Abstract
Background:
Allogeneic hematopoietic cell transplantation (HCT) survivors may benefit from routine screening for post-transplant complications. However, the impact of formal survivorship efforts to promote screening adherence is uncertain.
Objective:
Evaluate the effect of a formal HCT Survivorship Program to promote screening adherence
Methods:
We conducted a retrospective analysis of an academic formal HCT Survivorship Program with primary and specialty consult components. We included patients who underwent allogeneic HCT and were alive and relapse-free 1-year post-HCT. We excluded patients who died <2 years post-HCT or transferred care. We measured screening adherence to cardiovascular, pulmonary, ocular, secondary cancer, and endocrine evaluations. The primary outcome was proportion of patients completing ≥1 evaluation per screening domain prior to 2 years post-HCT. We examined screening adherence during 3 time periods: pre-survivorship (2012–2014) and 2 post survivorship (2016–2018, 2019–2021) using multivariate logistic and Cox proportional hazards regression.
Results:
410 patients (2012–2014: n=136, 2016–2018: n=153, 2019–2021: n=121) were included. Compared to the pre-survivorship period (16.9%), patients in 2016–2018 (47.7%, OR=4.9, p<0.0001) and 2019–2021 (34.7%, OR=2.7, p=0.001) were more likely to complete ≥1 evaluation per screening domain. Except for pulmonary function tests in 2019–2021, median time to completion of survivorship evaluations was shorter in the survivorship periods compared to pre-survivorship. Patients who completed a formal HCT survivorship consult in 2016–2018 and 2019–2021 were more likely to complete ≥1 evaluation per screening domain (OR=5.1, p=0.0004). Survivorship consult had similar effect on the primary screening outcome in 2016 – 2018 and 2019 – 2021 (consult*time interaction OR: 2.5, p=0.2). However, patients who received a consult in 2019–2021 were more likely to complete all screenings (consult*time interaction: OR=5.7, p=0.03).
Discussion:
Our HCT Survivorship Program with primary and specialty components improved screening adherence. Additional studies are needed to evaluate efficacy, dissemination, and implementation of formal HCT survivorship programs.
Keywords: Allogeneic hematopoietic cell transplantation, survivorship, screenings, GVHD, cardiovascular health, bone health
Graphical Abstract
Background
Advances in the treatment of hematologic malignancies, allogeneic hematopoietic cell transplantation (HCT), and supportive care continue to improve post-HCT outcomes, and the number of long-term HCT survivors in the past decade has dramatically increased.1,2 With improved post-HCT survival, it is increasingly important to consider late-treatment effects from chemotherapy and/or radiation and chronic graft-vs-host disease (GVHD) which may lead to decrements in quality of life (QOL) and survival,3–5 especially since life expectancy post-HCT remains lower than that of the general population.2 Allogeneic HCT survivors are at increased risk of cardiovascular disease,6 secondary malignancy,7,8 endocrine dysfunction, and osteoporosis and associated fragility fractures which dramatically compromise their QOL and survival.3,9
Survivorship care reduces the morbidity and mortality of late HCT effects through routine early preventative care and systematic long-term follow-up.10 Hence, several international HCT organizations (e.g., American Society for Transplantation and Cellular Therapies (ASTCT)) have issued consensus guidelines on routine screening for HCT survivors including counseling, clinical exams, and screening labs and diagnostic imaging.10–16 In addition, HCT providers are encouraged to develop individualized care plans based on patient’s goals, treatment exposures, and risk of late effects.17 Crafting and implementing a HCT survivorship care plan often requires the interdisciplinary collaboration of multiple specialists beyond the HCT team including primary care, oncology and subspecialties such as cardiology, endocrinology, and ophthalmology.5 However, many barriers including the complexity of HCT survivor needs and lack of clarity on responsibility for survivorship care preclude routine use of HCT survivorship care plans.18 In addition, current care models pose challenges for patients and HCT providers as adherence to current HCT survivorship guidelines for screening may require up to 34 additional visits annually.11,12 Lack of medical specialists, limited funding, and low patient/provider interest further limit much needed quality post-HCT survivorship care.19,20
Although the ASTCT Practice Guidelines Committee recommends long-term follow-up clinics dedicated to survivorship care,15,16,19 data on the optimal survivorship care models which patients and clinicians can consistently adhere to are lacking. While hybrid shared care model between HCT specialists and primary care providers is an alternative to the ASTCT recommendation,19,21–23 some cancer centers have established disease-agnostic survivorship clinics.24 Further, some HCT programs have developed consultative survivorship models, in which dedicated survivorship teams may be involved at set time points in a patient’s care to provide counseling and recommendations to the primary HCT team.25 However, there are limited data on the efficacy of these different models to promote adherence to the recommended comprehensive medical evaluations and screenings essential for HCT survivors.
