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Permanent impairment-free, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant
Permanent impairment after allogeneic transplant
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Permanent impairment-free, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant Yoshitaka Adachi MD , Kazutaka Ozeki MD, PhD , Shun Ukai MD , Ken Sagou MD , Nobuaki Fukushima MD, PhD , Akio Kohno MD, PhD PII: DOI: Reference:
S1083-8791(20)30058-6 https://doi.org/10.1016/j.bbmt.2020.01.025 YBBMT 55918
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Biology of Blood and Marrow Transplantation
Received date: Accepted date:
25 October 2019 28 January 2020
Please cite this article as: Yoshitaka Adachi MD , Kazutaka Ozeki MD, PhD , Shun Ukai MD , Ken Sagou MD , Nobuaki Fukushima MD, PhD , Akio Kohno MD, PhD , Permanent impairmentfree, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant, Biology of Blood and Marrow Transplantation (2020), doi: https://doi.org/10.1016/j.bbmt.2020.01.025
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
Highlights
We estimated permanent impairment of six vital organs in allogeneic transplant.
The 5-year permanent impairment-free, relapse-free survival (PIRFS) was 40.6%.
PIRFS is an endpoint to assess long-term transplant success from a novel perspective.
Permanent impairment-free, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant Yoshitaka Adachi1)2), MD, Kazutaka Ozeki2), MD, PhD, Shun Ukai2), MD, Ken Sagou2), MD, Nobuaki Fukushima2), MD, PhD, Akio Kohno2), MD, PhD 1) Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan 2) Department of Hematology and Oncology, Konan Kosei Hospital, Konan, Japan Corresponding author: Yoshitaka Adachi, MD Department of Hematology and Oncology, Nagoya University Graduate School of Medicine 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan Phone No: +81-52-744-2145 Fax No: +81-52-744-2157 E-mail: [email protected] Short title: Permanent impairment after allogeneic transplant Financial Disclosure Statement The authors declare no conflict of interest.
Abstract Permanent impairment (PI) of vital organs is one of the transplant-related health problems affecting the quality of life and morbidity even in patients who do not develop graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT), but no data are available on PI of multiple organs. This retrospective study aims to estimate a novel composite endpoint of PI-free, relapse-free survival (PIRFS) in 164 allo-HCT recipients. We defined PI as >26%–30% impairment of the whole person in six vital organs using the whole person impairment rating. Conventional GVHD-free/relapse-free survival (GRFS) and PIRFS at 5 years were 33.8% (95% CI: 26.5%–41.3%) and 40.6% (95% CI: 32.6%–48.4%). In the whole cohort, PIRFS was higher than GRFS at any time after allo-HCT. However, PIRFS was lower than GRFS after day 397 posttransplant in patients who underwent umbilical cord blood transplantation (UCBT). In UCBT recipients, 5-year GRFS and PIRFS were 47.6% (95% CI: 34.3%–59.7%) and 39.2% (95% CI: 26.6%–51.5%). The cumulative incidence of PI after 5 years was 20.9% (95% CI: 13.7%–29.0%) in patients surviving for ≥6 months without relapse. The multivariate analysis revealed that high disease risk (HR, 1.91; 95% CI: 1.26–2.88; P < 0.01) and Karnofsky performance status ≤90% at transplant (HR, 1.73; 95% CI: 1.14–2.63; P = 0.01) correlated with the lower PIRFS, whereas
UCBT (HR, 2.35; 95% CI: 1.11–4.99; P = 0.03), grade III–IV acute GVHD by day 180 (HR, 3.59; 95% CI: 1.04–12.4; P = 0.04), and thrombotic microangiopathy by day 180 (HR, 2.74; 95% CI: 1.10–6.87; P = 0.03) significantly correlated with the higher incidence of PI. Over 1 of 5 long-term survivors had PI. Hence, this study proposes that PIRFS is a useful endpoint to assess long-term transplant success from a perspective different from those established previously. Keywords permanent impairment; graft-versus-host disease-free relapse-free survival; permanent impairment-free relapse-free survival; umbilical cord blood; thrombotic microangiopathy; long-term transplant success
