Financial Burden in Blood or Marrow Transplantation Survivors During the COVID-19 Pandemic: A BMTSS Report.

PURPOSE: The financial burden experienced by blood or marrow transplant (BMT) survivors during the COVID-19 pandemic remains unstudied. We evaluated the risk for high out-of-pocket medical costs and associated financial burden experienced by BMT survivors and a sibling comparison group during the COVID-19 pandemic. METHODS: This study included 2,370 BMT survivors and 750 siblings who completed the BMT Survivor Study survey during the pandemic. Participants reported employment status, out-of-pocket medical costs, and financial burden. Medical expenses ≥ 10% of the annual household income constituted high out-of-pocket medical costs. Logistic regression identified factors associated with high out-of-pocket medical costs and financial burden. RESULTS: BMT survivors were more likely to incur high out-of-pocket medical costs (11.3% v 3.1%; adjusted odds ratio [aOR], 2.88; 95% CI, 1.84 to 4.50) than the siblings. Survivor characteristics associated with high out-of-pocket medical costs included younger age at study (aORper_year_younger_age, 1.02; 95% CI, 1.00 to 1.03), lower prepandemic annual household income and/or education (< $50,000 US dollars and/or < college graduate: aOR, 1.96; 95% CI, 1.42 to 2.69; reference: ≥ $50,000 in US dollars and ≥ college graduate), > 1 chronic health condition (aOR, 2.82; 95% CI, 2.00 to 3.98), ≥ 1 hospitalization during the pandemic (aOR, 2.11; 95% CI, 1.53 to 2.89), and being unemployed during the pandemic (aOR, 1.52; 95% CI, 1.06 to 2.17). Among BMT survivors, high out-of-pocket medical costs were significantly associated with problems in paying medical bills (aOR, 10.57; 95% CI, 7.39 to 15.11), deferring medical care (aOR, 4.93; 95% CI, 3.71 to 6.55), taking a smaller dose of medication than prescribed (aOR, 4.99; 95% CI, 3.23 to 7.70), and considering filing for bankruptcy (aOR, 3.80; 95% CI, 2.14 to 6.73). CONCLUSION: BMT survivors report high out-of-pocket medical costs, which jeopardizes their health care and may affect health outcomes. Policies aimed at reducing financial burden in BMT survivors, such as expanding access to patient assistance programs, may mitigate the negative health consequences.

Use of Potentially Inappropriate Medications in Older Allogeneic Hematopoietic Cell Transplantation Recipients.

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Geriatric assessment in older alloHCT recipients: association of functional and cognitive impairment with outcomes.

Use of allogeneic hematopoietic cell transplantation (alloHCT) is increasing in older patients with hematologic malignancies. Studies suggest that geriatric assessment (GA), incorporating functional measures such as instrumental activities of daily living (IADL), delineates subtle age-related impairments that enhance risk-stratification. The objective of this multi-institutional retrospective study was to evaluate the prognostic utility of GA metrics collected pre-alloHCT. Eligibility criteria included age ≥50 and pre-alloHCT GA inclusive of at least IADL. Beyond IADL, additional geriatric metrics were collected where available and included Medical Outcomes Study Physical Health score (MOS-PH), Timed Up and Go (TUG), and cognition by Blessed Orientation Memory Concentration (BOMC). Three hundred thirty subjects were included, with a median age of 63 (range 50 to 77). Impairments were frequent: 36% had at least 1 IADL impairment; 14% had TUG ≥13.5 seconds; and 17% had cognitive impairment (BOMC ≥ 7). Median MOS-PH score was 80. IADL and age were not significantly associated with nonrelapse mortality (NRM) or overall survival (OS). In multivariate analysis, only impaired cognition and Hematopoietic Cell Transplant-Comorbidity Index score ≥3 showed an independent association with 1-year NRM (subdistribution hazard ratio [SHR], 2.36; P = .01; and SHR, 2.19; P = .009, respectively). Cognitive impairment independently conferred inferior 1-year OS (hazard ratio, 1.94; P = .01). In a preplanned subgroup analysis in 224 patients aged ≥60 years, cognitive impairment remained the sole GA metric predictive of NRM (2-year NRM: SHR, 2.72; P = .007). These data suggest that cognitive impairment elevates risk of post-alloHCT NRM in older patients.

