et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J. Clin. Oncol. 2011;29:805-813.
73.
McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28:1878-1887.
74.
Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874-1883.
27
Page 27 of 36
75.
Versluis J, Hazenberg CL, Passweg JR, et al. Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis. Lancet Haematol. 2015;2:e427-436.
76.
Hurria A, Mohile S, Gajra A, et al. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer. J. Clin. Oncol. 2016;34:2366-2371.
77.
Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:3457-3465.
78.
Brunner AM, Kim HT, Coughlin E, et al. Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Biol. Blood Marrow Transplant. 2013;19:1374-1380.
79.
Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919.
80.
Sorror ML, Logan BR, Zhu X, et al. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol. Blood Marrow Transplant. 2015;21:1479-1487.
81.
Vaughn JE, Storer BE, Armand P, et al. Design and Validation of an Augmented Hematopoietic Cell TransplantationComorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation. Biol. Blood Marrow Transplant. 2015;21:1418-1424.
82.
Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J. Clin. Oncol. 2014;32:3249-3256.
83.
Muffly LS, Kocherginsky M, Stock W, et al. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. Haematologica. 2014;99:1373-1379.
84.
Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121:2854-2863.
28
Page 28 of 36
85.
Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood. 2013;121:2567-2573.
86.
Muffly LS, Boulukos M, Swanson K, et al. Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients. Biol. Blood Marrow Transplant. 2013;19:429434.
87.
Holmes HM, Des Bordes JK, Kebriaei P, et al. Optimal screening for geriatric assessment in older allogeneic hematopoietic cell transplantation candidates. J. Geriatr. Oncol. 2014;5:422-430.
88.
Olin RL, Andreadis C, Martin TG, et al. Comprehensive Geriatric Assessment Identifies Significant Functional Impairments in Older Hematopoietic Cell Transplant Recipients. Biology of Blood and Marrow Transplant.20:S65-S66.
89.
Wood WA, Le-Rademacher J, Syrjala KL, et al. Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer. 2016;122:91-98.
90.
Wood WA, Deal AM, Reeve BB, et al. Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study. Bone Marrow Transplant. 2013;48:1342-1349.
91.
Jones LW, Devlin SM, Maloy MA, et al. Prognostic Importance of Pretransplant Functional Capacity After Allogeneic Hematopoietic Cell Transplantation. Oncologist. 2015;20:1290-1297.
92.
Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J. Clin. Oncol. 2002;20:494-502.
93.
Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121:4287-4294.
29
Page 29 of 36
94.
Cruz M, Covinsky K, Widera EW, Stijacic-Cenzer I, Lee SJ. Predicting 10-year mortality for older adults. JAMA. 2013;309:874-876.
95.
Artz AS, Logan BR, Zhu X, et al. Pre-Transplant C-Reactive Protein (CRP), Ferritin and Albumin As Biomarkers to Predict Transplant Related Mortality (TRM) after Allogeneic Hematopoietic Cell Transplant (HCT). Blood. 2014;124:422-422.
96.
Pasquini MC, Logan B, Wu J, et al. Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Blood. 2015;126:LBA-8LBA-8.
97.
Persoon S, Kersten MJ, van der Weiden K, et al. Effects of exercise in patients treated with stem cell transplantation for a hematologic malignancy: a systematic review and meta-analysis. Cancer Treat. Rev. 2013;39:682-690.
98.
Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311:2387-2396.
99.
By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J. Am. Geriatr. Soc. 2015;63:2227-2246.
100.
Randall J, Keven K, Atli T, Ustun C. Process of allogeneic hematopoietic cell transplantation decision making for older adults. Bone Marrow Transplant. 2016;51:623-628.
101.
Artz AS, Chow S. Hematopoietic cell transplantation in older adults: deciding or decision-making? Bone Marrow Transplant. 2016.
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Figure 1. Allogeneic Transplant Malignant Indications and Change Over Time in the United States Reported to the Center for International Blood and Marrow Transplantation Registry.