For this analysis, we evaluated the effects of a single center’s post-HCT survivorship program on recommended post-HCT survivorship medical screening evaluations. We hypothesized that our formal HCT Survivorship Program would increase adherence to key survivorship screening metrics in cardiovascular health, chronic GVHD screenings including pulmonary function tests (PFTs) and formal corneal exams, bone and endocrine health, and secondary cancer screenings.
Methods
Study Design
We conducted a retrospective study of an HCT Survivorship Program at an academic center. The study was conducted from October 2022 – September 2023 and was approved by the Dana-Farber Harvard Cancer Center IRB.
Inclusion/exclusion criteria
We examined three time periods: a Pre-survivorship baseline period (July 1, 2012- December 30, 2014) and two post survivorship periods (July 1, 2016- December 31, 2018 and July 1, 2019- June 30, 2021) to evaluate initial and sustained effects of the formal Survivorship program. We aimed to assemble a cohort of HCT survivors eligible for a 1 year survivorship consultation and alive for 1 year of subsequent follow-up. Accordingly, for each study period, we included patients who underwent allogeneic HCT during the study period and were alive at 1-year post-HCT without disease relapse. In cases where patients underwent multiple HCTs, the latest transplant was selected as the reference point to evaluate survivorship metrics. We excluded patients who died prior to 2 years post-HCT or transferred their care to another HCT center. To minimize exposure to the formal Survivorship Program in the “Pre-Survivorship” cohort, we did not include patients undergoing HCT in 2015 as formal Survivorship programming would have likely influenced Survivorship care.
The MGH HCT Survivorship Program
The Massachusetts General Hospital (MGH) HCT Survivorship Program was formally established in 2016 and includes specialty HCT clinicians with expertise in survivorship including one physician, one nurse practitioner, and one licensed clinical social worker. Prior to 2016, survivorship care was done at the discretion of individual HCT clinicians, and there was no formal survivorship care model. The clinicians of the HCT Survivorship program delivered medical and psychosocial consultations for HCT recipients and ongoing education for primary clinicians in the HCT program. The Survivorship Program provided educational material on pertinent survivorship medical screenings, semi-annual educational lectures on survivorship topics, and resources for clinical care including such as Electronic Health Record (EHR) smart phrases to primary HCT clinicians. Figure 1 displays timepoints of HCT Survivorship Program Interventions.
Figure 1.
Timeline and components of survivorship care in the HCT Survivorship Program
Around day 100 post-HCT, a primary HCT nurse practitioner conducted a formal embedded outpatient survivorship visit to assess initial survivorship needs, to initiate and follow-up on recommended screenings, to offer guidance on lifestyle modifications, and to provide education on chronic GVHD If patients were still recovering from acute toxicities or remained inpatient, the timing of the day 100 visit was delayed at the discretion of the primary HCT team. In this cohort, all patients in the Survivorship study periods received a formal outpatient day 100 Survivorship visit. Following the day 100 visit, the primary HCT team continued to address survivorship needs, to ensure completion of recommended screenings, to follow-up study results, and to coordinate ongoing management and surveillance as part of routine post-HCT outpatient care (Figure 1, “blue arrows”). HCT clinicians tracked systematic completion of survivorship screenings using comprehensive EHR templates and smartphrases. At one year post-HCT, patients without evidence of relapsed hematologic malignancy were eligible to participate in a comprehensive survivorship consultation. However, patients were not required to complete this consultation visit. During the consult visit, a survivorship-focused HCT clinician evaluated patients. If complex survivorship needs were identified during this visit, patients were referred for additional subspecialty care (i.e., Cardiology, Endocrinology, Ophthalmology, Psychology/Psychiatry, etc.). At the end of the consultation, the HCT clinician provided an individualized survivorship care plan to the patient, primary HCT team, and primary care physician. The care plan included the patient’s medical teams, summarized prior oncology treatments, the HCT regimen, and HCT complications including GVHD, and provided personalized healthcare maintenance recommendations on topics including GVHD monitoring, cardiovascular health, endocrine health, and secondary cancer screening. The COVID-19 pandemic led to an interruption of one-year post-HCT survivorship consultations from March to November 2020. During the pandemic, the day 100 survivorship visits and ongoing survivorship education sessions continued to occur.
Study measures
Two study investigators measured adherence to medical screenings using the EHR and based on clinical experience and ASTCT guidelines classified screenings as cardiovascular (screening for diabetes with hemoglobin A1c and hyperlipidemia with lipid profile), pulmonary (pulmonary function testing – PFT with spirometry, lung volumes, and diffusion capacity), ocular (ophthalmologic exam), cancer (documentation of cancer screening plan and/or completion of secondary cancer screenings such as annual skin and oral exams, mammography, or colonoscopy), and endocrine (evaluation of Vitamin D levels and thyroid stimulating hormone, screening for iron overload, and completion of bone density scan). Dates of screenings were recorded and the months from transplant day 0 to screening completion were calculated. Survivorship metrics for individual measures and domains were recorded as dichotomous variables signifying completion of screening evaluation within 2 years of HCT. In addition, an indicator variable was created to indicate completion of a survivorship consult within two years post-HCT.
