Older patients with hematological malignancies are increasingly considered for hematopoietic cell transplantation (HCT) . The selection of an appropriate older candidate has historically been based on the clinician’s subjective assessment and the HCT comorbidity index (HCT-CI) [2,3,4]. Recently, comprehensive geriatric assessment (CGA) has emerged as a risk stratification tool for survival outcomes and treatment toxicities in older patients with advanced hematological malignancies [5, 6]. For HCT patients, specific domains of CGA such as instrumental activities of daily living (IADL) and gait speed may predict survival , however, the impact of CGA on transplant decision-making and treatment-related toxicities have not been reported.
In this retrospective study, we identified all patients who were referred to the outpatient geriatrics service prior to a planned HCT from 2011 to 2017 at our institution. Findings from the pre-HCT CGA and clinical, demographic, and outcome data were extracted from the electronic medical record using standard methods. CGA was performed by a member of the geriatrics team according to the published standard for cancer patients  and incorporated a patient-centered assessment in the form of an electronic rapid fitness assessment (eRFA) in the last 2 years . Components of CGA included assessment of basic and instrumental activities of daily living (ADL/IADL); cognition (Montreal cognitive assessment, MoCA); nutrition (mini nutritional assessment, MNA); medication review; fall risk; depression (geriatric depression scale, GDS); and mobility and muscle strength (timed up and go test) [8, 9]. We then systemically collected all grade 3 or higher toxicities according to CTCAE version 4.3 during the peri-transplant period up to day 100 for transplanted patients as described previously [10,11,12]. For patients who did not undergo transplant, we inquired the primary physician and reviewed medical decision-making and subsequent plans of action as documented in the electronic medical record.
In total, 59 geriatric referrals were made during the period, with 51% of them during the last 2 years (30 out of 59). The referrals were based on transplant physicians’ clinical assessment of individual patients, since no standard triggers existed at our institution. After excluding 11 patients with post-HCT referrals, we analyzed a cohort of 48 patients with pretransplant CGA (Table 1). Fifteen patients underwent autologous HCT, 18 patients allogeneic HCT, and 15 patients did not undergo HCT. The main reasons for forgoing HCT in these 15 patients were overall poor performance status/comorbidities (60%), patient decision (27%), and rapid disease relapse/progression (13%). For the 33 patients who underwent transplant, the median number of days from CGA to HCT was 32 (interquartile range, 16.8–48.8). During a median follow-up of 13 months for survivors, 11 patients (9 in the allogeneic group and 2 in the autologous group) died giving an estimated 1-year overall survival of 78% (95% CI, 0.58–0.90), with 91% (95% CI, 0.52–0.99) and 70% (95% CI, 0.42–0.86) for autologous or allogeneic patients, respectively. Day 100 mortality rate was 9% for the whole group. Overall, the causes of death were relapse (n = 5, 45%), sepsis/infection (n = 3, 27%), and graft-versus-host disease (n = 3, 28%). For the 15 patients who did not undergo transplant, the estimated 1-year overall survival was 88% (95% CI, 0.41–0.98) from the date of CGA. All death in this group of patients were from relapse or disease progression (n = 3). Formal statistical comparison among these groups were not performed because of small sample size.
The prevalence of functional impairment and geriatric deficits in this cohort of older patients are summarized in Table 1 (median age, 70.5). Almost half of the patients had impairment in their ADL and IADL. Almost a third of the patients screened positive for cognitive impairment (MoCA score <26/30). The median number of medications were 8.5 with 46% of patients using at least one potentially inappropriate medication (PIM) at the time of HCT, defined by the updated Beers’ criteria from the American Geriatrics Society . The most common ADL impairment was mobility, 81%, which included ambulation and transfer. The most common IADL impairment was patient’s inability to manage own medications (58%). The majority of patients, 87%, had more than one ADL/IADL impairment and deficits. Almost half of the patients were at risk for malnutrition as detected by MNA. Not surprisingly, the group of patients who did not undergo transplant appeared to have more functional impairment and geriatric deficits, although low numbers of patient precluded formal statistical comparison (Table 1). In-depth chart review for this subset of patients revealed that referral physicians had generally taken geriatricians’ recommendations in transplant decision-making, namely, recommending against transplantation for patients with significantly impaired function/high comorbidities. They also had made efforts to improve patients’ geriatric deficits such as intensification of rehabilitation, cognitive therapy, and medication adjustment.