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Table 1: Geriatric Evaluation For Older AML Candidacy For Allogeneic Domains Common Tools Comorbidity Hematopoietic cell transplantation-comorbidity index Function
Instrumental activities of daily living Timed up and go, grip strength, 4 meter walk
Social Support and Function
Illness specific subscales of social support (ISSS) Center specific tool Min-mental state examination or Montreal cognitive assessment
Cognition
Psychological
Geriatric depression scale Mental health inventory 17
Nutritional status
Weight loss, body mass index
Polypharmacy
>5 medications
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Transplant Additional Geriatric Questions Remote cancer, urinary problems, visual or hearing impairment, diastolic dysfunction, prior renal impairment, osteoporosis Arthritis, falls, maximum ability for physical activity, exercise, balance Back-up caregiver, alcohol use, stairs at home , person preparing meals, power of attorney Prior confusion, memory impairment and duration Assess retention of information without family member interjection Sleep problems, motivation for transplant, coping skills, preparation for setbacks, life goals (e.g., specific event) Last dental evaluation, dentures, use of supplements, effect of prior therapy on nutrition and weight over the counter medications, side effects from prior medication, clarify remote allergies
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Table 2. Aging and Frailty Assessments Molecular Markers
Immune Dysregulation Heme Parameters Serum markers
Clinical Tools
Aging Frailty X
INK4A
p16
Leukocyte Telomere Length DNA Methylation miRNA Immunosenescence
x
x
x
SASP Anemia IL-6 CRP NT-proBNP Albumin D-dimer TNF sICAM-1 Geriatric Assessment Metrics
x x x x x x
x x x x x x x
x
x x
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Transplant x
Myeloma
x x
x x
x
x x
x
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Table 3: Provisional Framework for Allogeneic Hematopoietic Cell Transplant Eligibility Criteria for Acute Myeloid Leukemia Patients 60 years and Older with Adequate Disease Control Factor Fit Vulnerable Usually Exclude or Trial (All of the below) (Any of the below) (Any of the below) Age < 66 years 66-75 >75 Comorbidity HCT-CI 0-2 HCT-CI 3-5 6+ or severe organ dysfunction KPS (%) Function IADL Performance*
90-100
70-80
<70
Normal No impairment
Any limitation Impaired
Limitations and HCT-CI 4+ Severely limited
Cognitive
No impairment
Other Factors
Normal
Mild cognitive impairment, prior confusion Weight loss, single or limited caregiver, falls, albumin <3.5 g/dL, limited motivation
Moderate cognitive impairment Weight loss, single or limited caregiver, falls, albumin <3.5 g/dL, limited motivation + others
*Performance is measured by timed up and go, 4 meter walk, and grip strength. 6 minute walk used for pre-habilitation baseline HCT-CI, hematopoietic cell transplantion-comorbidity index/sorror index; KPS, Karnofsky performance score; IADL, Lawton instrumental activities of daily living (omitting ability to do laundry)
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Table 4: Standard Optimization Platform For Older Allogeneic Transplant Recipients Utilized at University of Chicago Health Area Standard Optimization Recommendations Geriatric Assessment (GA) Interventions individualized based on GA detected limitations in table 2. Multi-disciplinary team meeting and written optimization plan before transplant. Comorbid conditions Cultivate preferred subspecialists and request post-transplant follow-up. Referral to Geriatrics or Geriatric Oncology for geriatric syndromes (e.g., falls, incontinence) Function Structured pre-habilitation based on baseline activity and limitations. Home safety assessment (fall risk, stairs, proximity of bathroom) Social Support Pre-transplant family meeting, caregiver present during cytopenia and “on-call” if issues. Request secondary caregivers. Enlist caregivers in optimization plan. Cognition Delirium awareness and precautions, medication avoidance, encourage presence of caregivers, add written material to verbal instructions, call patient to reinforce education. Emotional health Offer cognitive therapy and support group to avoid additional medications unless required Nutrition Develop nutritional plan prior to transplant included preferred supplements if used. Medications Reduce unnecessary medications. Re-evaluate day 30 to 100 post-transplant. Other Infection mitigation plan for grand-children, evaluate remote drug allergies (e.g., penicillin allergy in childhood), more frequent followup, smooth survivorship transition from transplant center.
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Figure 1.
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