Our primary outcome was proportion of patients completing ≥1 evaluation per screening domain prior to 2 years post-HCT. Secondary outcomes included proportion of patients completing all recommended screening evaluations prior to 2 years post-HCT and median months from transplant to screening evaluation completion. We additionally assessed months to individual survivorship screening evaluation within two years of HCT. In the calculation of proportions for primary and secondary outcomes, we considered all study patients eligible for screenings and included them in the denominator. In the calculation of proportion of patients completing mammograms, we included patients eligible for breast cancer screening in the denominator (female and aged ≥ 50 years or had received a conditioning regimen with total body irradiation).
We additionally collected patient demographics (including age, race, ethnicity, and gender), clinical data (including diagnosis, donor, conditioning regimen, graft-versus-host disease [GVHD] prophylaxis, Hematopoietic Cell Transplantation-specific Comorbidity Index [HCT-CI], development of acute or chronic GVHD within two years post-HCT, and relapse after one year post-HCT.
Statistical Analysis
We calculated descriptive statistics, including means or medians for continuous variables and proportions for categorical variables. Differences in demographic and clinical characteristics of patients over the study period were assessed using ANOVA and chi square tests for continuous and categorical variables, respectively. Characteristics that changed significantly over time (e.g., donor type, GVHD prophylaxis regimen, and HCT-CI score) were included as covariates for multivariate logistic regression when examining study outcomes.
To evaluate the effect of the MGH HCT Survivorship Program, we conducted chi-squared tests to evaluate the association of individual screening completion and study period. We used multivariate logistic regression to assess the association between study period and completion of at least one screening evaluation per domain controlling for HCT-CI score, donor type, and GVHD prophylaxis regimen. The pre-survivorship period (2012–2014) served as the reference group.
We used univariate logistic regression to assess the association between study period and the completion of all screening evaluations. Given small number of patients who received all evaluations across study periods, we confined this analysis to univariate regression only. Finally, we used Cox Proportional Hazard regression to evaluate differences in time to individual screening evaluation completion by the study period, controlling for HCT-CI score, donor type, and GVHD prophylaxis regimen. As follow-up to 2 year post-HCT was complete for the study cohort, no patients were censored in survival analyses.
To evaluate the effect of the one-year HCT Survivorship Consult, we used univariate logistic regression to evaluate the association of a survivorship consult on study outcomes during the post-survivorship time periods (2016–2018, 2019–2021). To evaluate change in the effect of HCT survivorship consult over time, we included an interaction term of survivorship consult-by-study-period. Due to sample size limitations, we used univariate regression models.
P values were 2-sided and a threshold of < 0.05 was considered statistically significant. All analyses were performed using R software (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria).
Results
Figure 2 displays the study flow diagram. 410 patients were included in final analyses (Pre-Survivorship: n=136, Post-Survivorship 2016–2018: n=153, Post-Survivorship 2019–2021: n=121). Table 1 lists the demographic and clinical characteristics of the study population across time periods. HCT survivors were predominantly White (n=349, 85.1%), male (n=245, 59.8%), underwent HCT for acute leukemia (n=202, 49.3), and received reduced intensity conditioning (n=297, 72.4%). Mean HCT-CI score (1.4 vs 2.2 vs 1.7, p=0.001), HCT donor type (p=0.01), and use of posttransplant cyclophosphamide (PTCy) as GVHD prophylaxis (8.8% vs 26.1% vs 28.9%, p<0.0001) were significantly different across study periods. Survivorship screening evaluation outcomes by study period
Figure 2.
Study flow diagram
HCT: allogeneic hematopoietic cell transplantation, NRM: non-relapse mortality, LTFU: lost to follow-up
Table 1.