Assessment of Late Mortality Risk After Allogeneic Blood or Marrow Transplantation Performed in Childhood.

Importance: Allogeneic blood or marrow transplantation (BMT) is a curative option for malignant and nonmalignant diseases of childhood. However, little is known about trends in cause-specific late mortality in this population during the past 3 decades. Objectives: To examine cause-specific late mortality among individuals who have lived 2 years or more after allogeneic BMT performed in childhood and whether rates of late mortality have changed over time. Design, Setting, and Participants: A retrospective cohort study was conducted of individuals who lived 2 years or more after undergoing allogeneic BMT performed in childhood between January 1, 1974, and December 31, 2010. The end of follow-up was December 31, 2016. Exposure: Allogeneic BMT performed in childhood. Main Outcomes and Measures: All-cause mortality, relapse-related mortality, and non-relapse-related mortality. Data on vital status and causes of death were collected using medical records, the National Death Index Plus Program, and Accurint databases. Results: Among 1388 individuals (559 females and 829 males) who lived 2 years or more after allogeneic BMT performed in childhood, the median age at transplantation was 14.6 years (range, 0-21 years). In this cohort, there was a total of 295 deaths, yielding an overall survival rate of 79.3% at 20 years after BMT. The leading causes of death were infection and/or chronic graft-vs-host disease (121 of 244 [49.6%]), primary disease (60 of 244 [24.6%]), and subsequent malignant neoplasms (45 of 244 [18.4%]). Overall, the cohort had a 14.4-fold increased risk for death (95% CI, 12.8-16.1) compared with the general population (292 deaths observed; 20.3 deaths expected). Relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9; 95% CI, 2.0-4.1). The absolute excess risk for death from any cause was 12.0 per 1000 person-years (95% CI, 10.5-13.5). The cumulative incidence of non-relapse-related mortality exceeded that of relapse-related mortality throughout follow-up. The 10-year cumulative incidence of late mortality decreased over time (before 1990, 18.9%; 1990-1999, 12.8%; 2000-2010, 10.9%; P = .002); this decrease remained statistically significant after adjusting for demographic and clinical factors (referent group: <1990; 1990-1999: hazard ratio, 0.64; 95% CI, 0.47-0.89; P = .007; 2000-2010: hazard ratio, 0.49; 95% CI, 0.31-0.76; P = .002; P < .001 for trend). Conclusions and Relevance: Late mortality among children undergoing allogeneic BMT has decreased during the past 3 decades. However, these patients remain at an elevated risk of late mortality even 25 years or more after transplantation when compared with the general population, necessitating lifelong follow-up.

Positron Emission Tomography-Based Assessment of Metabolic Tumor Volume Predicts Survival after Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is curative for 60% of patients with relapsed or refractory Hodgkin lymphoma (R/R HL). A more precise assessment of the depth of remission before AHCT may help to identify patients likely to benefit from AHCT. We aimed to determine whether positron emission tomography (PET)-based quantitative parameters of total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and maximal standardized uptake volume (SUVmax) measured before AHCT predict progression-free survival (PFS) after transplant. Pretransplant PET/computed tomography images of 96 consecutive patients with R/R HL were analyzed. Median TMTV, TLG, and SUVmax were 7.97 cm3 (range, 1.3 to 102.1), 23.7 (range, 4.0 to 813.1), and 5.23 (range, 2.7 to 23.2). Two-year PFS in patients with high TMTV (TMTVhigh; more than median; n = 17) was only 12% (95% CI, 1% to 38%) compared with 53% (95% CI, 28% to 73%; P = .05) in patients with TMTVlow (lower or equal to median; n = 17) and 63% (95% CI, 50% to 74%) in 61 patients with no metabolically active tumor (TMTV0; P > .01). In concordance, high TLG (>19) and SUVmax (>4.9) predicted inferior 2-year PFS. In multivariate analysis patients with TMTVhigh had a 3.5-fold higher risk of treatment failure compared with TMTV0/TMTVlow (HR, 3.49; 95% CI, 1.75 to 6.93; P < .01). Deauville (D)-scores of 4 to 5 before AHCT predicted worse PFS compared with D-scores of 1 to 3 (HR, 3.7; 95% CI, 1.92 to 7.28; P < .01). Yet, TMTV and D-scores were disconcordant in 12 subjects; 9 patients in the D4 group with TMTVlow had 2-year PFS of 44% (95% CI, 14% to 72%), which was 2-fold higher than predicted by D4 score. In conclusion, in patients with R/R HL and PET-positive residual disease, TMTVhigh can identify very poor AHCT responders. Patients with TMTVlow, TLG, and SUVmax before AHCT have similar outcomes to those without metabolically active disease.