Introduction Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a promising treatment procedure for patients with hematological diseases. Remarkable advances in transplantation techniques and supportive care practices have enhanced the long-term survival after allo-HCT, and transplant-related health problems affecting the quality of life have garnered considerable interest lately [1-4]. Graft-versus-host disease (GVHD) is the leading cause of mortality and late morbidity after
allo-HCT. GVHD-free, relapse-free survival (GRFS), a composite endpoint incorporating the occurrence of GVHD as an event, has been extensively used to assess transplant success in clinical studies [5-7]. Recently, “current GRFS” and “refractory GRFS” were developed to measure transplant success more precisely because GVHD could resolve completely or partially posttreatment [8,9]. However, even allo-HCT recipients who do not develop GVHD are at risks for several complications, including infectious diseases, thrombotic microangiopathy (TMA), and organ failure after allo-HCT [10-14], which can often cause permanent impairment (PI). PI worsens the quality of life and, sometimes, results in non-relapse death [15,16]. Hence, it is imperative to assess the proportion of allo-HCT recipients who survive without PI to evaluate transplant success. Although several studies have focused on single organ impairment after allo-HCT [12,14,15,17-23], no data are available on PI of multiple vital organs. Hence, this study aims to investigate the cumulative incidence of PI and the likelihood of survival after allo-HCT without PI, relapse, or death, which we termed “PI-free, relapse-free survival (PIRFS).” Furthermore, this study compares PIRFS with conventional GRFS. Materials and Methods Patients
A total of 167 adult patients underwent first allo-HCT for the treatment of hematological diseases at the Konan Kosei Hospital (Konan, Japan) between January 2008 and December 2017. Of these, we excluded 3 patients who already had organ impairment as defined in this study at transplant. Hence, we analyzed 164 patients. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Konan Kosei Hospital. Furthermore, we obtained written informed consent from all patients before undergoing allo-HCT. Donor selection and treatment procedures Although the first choice for a donor was a human leukocyte antigen (HLA)–matched sibling, in the absence of a suitable HLA-matched sibling donor, we selected bone marrow or peripheral blood from an HLA-matched unrelated donor, peripheral blood from an HLA-haploidentical related donor, or single-unit umbilical cord blood (UCB) as a graft source. Sometimes, we used UCB for patients in urgent need of allo-HCT. A UCB donor was selected on the basis of cell dose and HLA-A, HLA-B, and HLA-DR matching at the antigen level. We evaluated the HLA-matching between the recipient and unrelated donors of the bone marrow or peripheral blood based on the compatibility of HLA-A, HLA-B, HLA-C, and HLA-DRB1 at the allelic level. In addition, based on the patients’ age, disease risk,
significant comorbidities, and donor types, we decided the type of conditioning regimens. Typically, the GVHD prophylaxis contained tacrolimus or cyclosporine and short-term methotrexate. However, tacrolimus, mycophenolate mofetil, and posttransplantation cyclophosphamide were used in cases of allo-HCT from haploidentical related donors. Furthermore, patients who developed GVHD, requiring systemic treatment, were primarily treated with prednisolone at 0.5–1 mg/kg/day. Definitions Regarding the disease risk, low-risk diseases included acute leukemia in the first or second complete remission, chronic myeloid leukemia in the first or second chronic phase, myelodysplastic syndrome in refractory anemia or refractory anemia with ring sideroblasts, chemotherapy-sensitive lymphoma or multiple myeloma, and non-malignant hematological diseases. Notably, high-risk diseases included all other diagnoses [24]. We defined regimens with a total busulfan dose of >9 mg/kg, melphalan dose of >140 mg/m2, total body irradiation (TBI) of >5 Gy for a single dose, or TBI of >8 Gy fractionated as myeloablative conditioning [25]. In addition, reduced-intensity conditioning was fludarabine-based with or without low-dose TBI (≤4 Gy). Our institute does not use non-myeloablative regimens. We evaluated hematopoietic cell transplantation–specific comorbidity index scores as described previously