Patient characteristics by study period
| Pre-Survivorship (N=136) | Post-Survivorship 2016–201(N=153) | Post-Survivorship 2019–2021 (N=121) | P-value | |
|---|---|---|---|---|
|
| ||||
| Age at transplant | ||||
| Mean years (SD) | 53.8 (15.1) | 56.1 (14.5) | 57.3 (15.7) | 0.17 |
|
| ||||
| Gender | ||||
| Male | 77 (56.6%) | 91 (59.5%) | 77 (63.6%) | 0.42 |
| Female | 59 (43.4%) | 62 (40.5%) | 43 (35.5%) | |
| Other | 0 (0%) | 0 (0%) | 1 (0.8%) | |
|
| ||||
| Race | ||||
| White | 119 (87.5%) | 130 (85.0%) | 100 (82.6%) | 0.41 |
| Black | 0 (0%) | 8 (5.2%) | 4 (3.3%) | |
| Asian | 4 (2.9%) | 3 (2.0%) | 7 (5.8%) | |
| American Indian/Alaskan | 0 (0%) | 1 (0.7%) | 0 (0%) | |
| Native Other | 13 (9.6%) | 11 (7.2%) | 10 (8.3%) | |
|
| ||||
| Ethnicity | ||||
| Non-Hispanic | 127 (93.4%) | 143 (93.5%) | 116 (95.9%) | 0.63 |
| Hispanic | 9 (6.6%) | 10 (6.5%) | 5 (4.1%) | |
|
| ||||
| Diagnosis | ||||
| Acute Leukemia | 66 (48.5%) | 77 (50.3%) | 59 (48.8%) | 0.77 |
| MDS/MPN | 30 (22.1%) | 45 (29.4%) | 33 (27.3%) | |
| Lymphoma | 25 (18.4%) | 21 (13.7%) | 17 (14.0%) | |
| Myeloma | 2 (1.5%) | 1 (0.7%) | 0 (0%) | |
| Aplastic Anemia | 8 (5.9%) | 6 (3.9%) | 7 (5.8%) | |
| Other | 5 (3.7%) | 3 (2.0%) | 5 (4.1%) | |
|
| ||||
| Cell Source | ||||
| PBSC | 116 (85.3%) | 130 (85.0%) | 104 (86.0%) | 0.009 |
| BM | 14 (10.3%) | 23 (15.0%) | 17 (14.0%) | |
| Cord | 6 (4.4%) | 0 (0%) | 0 (0%) | |
|
| ||||
| Donor type | ||||
| MRD | 38 (27.9%) | 39 (25.5%) | 23 (19.0%) | 0.018 |
| MUD | 67 (49.3%) | 78 (51.0%) | 72 (59.5%) | |
| Haploidentical | 13 (9.6%) | 24 (15.7%) | 18 (14.9%) | |
| MMUD | 12 (8.8%) | 12 (7.8%) | 8 (6.6%) | |
| Cord | 6 (4.4%) | 0 (0%) | 0 (0%) | |
|
| ||||
| Conditioning intensity | ||||
| RIC | 97 (71.3%) | 104 (68.0%) | 96 (79.3%) | 0.11 |
| MAC | 39 (28.7%) | 49 (32.0%) | 25 (20.7%) | |
|
| ||||
| GVHD prophylaxis | ||||
| MTX/CNI | 100 (73.5%) | 99 (64.7%) | 85 (70.2%) | <0.0001 |
| PTCy-based | 12 (8.8%) | 40 (26.1%) | 35 (28.9%) | |
| Other | 24 (17.6%) | 14 (9.2%) | 1 (0.8%) | |
|
| ||||
| HCTCI | ||||
| Mean (SD) | 1.4 (1.7) | 2.2 (2.1) | 1.7 (1.7) | 0.001 |
|
| ||||
| Any acute GVHD | 60 (44.1%) | 68 (44.4%) | 43 (35.5%) | 0.26 |
|
| ||||
| Any chronic GVHD | 97 (71.3%) | 117 (76.5%) | 80 (66.1%) | 0.17 |
|
| ||||
| Relapse post-1 year | 1 (0.7%) | 5 (3.3%) | 4 (3.3%) | 0.29 |
MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; BM: bone marrow; PBSC: peripheral blood stem cell; RIC: reduced intensity conditioning; MAC: myeloablative conditioning; MTX/CNI: methotrexate/calcineurin inhibitor; PTCy: posttransplant cyclophosphamide; MRD: matched related donor; MUD: matched unrelated donor; MMUD: mismatched unrelated donor; GVHD: graft-versus-host disease; HCTCI: hematopoietic cell transplantation-comorbidity index.
Figure 3 displays the proportion of patients receiving all survivorship screenings per domain within 2 years post-HCT. Table 2 displays completion of individual survivorship screenings by domain across study time periods. After implementation of the HCT Survivorship Program, a higher proportion of patients completed formal corneal exams (55.9% vs. 76.5% vs. 73.6%, p=0.0003), and completed bone density exams (30.9% vs. 75.8% vs. 61.2%, p<0.0001). In addition, the proportion of patients with documented secondary cancer screening plan or completion of secondary cancer screenings increased with the HCT Survivorship program (33.1% vs 65.4% vs. 53.7%, p<0.0001). Among patients eligible for breast cancer screening, the proportion of patients completing mammogram (26.4% vs 53.9% vs 45.7%, p =0.014) increased after implantation of the Survivorship Program. The proportion of patients completing recommended endocrine and cardiovascular screenings increased after implementation of the Survivorship Program (Table 2). The proportion of patients completing PFTs decreased in the second survivorship period, 2019–2021 (80.9% vs. 81.7% vs. 56.2%, p<0.0001), likely owing to decreased availability resulting from the COVID-19 pandemic. Supplementary Figure 1 displays a quarterly breakdown of PFT completion in the second survivorship period (July 2019 – June 2021).
Figure 3.
Proportion of patients completing all individual survivorship screenings per domain by study period. Screening domains: Pulmonary (Pulm) = pulmonary function test, Cancer screen = documented discussion or completion of secondary cancer screening, Endocrine = laboratory evaluation of vitamin D, thyroid function, iron panel, and bone density scan, Cardiovascular (CV) = cholesterol and diabetes screening.