Physiologic Frailty in Nonelderly Hematopoietic Cell Transplantation Patients: Results From the Bone Marrow Transplant Survivor Study.

IMPORTANCE: Frailty results in decreased physiological reserve and diminished resistance to stressors; approximately 10% of those in the elderly population (those ≥65 years) are frail. High-intensity treatments and complications after hematopoietic cell transplantation (HCT) injure normal tissues and may increase the risk of frailty even among nongeriatric HCT patients. OBJECTIVE: To determine the prevalence of frailty in young adult HCT patients (18- to 64-year-olds) and siblings; and the impact of frailty on subsequent mortality in HCT survivors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study, conducted in August 2015 examined 998 HCT survivors, who underwent transplant procedures between 1974 and 1998, who have survived at least 2 years after HCT, and 297 frequency-matched siblings. The study was performed at City of Hope or University of Minnesota with participants completing surveys at home or in the clinic. Hematopoietic cell transplantation survivors and siblings participating in the Bone Marrow Transplant Survivor Study (BMTSS) completed a frailty survey between February 13, 1999 and June 15, 2005 (median time since HCT: 7.9 years); HCT survivors were followed for subsequent mortality (median: 10.3 years from survey). MAIN OUTCOMES AND MEASURES: Prevalence and predictors of frailty; impact of frailty on subsequent mortality in HCT survivors. Frailty phenotype defined as exhibiting 3 or more of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The national Death Index, Social Security Death Index and medical records were used for mortality assessment as of December 21, 2011. RESULTS: The 998 HCT survivors were a mean (SD) of 42.5 (11.6) years of age, and the 297 matched siblings were 43.8 (10.9) years of age. The prevalence of frailty among young adult HCT patients exceeded 8%. The HCT survivors were 8.4 times more likely to be frail than their siblings (95% CI, 2.0-34.5; P = .003). Among HCT recipients, allogeneic HCT recipients with chronic graft-vs-host disease (GvHD) were at increased risk of frailty compared with autologous HCT (OR,15.02; 95% CI, 6.6-34.3; P < .001); resolved chronic GvHD (OR, 2.7; 95% CI, 1.1-6.9; P = .04). Cumulative incidence of subsequent all-cause mortality was 39.3% and 14.7% at 10 years for HCT recipients with and without frailty, respectively (P < .001). Frailty was associated with a 2.76-fold (95% CI, 1.7-4.4; P < .001) increased risk of subsequent mortality after adjusting for relevant prognosticators. CONCLUSIONS AND RELEVANCE: The prevalence of frailty among young-adult HCT survivors approaches that seen in the elderly general population. Frail HCT survivors are at increased risk of subsequent mortality when compared with nonfrail survivors. This study identifies vulnerable populations needing close monitoring to anticipate and manage morbidity and prevent mortality.

Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation.

Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13,131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

The National Marrow Donor Program's Symposium on Hematopoietic Cell Transplantation in 2020: a health care resource and infrastructure assessment.

Hematopoietic cell transplantation (HCT) is the only known curative therapy for many patients with life-threatening hematologic and oncologic diseases. It is estimated that the National Marrow Donor Program(®) (NMDP) will facilitate 10,000 transplants by 2015, double the current number. To better understand the existing personnel and center infrastructure for HCT in the country and to address system capacity challenges to the future growth of HCT, the NMDP convened a diverse group of stakeholders and thought leaders representing HCT physicians, physician assistants, nurse practitioners, nurses, pharmacists, other healthcare providers, HCT program directors, hospital administrators, payors, and professional organizations. Working groups were formed to identify: capacity issues because of shortages in human resources, structural constraints, and patient access barriers including diversity and healthcare disparity challenges; recommendations to address challenges; and stakeholders to engage. This report details the deliberations and recommendations of a national symposium, "Hematopoietic Cell Transplantation in 2020: A Health Care Resource and Infrastructure Assessment," held in September 2010.