by Sorror et al. [24]. In addition, acute GVHD was graded according to the established criteria [26], and we diagnosed chronic GVHD as reported previously [27]. The DFS was defined as the time from transplantation to relapse of the underlying malignancy for which allo-HCT was performed or death. GRFS was defined as the time from transplantation to the onset of grade III–IV acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death as described previously by Holtan et al. [5]. PIRFS events were defined as PI diagnosis described below, relapse, or death from any cause after allo-HCT. That is, we defined PIRFS as the time from transplantation to PI diagnosis, relapse or death. Permanent impairment assessment We assessed PI of multiple vital organs. In this study, we assessed the function of the following organs: heart, lungs, liver, digestive tracts, kidneys, and central nervous system. Using “The American Medical Association’s Guides to the Evaluation of Permanent Impairment,” we assessed the degree of PI on the same scale in different organs [28]. In addition, we defined PI as around ≥26%–30% impairment of the whole person for >6 months to consider the impairment as permanent. The date of PI diagnosis was defined as 180 days after the onset of impairment. We excluded the impairment in the first 6 months after allo-HCT to avoid misclassifying reversible impairment as permanent. The renal function was assessed
by calculating the estimated glomerular filtration rate (GFR) as reported previously [29]. Moreover, renal impairment was defined as an estimated GFR ≤45 mL/min/1.73 m2 (≥30% impairment of the whole person). We defined liver impairment as follows: (1) progressive chronic liver disease with objective evidence or history of jaundice, ascites, or bleeding esophageal or gastric varices within past year; and (2) possibly affected nutrition and strength; or (3) intermittent hepatic encephalopathy (≥30% impairment of the whole person). Pulmonary impairment was defined as follows: (1) measured forced vital capacity ≤59% of predicted; or (2) measured forced expiratory volume in the first second ≤59% of predicted; or (3) diffusing capacity for carbon monoxide ≤59% of predicted (around ≥26% impairment of the whole person). However, we did not assess the maximum oxygen consumption and metabolic equivalents. Cardiac, gastrointestinal, and central nervous system impairments were evaluated based on each disease (≥30% impairment of the whole person). Notably, we had a long-term follow-up program to provide lifelong support to patients who underwent allo-HCT. We assessed the severity and activity of chronic GVHD and the function of vital organs for survivors without relapse after allo-HCT semiannually in the first year and annually from the second year on. We also evaluated renal function at least every 3 months. After a patient developed some kind of organ impairment or GVHD, we assessed relevant
organ function at least every 3 months. Furthermore, we ascertained whether the recovery of organ function was noted during the follow-up period after the PI diagnosis. Endpoints and statistical analysis
Using the Fisher’s exact test and the Wilcoxon rank-sum test, we compared categorized and continuous variables, respectively. We estimated the univariate probabilities of GRFS and PIRFS using the Kaplan–Meier curves and compared using log-rank tests [30]. The occurrence of PI was estimated by cumulative incidence curves using landmark analysis at 6 months after transplant because we aimed to evaluate PI in patients surviving ≥6 months after allo-HCT. Death and relapse were the competing events for the analysis of PI [31]. Gray’s test was used to assess the difference between various subgroups for the cumulative incidence of PI. Then, Cox regression models [32] were developed to determine the independent effect of variables on GRFS and PIRFS. Using proportional hazard models of Fine and Gray [33], we examined the independent effect of variables on the cumulative incidence of PI. We included pretransplant variables when a significant level of P <0.1 and proportionality were detected in the univariate Cox regression analysis for GRFS and PIRFS. We included not only pretransplant variables but also posttransplant variables within 6 months on the landmark analysis for the cumulative incidence of PI. Notably, a significance level of P <0.05