Table 2.
Proportions of Patients Completing Survivorship Screening Over Time
| Pre-Survivorship (N=136) | Post-Survivorship 2016–2018 (N=153) | Post-Survivorship 2019–2021 (N=121) | P-value | |
|---|---|---|---|---|
|
| ||||
| PFTs | 110 (80.9%) | 125 (81.7%) | 68 (56.2%) | <0.0001 |
| Corneal exam | 76 (55.9%) | 117 (76.5%) | 89 (73.6%) | 0.0003 |
| Cancer screening * | 45 (33.1%) | 100 (65.4%) | 65 (53.7%) | <0.0001 |
| Mammogram | 14/53 (26.4%) | 28/52 (53.9%) | 16/35 (45.7%) | 0.014 |
| Endocrine (All) | 37 (27.2%) | 111 (72.5%) | 70 (57.9%) | <0.0001 |
| Vitamin D | 122 (89.7%) | 149 (97.4%) | 116 (95.9%) | 0.01 |
| TSH | 132 (97.1%) | 151 (98.7%) | 117 (96.7%) | 0.51 |
| Iron panel | 103 (75.7%) | 146 (95.4%) | 119 (98.3%) | <0.0001 |
| Bone density | 42 (30.9%) | 116 (75.8%) | 74 (61.2%) | <0.0001 |
| Cardiovascular (All) | 64 (47.1%) | 125 (81.7%) | 109 (90.1%) | <0.0001 |
| Lipid panel | 84 (61.8%) | 146 (95.4%) | 112 (92.6%) | <0.0001 |
| HgA1c | 79 (58.1%) | 127 (83.0%) | 115 (95.0%) | <0.0001 |
| ≥1 screening measure per domain | 23 (16.9%) | 73 (47.7%) | 42 (34.7%) | <0.0001 |
| All screening | 13 (9.6%) | 54 (35.3%) | 28 (23.1%) | <0.0001 |
PFT: pulmonary function test; TSH: thyroid stimulating hormone; HgA1c: hemoglobin A1c
Documentation of cancer screening plan and/or completion of skin exam, oral exam, mammography, or colonoscopy
Composite outcomes of survivorship screening by study period
After implementation of the HCT Survivorship Program, a higher proportion of patients received at least one screening evaluation per domain (16.9% vs. 47.7% vs 34.7%, p < 0.0001). In multivariate analyses controlling for comorbidity index, HCT donor type, and GVHD prophylaxis regimen, patients in post-survivorship periods 2016–2018 (odds ratio [OR] = 4.91, confidence interval [CI]: 2.78–8.93, p < 0.001) and 2019–2021 (OR = 2.73, CI: 1.48–5.12, p = 0.001) were more likely to receive at least one survivorship screening evaluation in each survivorship domain compared to patients in the pre-Survivorship period. Similarly, patients in Post-Survivorship periods 2016–2018 (35.3%, OR = 5.16, CI: 2.74–10.37, p < 0.001) and 2019–2021 (23.1%, OR = 2.85, CI: 1.42–5.97, p = 0.004) were more likely to receive all survivorship screening evaluations compared to patients in the pre-survivorship era (9.6%).
Time to screening evaluations by study period
Table 3 displays median time to survivorship screenings in the Survivorship periods compared to the time to screenings in in the pre-Survivorship period (Table 3). Patients in the Survivorship study periods were more likely to receive corneal exams, documented cancer screening plans, screening mammography, bone density scans, and laboratory evaluations including Vitamin D, iron panel, lipid panel, and hemoglobin A1c within 2 years of HCT and had significantly shorter median time to screening evaluation (Table 3). On the other hand, while there was no difference in median time to PFTs between 2012–2014 and 2016–2018, the median time to PFTs from 2019 – 2021 was significantly longer (18 vs 12 months; HR 0.5; CI 0.4–0.7). There was no difference in time to TSH in the post-survivorship 2016–2018 (median = 4 months; HR = 1.3, CI: 1.0–1.6, p = 0.08) and 2019–2021 periods (median = 3 months; HR = 1.2, CI: 0.9–1.6, p = 0.14) as compared to pre-survivorship (median = 5.5 months). Figure 4 demonstrates incidence curves of screenings by study period.
Table 3.