We next examined the outcomes of the 33 patients who underwent allogeneic or autologous HCT (Table 2). The proportions of patients with high-risk HCT-CI were not significantly different while high disease risk index (DRI) patients were exclusively in the allogeneic transplant group. Most allogeneic transplant patients, 89%, had matched related or unrelated donors; and 83% received peripheral blood stem cell grafts, 28% of which were T cell depleted. Most patients, 72%, received reduced-intensity conditioning regimen. Only five patients underwent an ablative regimen using busulfan, melphalan, and fludarabine and a T-cell-depleted graft in the context of a clinical trial . For autologous transplant patients, the conditioning regimens included mephalan (200 or 140 mg/m2), 60%, and BEAM (BCNU, etoposide, cytarabine, mephalan) or TBC (thiotepa, busulfan, cyclophosphamide)-based regimen, 40%. For the overall cohort, significantly more death occurred in patients who underwent allogeneic transplantation (Table 2). For the entire study population, there were 168 individually graded toxicities (≥3) in the peri-transplant period with a median number of 4. Metabolic toxicities accounted for 24% of all toxicities, with electrolyte abnormalities as the leading cause (33%). Twenty percent of all toxicities were infectious, which included febrile neutropenia with or without an identified source as the leading cause (21%). Cardiovascular toxicities accounted for 13% of all toxicities, with hypertension as the leading diagnosis (61%). As expected, patients who underwent allogeneic transplant had higher median numbers of toxicities, 8, than patients who received an autologous transplant, 2 (p = 0.003, Table 2).
This study reveals several notable findings. First, we note that the number of geriatrics referrals was low at our institution considering that more than 50 patients older than age 60 are transplanted yearly at our center. This may reflect the lack of well conducted, multi-center prospective studies documenting its utility, leaving such referrals to the discretion of transplant physicians and the availability of local resources. In addition, the culture of integrating geriatrics into HCT care maybe suboptimal at our institution, where top geriatrics referrals have been from the medical and gynecology oncology services. Interestingly, even with such a small cohort, it appears that geriatrics referral and CGA may have influenced the transplant decision-making process based on discussions and review of physician documentations in patients who did not proceed to transplantation. Documented interventions based on CGA included medication adjustment, intensification of physical and occupational therapy, referral to neuropsychology for formal neuropsychiatric testing, and nutritional counseling. These observations require additional investigation, for example, through conduction of national surveys of transplant physicians. Second, our cohort, with a median age over 70 and a higher prevalence of functional impairment and geriatric deficits in ADL, IADL, nutrition, and cognition, is a much older, frailer patient population than what has been published previously using CGA in HCT patients [7, 15,16,17]. In fact, the level of deficits is similar to the pre-surgical geriatric assessment patients in their 80s at our institution. These results suggest that our transplant physicians may have already pre-screened the larger group of older candidates. Interestingly, there is no formal trigger of geriatrics consult at our institution, and survey of our transplant physicians has not identified any uniformed criteria for screening and referral of older adults. Some physicians utilized age cutoff of 65–70, while others used high comorbidities, or intuition and subjective clinical assessment. In addition, there was no set standard of how to utilize information from CGA, and based on chart reviews, there were variable levels of changes made based on CGA. We are in the process of developing institutional guideline and designing survey instruments for the broader transplant community. Finally, our comprehensive analysis of toxicities reveals that this cohort of older patients, especially those underwent allogeneic transplant, suffered from a higher rate of grade 3 or higher organ toxicities and complications with a median of 8 during the peri-transplant period despite using mostly reduced-intensity conditioning regimen and/or T-cell-depleted graft. Previous studies from our institution have demonstrated a median of 6 grade 3 or higher organ toxicities in older allogeneic transplant patients [10,11,12, 18]. Since peri-transplant toxicities are correlated with survival outcomes, this group of patients could benefit from intensive geriatrics supportive care and meticulous management of comorbidities and organ toxicities [10,11,12].
Our study has several limitations. First, it is a retrospective, single institution study with small sample size, which limits our ability to perform multivariable analyses on survival outcomes and toxicities. Second, detailed information on how exactly physicians utilized CGA findings to guide transplant decision-making for each individual patient is unclear. Third, the small sample size and relatively short follow-up period does not allow us to examine the contribution of individual geriatric assessment domains to survival and toxicity outcomes. Finally, there is likely an intrinsic bias associated with our findings, since these patients were pre-selected by transplant physicians for geriatric evaluation thus may not represent the general older transplant patients. Despite these limitations, our results add to the growing literature on the use of CGA to identify geriatric vulnerabilities prior to HCT and to predict transplant outcomes and toxicities. Moreover, the significant functional, cognitive, and nutritional deficits identified suggest that all older patients could potentially benefit from CGA-based screening pre-HCT, and multidisciplinary care in collaboration with the geriatrics service for frail elders. Prospective studies are needed to address this question, as well as the impact of potential interventions designed for individual geriatric syndromes such as functional impairments or increased risk for malnutrition before HCT . Innovative models for integrating geriatrics supportive care into routine transplant care such as co-localized clinics, an inpatient consult service, or a co-rounding model, should also be evaluated as means to improve the quality and the value of transplant care, in manners similar to the integration of oncology and palliative supportive care .
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This research was supported in part by the New York State Empire Clinical Research Investigator Program (ECRIP) and the NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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The authors declare that they have no conflict of interest.
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Lin, R.J., Shahrokni, A., Dahi, P.B. et al. Pretransplant comprehensive geriatric assessment in hematopoietic cell transplantation: a single center experience. Bone Marrow Transplant 53, 1184–1187 (2018). https://doi.org/10.1038/s41409-018-0151-3
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