(two-sided) was needed in the multivariate analysis. All statistical analyses in this study were performed using EZR on R commander version 1.32 [34]. Results Patients’ characteristics In this study, we enrolled 164 patients [median age: 50 (range: 16–70) years] with various hematological diseases. Table 1 summarizes the patients’ clinical characteristics. We did not use T-cell depletion as GVHD prophylaxis in this study. The most UCB units were 4/6-matched to patients for HLA-A, -B, and -DR antigens. In addition, the majority of patients, including all patients undergoing umbilical cord blood transplantation (UCBT), received tacrolimus in combination with short-term methotrexate as GVHD prophylaxis, while the remaining received cyclosporine instead of tacrolimus, and four who underwent haploidentical
allo-HCT received
tacrolimus
and
mycophenolate
mofetil
besides
posttransplantation cyclophosphamide. The majority of UCBT recipients received the TBI-containing conditioning regimen. In addition, high-dose cytarabine was added to the conventional cyclophosphamide and TBI regimen as myeloablative conditioning in UCBT. For the landmark analysis, we excluded 25 patients with relapse or progression disease, and 18 patients with non-relapse death within 180 days after allo-HCT. Hence, we included the
remaining 121 patients who survived for ≥6 months without relapse in the landmark analysis for the cumulative incidence of PI. The median follow-up period for surviving patients was 58.6 (range: 12–131) months. DFS, GRFS, and PIRFS In the entire cohort, 2-year DFS, GRFS, and PIRFS were 59.5% (95% CI: 51.5%–66.6%), 37.0% (95% CI: 29.7%–44.4%), and 47.9% (95% CI: 40.0%–55.4%), respectively. In addition, 5-year DFS, GRFS, and PIRFS were 53.8% (95% CI: 45.6%–61.4%), 33.8% (95% CI: 26.5%–41.3%), and 40.6% (95% CI: 32.6%–48.4%), respectively (Fig. 1). PIRFS was higher than GRFS at any time after allo-HCT in the entire cohort. We also observed this tendency in patients who underwent non-UCBT (Fig. 2A). However, in patients who underwent UCBT, the PIRFS curve declined across the GRFS curve at 397 days posttransplant (Fig. 2B). In patients who underwent UCBT, 5-year DFS, GRFS, and PIRFS were 57.1% (95% CI: 43.4%–68.7%), 47.6% (95% CI: 34.3%–59.7%), and 39.2% (95% CI: 26.6%–51.5%), respectively. Univariate and multivariate analyses of risk factors for GRFS and PIRFS Both univariate and multivariate analyses were performed to detect the pretransplant variables related to GRFS and PIRFS. Among various variables listed in Table 2, the
univariate analysis revealed that age ≥50 years, high-risk disease, BU >8 mg/kg, TBI ≤6 Gy, and non-UCBT significantly correlated with lower GRFS (Table 2). The adjustment of potential variables by the multivariate analysis revealed that high-risk disease (HR, 2.16; 95% CI: 1.48–3.16; P <0.01) and non-UCBT (HR, 1.75; 95% CI: 1.16–2.70; P <0.01) significantly correlated with lower GRFS. Conversely, age ≥50 years, high-risk disease, Karnofsky performance status (KPS) ≤90%, and hematopoietic cell transplantation–specific comorbidity index scores ≥3 significantly correlated with lower PIRFS by the univariate analysis. Furthermore, the multivariate analysis revealed that high-risk disease (HR, 1.91; 95% CI: 1.26–2.88; P < 0.01) and KPS ≤90% (HR, 1.73; 95% CI: 1.14–2.63; P = 0.01) correlated with lower PIRFS. Cumulative incidence of permanent impairment We analyzed 121 patients in the landmark analysis for the cumulative incidence of PI (Table 1). Figure 3 shows the cumulative incidence of PI in patients who survived for ≥6 months without relapse posttransplant. The cumulative incidence of PI by 5 years after allo-HCT was 20.9% (95% CI: 13.7%–29.0%) in the entire cohort (Fig. 3A). The cumulative incidence of PI was significantly higher in patients who underwent UCBT than in those who underwent non-UCBT in the Gray test—30.6% (95% CI: 17.2%–45.1%) for UCBT and 15.1% (95% CI:
7.6%–25.0%) for non-UCBT (P = 0.016; Fig. 3B). The cumulative incidence of respiratory PI by 5 years after allo-HCT was 10.4% (95% CI: 5.4%–17.3%). The cumulative incidence of renal PI 5 years after allo-HCT was 10.7% (95% CI: 5.8%–17.3%). The median period from transplantation to PI diagnosis was 17 (range: 12–83) months. Twenty out of 26 patients who were diagnosed as having PI developed PI within 2 years after allo-HCT. In addition, we assessed the degree of impairment precisely in all patients with persistent impairment from our electronic medical chart. Of note, the organ impairment did not recover in all patients who were diagnosed with PI during the follow-up period. The median follow-up period after the PI diagnosis was 28.5 (range: 2.2–108) months. Moreover, we assessed the risk factors for the cumulative incidence of PI in patients who survived for ≥6 months without relapse after allo-HCT. Besides the pretransplant variables shown in Table 2, we included the following posttransplant complications within 6 months after allo-HCT: grade II–IV acute GVHD; grade III–IV acute GVHD; cytomegalovirus antigenemia; veno-occlusive disease; TMA; and sepsis. Table 3 presents variables with a P < 0.1 in the univariate analysis. The univariate analysis revealed that KPS ≤90%, MEL ≤100 mg/m2, UCB, grade III–IV acute GVHD, and TMA significantly correlated with the higher cumulative incidence of PI. The adjustment of potential variables by the multivariate analysis revealed that UCB (HR, 2.35;
95% CI: 1.11–4.99; P = 0.03), grade III–IV acute GVHD (HR, 3.59; 95% CI: 1.04–12.4; P = 0.04), and TMA (HR, 2.74; 95% CI: 1.10–6.87; P = 0.03) significantly correlated with the higher cumulative incidence of PI. Types of PI Table 4 shows the types of PI. If a patient developed multiple PI of different organs, PI that developed earliest after allo-HCT was described. We observed PI in 26 patients. The leading cause of chronic kidney disease (CKD) as renal PI was TMA. After the development of hemorrhagic cystitis, a patient was diagnosed with renal PI. In three patients with mild kidney failure, the renal function was aggravated by viral infectious diseases. The leading cause of respiratory PI was bronchiolitis obliterans. In addition, recurrent pneumothorax (air leak syndrome) was one of the causes of respiratory PI in two patients. Moreover, two patients who were diagnosed with cardiomyopathy had fatigue on exertion and required diuretics regularly to alleviate symptoms. Besides, we observed a decline in the cognitive function and dysgraphia in a patient who developed leukoencephalopathy. Furthermore, a patient who developed encephalitis had a persistent disturbance of consciousness and became bedridden. Discussion
This study estimated PIRFS in 164 patients and the cumulative incidence of PI in 121 patients who survived for ≥6 months without relapse. We observed that 5-year PIRFS was 40.6% and that over 1 of 5 long-term survivors had some PI. To date, several studies have reported complications after allo-HCT focusing on each organ [12,14,15,17-23,35]. Unlike other studies, this study focused on irreversible impairment rather than temporary impairment because we assumed that irreversible impairment causes adverse effects on the quality of life and late morbidity in long-term survivors. A study proposed GRFS as a composite endpoint that measured freedom from ongoing morbidity and denoted ideal allo-HCT recovery [5]. Considering that PI caused by complications other than cGVHD could exert a considerable negative impact on health and quality of life after allo-HCT, we proposed PIRFS as a novel composite endpoint that reflected deterioration in the quality of life and non-lethal morbidity more realistically in long-term survivors of allo-HCT. This study revealed that PIRFS was higher than GRFS at any time after allo-HCT in the entire cohort, suggesting that patients who developed severe acute GVHD or systemic therapy-requiring chronic GVHD did not necessarily have PI of vital organs. In UCBT recipients, however, PIRFS was lower than GRFS after around 1-year posttransplant, revealing that many patients had PI, although they did not develop severe