Median time (months after allogeneic hematopoietic cell transplantation) to medical survivorship evaluation by study period. 95% confidence interval and p-values generated from Cox proportional hazard models controlling for comorbidity index, donor type, and GVHD prophylaxis regimen. Reference time period is Pre-Survivorship era (2012 – 2014)
| Pre-Survivorship 2012 – 2014 | Post Survivorship 2016 – 2018 | Post Survivorship 2019 – 2021 | |||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| Evaluation | Median months (CI) | Median months (CI) | HR (CI) | P-value | Median months (CI) | HR (CI) | P-value |
| PFTs | 12 (11, 13) | 9 (7, 11) | 1.2 (0.9, 1.6) | 0.2 | 18 (15, NR) | 0.5 (0.4, 0.7) | <0.001 |
|
| |||||||
| Corneal exam | 17 (12, NR) | 8 (7, 10) | 2.0 (1.5, 2.7) | <0.001 | 11 (9,13) | 1.6 (1.1, 2.2) | 0.007 |
|
| |||||||
| Cancer screening* Mammogram | NR NR |
13 (12, 18) 21 (17, NR) |
2.9 (2.0, 4.2) 2.2 (1.2, 4.2) |
<0.001 0.02 |
23 (16, NR) NR |
1.9 (1.2, 2.8) 2.0 (0.9, 4.1) |
0.003 0.06 |
|
| |||||||
| Bone density scan | NR | 11 (10,12) | 4.5 (3.1, 6.5) | <0.001 | 15 (13, 20) | 2.7 (1.8, 4.0) | <0.001 |
|
| |||||||
| Vitamin D level | 8 (6, 11) | 3 (3, 4) | 2.1 (1.6, 2.7) | <0.001 | 3 (3, 3) | 2.7 (2.0, 3.5) | <0.001 |
|
| |||||||
| Thyroid evaluation | 5.5 (3, 6) | 4 (3, 5) | 1.3 (1.0, 1.6) | 0.08 | 3 (3, 5) | 1.2 (0.9, 1.6) | 0.1 |
|
| |||||||
| Iron overload evaluation | 11 (11, 12) | 6 (5, 7) | 2.1 (1.6, 2.7) | <0.001 | 5 (4, 6) | 2.6 (1.9, 3.4) | <0.001 |
|
| |||||||
| Lipid panel | 16 (13, 24) | 6 (5, 9) | 3.5 (2.6, 4.6) | <0.001 | 6 (6, 7) | 3.1 (2.3, 4.2) | <0.001 |
|
| |||||||
| Diabetes screen | 23 (19, NR) | 9 (7,11) | 2.3 (1.7, 3.1) | <0.001 | 6 (4, 6) | 4.1 (3.0, 5.7) | <0.001 |
HR: hazard ratio; CI: confidence interval; NR: not reached; PFTs: pulmonary function test
Documentation of cancer screening plan and/or completion of skin exam, oral exam, mammography, or colonoscopy
Figure 4.
Incidence curves of completion of individual survivorship screenings by study period
Effect of Survivorship Consultation 1-year post-HCT on completion of screening evaluations
During the Survivorship study periods, 19% (52/274) of patients completed a dedicated Survivorship consult prior to 2 years post-HCT. Patients receiving survivorship consults did not have significant differences in sociodemographic, clinical, and HCT characteristics compared to those who did not receive a 1 year consultation (Supplementary Table 1). Table 4 compares individual screening evaluation completion at 2 years post-HCT between patients who completed a formal Survivorship Consultation at 1 year post-HCT and those who did not. Overall, patients who completed a 1-year survivorship consult were more likely to complete at least one screening evaluation per domain (p < 0.0001) and complete all recommended screenings (p < 0.0001). 1-year survivorship consultation was associated with a higher proportion of patients undergoing PFTs (p = 0.0002) and having a documented cancer screening discussion (p < 0.0001). There were no statistical differences in proportion completing corneal exams (p = 0.054), endocrine screenings (p = 0.48) or cardiovascular screenings (p = 0.36). Figure 5 displays the timing of completion of individual screenings after receipt of a survivorship consult in the post-survivorship study periods. While many patients had completed cardiovascular and endocrine screenings prior to consultation, initiation of secondary cancer screenings (+51.4%) and completion of pulmonary function tests (+15.4%) often occurred after the consult visit.
Table 4.
Proportion of patients completing survivorship screenings by receipt of formal survivorship consult in the Survivorship study periods (2016–2018 and 2019 – 2021)
| Screening Evaluation | No Survivorship Consult (N=222) | Survivorship Consult (N=52) | P-value |
|---|---|---|---|
|
| |||
| PFT | 145 (65.3%) | 48 (92.3%) | 0.0002 |
|
| |||
| Corneal exam | 161 (72.5%) | 45 (86.5%) | 0.054 |
|
| |||
| Cancer screening * | 114 (51.4%) | 51 (98.1%) | <0.0001 |
|
| |||
| Endocrine (All) | 144 (64.9%) | 37 (71.2%) | 0.48 |
| Vitamin D | 214 (96.4%) | 51 (98.1%) | 0.86 |
| TSH | 216 (97.3%) | 52 (100%) | 0.50 |
| Iron panel | 215 (96.8%) | 50 (96.2%) | 1.00 |
| Bone density | 151 (68.0%) | 39 (75.0%) | 0.41 |
|
| |||
| Cardiovascular (All) | 187 (84.2%) | 47 (90.4%) | 0.36 |
| Lipid panel | 208 (93.7%) | 50 (96.2%) | 0.72 |
| A1c | 194 (87.4%) | 48 (92.3%) | 0.45 |
|
| |||
| At least one screening measure by domain | 74 (33.3%) | 41 (78.8%) | <0.0001 |
|
| |||
| All screening | 53 (23.9%) | 29 (55.8%) | <0.0001 |
PFT: pulmonary function test; TSH: thyroid stimulating hormone; HgA1c: hemoglobin A1c
Documentation of cancer screening plan and/or completion of skin exam, oral exam, mammography, or colonoscopy
Figure 5.