Costs of pediatric allogeneic hematopoietic-cell transplantation.

BACKGROUND: Allogeneic hematopoietic-cell transplantation (HCT), although curative for some high-risk diseases, is a complex and costly procedure. The costs of transplantation among children have not been described previously. PROCEDURE: We compared the costs of HCT within the first 100-days among children who received myeloablative HCT from either a matched related donor (MRD, N = 27), matched unrelated donor (MUD, N = 28) or unrelated umbilical cord blood (UCB, N = 91). We also conducted analyses to describe predictors of higher costs of transplantation. RESULTS: The 100-day probabilities of overall survival were 96%, 96% and 87% for MRD, MUD and UCB, respectively. The mean cost per day survived (excluding costs of graft acquisition) was $3,446 (standard deviation (SD), $851) for MRD, $4,050 (SD, $1,194) for MUD and $4,522 (SD, $2,053) for UCB recipients. The costs of MUD and UCB HCT remained similar when costs of graft acquisition were considered within total costs of transplantation. In multivariable analysis, adjusting for important patient, disease, and transplant related characteristics, factors associated with higher costs within the first 100-days were HCT using MUD or UCB, Lansky score <90 at transplant, graft failure, need for dialysis, need for mechanical ventilation and occurrence of hepatic veno-occlusive disease. CONCLUSIONS: Within the first 100-days, the costs of MUD and UCB HCT are similar, while MRD HCT is less costly. These costs are primarily driven by severe post-transplant complications and graft failure.

Costs of hematopoietic cell transplantation: comparison of umbilical cord blood and matched related donor transplantation and the impact of posttransplant complications.

Allogeneic hematopoietic cell transplantation (HCT) is a complex and costly procedure. Unrelated umbilical cord blood (UCB) is an alternative graft source for patients without matched related donors (MRD); however, costs of UCB HCT have not been described. We compared the costs of HCT within the first 100 days among recipients of MRD (myeloablative = 67, nonmyeloablative = 54) or UCB (myeloablative = 63, nonmyeloablative = 110) HCT. Cost and hospitalization data were obtained from the institutional accounting department. The 100-day probabilities of overall survival (OS) and cumulative incidence of treatment-related mortality (TRM) were comparable among 4 transplant types; however, neutrophil recovery was delayed and graft failure was more likely in UCB recipients. The median cost per day survived (excluding costs of graft acquisition) was $1016 for myeloablative MRD, $2082 for myeloablative UCB, $612 for nonmyeloablative MRD, and $1156 for nonmyeloablative UCB recipients, respectively (P < .001). In multivariate analysis, adjusting for important patient, disease, and HCT-related characteristics, as well as major post-HCT complications, factors associated with higher costs within the first 100 days were myeloablative UCB HCT (relative risk 1.3 [95% confidence intervals, 1.1-1.5] versus myeloablative MRD HCT), graft failure (1.8 [1.7-1.9]), need for dialysis (1.3 [1.1-1.5]) or mechanical ventilation (1.3 [1.2-1.4]) and total hospital stay in the highest tertile (>48 days; 2.1 [1.9-2.3]). The median cost per day survived for patients with graft failure was $6976 (versus $1105 for no graft failure), dialysis was $4764 (versus $1102 for no dialysis), and $5099 for mechanical ventilation (versus $977 for no mechanical ventilation). Within the first 100 days, the absolute costs of myeloablative and nonmyeloablative UCB are higher than myeloablative and nonmyeloablative MRD transplantation. These costs are primarily driven by severe posttransplant complications, graft failure, and prolonged inpatient stay. Strategies to enhance engraftment will decrease the costs of UCB transplantation.

Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.

We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% +/- 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.