Proportion of patients completing individual medical screenings before and after receipt of survivorship consult in the survivorship study periods (2016–2018 and 2019–2021). Analyses limited to patients receiving survivorship consult prior to 2 years after HCT (n=52).
Completion of a survivorship consult had a similar effect in 2016–2018 and 2019–2021 on the likelihood of obtaining at least one recommended screen per survivorship domain (consult*time interaction term: OR = 2.50, CI: 0.57–11.97, p = 0.23). However, patients receiving a survivorship consult in the second survivorship period (2019–2021) were more likely to undergo all recommended screening evaluations. (consult*time interaction term: OR = 3.91, CI: 1.07–14.87, p = 0.04).
Discussion
In this retrospective analysis of the effects of a single academic center’s formal HCT Survivorship Program, we demonstrated the survivorship program was associated with increased adoption and timely completion of recommended GVHD, cardiovascular, endocrine, and secondary cancer screenings within 2 years of HCT. In addition, the presence of the HCT Survivorship Program was associated with a shortened time to completion of many recommended screenings. Adherence to screening evaluations decreased from 2019–2021 – particularly post-HCT PFTs. This decrease in adherence is most likely attributed to decreased availability of screening tests such as PFTs and bone density exams during the COVID-19 pandemic. While only a minority of patients received a dedicated survivorship consult, receipt of this consult was associated with increased likelihood of screening adherence particularly to initiation of secondary cancer screening, and this benefit was higher from 2019–2021.
To the authors’ knowledge, this is one of the first studies to demonstrate the positive effect of a formal HCT survivorship program on adherence to recommended chronic GVHD, cardiovascular, endocrine, and secondary cancer screening evaluations. Our survivorship program was associated with a substantial increase in adherence to recommended medical screenings and was clearly superior to usual ad hoc post-HCT survivorship care. While HCT guideline committees universally recommend the need for late-effects surveillance,10,12,15,16,19 practical and effective implementation remains challenging. In a recent evaluation of a hybrid survivorship model between HCT clinicians and primary care providers, only 25% of eligible patients underwent recommended metabolic screening for dyslipidemia and diabetes and 16 – 20% of eligible patients received recommended cancer screenings.21 While the heterogeneity of HCT program capabilities is significant and highly dependent on program size and patient population characteristics (i.e. distance to HCT center), our findings are noteworthy as greater than 90% of patients received recommended metabolic syndrome screenings and over 50% received counseling on recommended secondary cancer screenings. More importantly, adherence to key cancer screenings such as mammography nearly doubled. Our results strongly support the importance of developing structured formal survivorship programs to meet the increasing comprehensive needs of HCT survivors.
Our results suggest the incorporation of formal survivorship visits and screening evaluations into routine primary HCT care is critical in the successful execution of post-HCT survivorship care. The incidence curves of individual survivorship screenings (Figure 3), particularly those associated with metabolic syndrome and those requiring specialty referral such as corneal examination, start to separate at the time of the dedicated day 100 survivorship visit. Furthermore, many screenings were completed prior to the one year consultation, which only a minority of patients received. Our data suggest the primary HCT day 100 visit is essential to promoting adherence to recommended screenings. Indeed, HCT survivors prefer to receive survivorship care with their HCT team.11 In addition, HCT survivors have clearly identified ease of care coordination and long-term provider continuity as important factors in successful transitions to survivorship care,24 factors which the integration of primary HCT clinicians in our Survivorship Program provides. Further, incorporation of the primary HCT team into survivorship care anecdotally builds a HCT culture that values survivorship care. Although the COVID pandemic interrupted provision of survivorship consults for several months, and fewer patients in the 2019–2021 study period received specialty survivorship consultation, the primary HCT teams helped ensure continued delivery of survivorship care to many patients post-HCT. While this level of primary HCT involvement may not be feasible at all HCT centers, continuity of care, ease of care coordination, and patient-level trust in their HCT teams are important considerations in the development of Survivorship Programs. Future multi-center implementation studies are needed to ensure continued primary HCT team involvement and to integrate community hematology, oncology, and primary care providers.
The low completion rate of 1-year Survivorship consults is noteworthy and has several potential explanations. At the initiation of the formal Survivorship Program, we primarily relied on HCT clinician referral to schedule the one-year survivorship visit. We have subsequently changed operations to systematically identify patients eligible for the one-year survivorship consult and approach them directly for scheduling. In addition, the COVID-19 pandemic was a prominent contributor as there was an 8 month period in which no consults were offered (March to November 2020). Furthermore, in clinical practice, our Survivorship Program, accepts referrals outside the 2 year post-HCT window, which is often necessary for patients with complex survivorship needs. Finally, the clinical capacity of the survivorship program is insufficient to see 100% of eligible HCT survivors. Despite this low rate of 1-year consultations, our formal Survivorship Program improved screening adherence and highlights the benefits of a hybrid Survivorship program that incorporates primary and specialty survivorship components.
The decrease in adherence in the second Survivorship period (2019–2021) is also significant and informative to overcome barriers to sustained success of survivorship efforts. One clear factor in this study was the negative impact of the COVID-19 pandemic. All HCT survivors in the second Survivorship period became eligible for survivorship care at the onset and peak of the COVID-19 pandemic, and our findings support the previously published negative impact of COVID-19 on routine cancer survivorship care.26,27 In addition to the temporary disruption of the Survivorship Consults by the pandemic, obtaining routine and timely pulmonary function tests, bone density tests, and cancer screenings such as mammography and colonoscopy was limited. In particular, ability to obtain PFTs was most severely limited for patients undergoing HCT in 2019 and 2020. Also, immunosuppressed patients post-HCT were less likely to complete additional tests and in-person medical visits that may increase exposure to communicable illness. However, the improved completion of cardiovascular screenings during the COVID pandemic demonstrates that survivorship efforts continued during the pandemic, and the multi-level nature of our formal HCT Survivorship Program very likely facilitated and supported those efforts. Despite not offering survivorship consults during the first 6 months of the COVID pandemic, primary HCT survivorship care continued. Thus, it is important to have multiple time-points to address HCT survivorship needs – especially in challenging times such as the COVID-19 pandemic. It is also important to note that decrease in screening adherence in the second Survivorship period may be related to factors outside of the COVID pandemic. Indeed, adherence to PFTs screening among patients who underwent HCT in 2021 was still below the prior program benchmark. Factors such as patient reluctance to undergo additional testing and evolving clinician practice patterns may have also contributed. Thus, efforts to educate patients, to address patient barriers to screening, to reinforce clinician training, and to support HCT clinician survivorship efforts will be critical to sustain the positive effects of our formal Survivorship Program.
Our analysis has several limitations. First, this is a retrospective analysis of a single academic HCT center that serves a patient population with limited diversity. Our findings and Survivorship care model which emphasizes primary HCT clinician involvement and availability of specialty survivorship consultations may not be generalizable to all HCT centers. As the low percentage of patients completing the 1 year survivorship consult at our center demonstrates, it remains challenging to ensure all patients receive comprehensive survivorship care. Furthermore, while we controlled for differences across study periods, residual confounding remains, and this pre-post analysis is insufficient to establish causality. Second, we relied on institutional clinical data from the electronic health record and acknowledge that we may be missing clinical care and screening evaluations not performed at our institution – particularly regarding completion of recommended cancer screenings. While HCT recipients tend to receive most of their care and undergo evaluations within our system, it is possible that missing data could have led to under-reporting of adherence to screening evaluations -- especially in the pre-survivorship study period. Third, our inclusion of patients alive and relapse-free at 1 year post-HCT and exclusion of those dying between 1 and 2 years post-HCT may exclude an important population of HCT survivors such as those experiencing disease relapse and positively bias study results. Given formal survivorship efforts started at day 100, patients excluded from study cohort may have also had different completion of survivorship screenings which are not reflected in this analysis. Co-interventions including the COVID-19 pandemic negatively influenced study results and is discussed separately. Finally, this study focused on initial completion of HCT survivorship screenings, which is only the first step to ensure long-term health of HCT survivors. Future studies are critically needed to not only assess longitudinal screening adherence but also the impact of formal survivorship efforts to prevent late effects such as cardiovascular disease and secondary cancers and improve critical patient-reported outcomes including quality of life.
In conclusion, a formal integrated HCT Survivorship Program was associated with improved adherence to GVHD, cardiovascular, endocrine, and secondary cancer screenings among HCT survivors. Future studies assessing best practices to incorporate HCT teams into survivorship efforts and medical evaluations are needed to mitigate the late treatment effects and improve the quality of life and survival of patients after allogeneic HCT.
Supplementary Material
Highlights.
Our Survivorship Program increased adherence to screenings for late effects
The primary HCT team was critical to success of the Survivorship Program
Future studies to optimize survivorship care models are needed
Key Points.
A formal hematopoietic cell transplantation (HCT) Survivorship Program increases adherence to medical screening for late treatment effects and post-HCT complications
Incorporation of the primary HCT clinicians in survivorship efforts is likely critical to the success of HCT Survivorship Programs
Footnotes
Conflicts of Interest/Disclosures:
Spitzer: consulting for Bluebird Bio, Syneos Health, Ossium Health and Qihan Biotech
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