acute GVHD or systemic therapy-requiring chronic GVHD particularly in the UCBT setting. Tong et al. reported that UCBT without antithymocyte globulin reported higher 3-year GRFS than unrelated peripheral blood stem cell transplantation [36]. Moreover, in this study, multivariate analysis revealed that UCBT was markedly correlated with higher GRFS, but 5-year PIRFS in UCBT recipients was a bit lower than that in non-UCBT recipients. In addition, UCBT markedly correlated with the higher cumulative incidence of PI in patients surviving for ≥6 months without relapse. Although the cause of elevated incidence of PI in UCBT recipients remains unclear, it could be attributable to various factors. We added high-dose cytarabine to the conventional cyclophosphamide and TBI regimen to augment the antitumor effect [37], and added low-dose TBI (2–4 Gy) to decreased-intensity conditioning regimen to prevent graft failure, for patients receiving UCBT. In UCBT setting, multiple nephrotoxic antibiotics or antiviral drugs are often needed for a long time because of delayed neutrophil engraftment or high incidence of viral infection. We did not validate assumed risk factors mentioned above due to the small sample size and the heterogeneity in our cohort; therefore, further validation in the prospective study with larger cohorts of patients will be required to explore what we can do to prevent PI in advance. Furthermore, age at transplant did not markedly correlate with PIRFS and cumulative incidence of PI in the multivariate
analysis, suggesting that many of PI were markedly affected by the posttransplant complications, including TMA, viral infection, or GVHD, rather than aging changes in organs at transplant. In addition, the multivariate analysis revealed that grade III–IV acute GVHD and TMA, as well as UCBT, markedly correlated with the higher cumulative incidence of PI. Reportedly, TMA is clinically represented by a combination of microangiopathic hemolytic anemia, neurologic dysfunction, renal impairment, and fever [38,39]. Endothelial damage is crucial for the TMA pathogenesis and is induced by multiple factors, including immunosuppressants, high-dose chemotherapy as conditioning, GVHD, infection, and irradiation [40-43]. Neurological and renal damage sometimes results in irreversible impairment. A study reported that TMA was one of the risk factors for CKD after allo-HCT [44]. In this study, a patient who developed TMA needed maintenance dialysis. Hence, we need to develop appropriate prevention and treatment strategy against TMA to prevent PI. Of note, the kidneys were the most frequently impaired organ persistently after allo-HCT. Reportedly, the cumulative incidence of CKD at 10 years after allo-HCT was 25%–35% [45,46]. A study with a large, community-based population reported a graded correlation between a decreased estimated GFR and the risk of death, cardiovascular events, and hospitalization [47], thus; we
need to prevent the development of CKD for long-term survivors after allo-HCT. This study suggests that only assessment of GVHD is inadequate to estimate morbidity and quality of life for the long-term survivors because multiple causes of PI were complications other than GVHD (Table 4). We also think that both GRFS and PIRFS can be used as complementary endpoints in terms of both GVHD and PI. In addition, we assessed PI in all patients with persistent impairment, probably, because renal and respiratory impairment, which were assessed by only objective data, accounted for the majority of PI. Nevertheless, the efficacy of assessment of PI in a prospective study warrants further investigation. This study has several limitations. First, while we defined PI as impairment present >6 months, CKD is normally defined as abnormalities of the kidney structure or function, present for >3 months. We considered that 3 months was too short to consider impairment as permanent in the posttransplant setting; however, whether 6 months is optimal as the duration of impairment remains unclear. The duration necessary to regard impairment as permanent might differ by each organ. In addition, it remains unclear whether 5 years after allo-HCT is appropriate as the follow-up period to evaluate PI. We might underestimate PI when the follow-up period is too short. Conversely, we might overestimate PI because of the incorporation of factors with which allo-HCT is not directly related, such as aging, lifestyle,
and newly developed disease after allo-HCT, when the follow-up period is too long. PI could develop even in very late phases, such as 7 years after allo-HCT, suggesting the importance of long-term follow-up for survivors after allo-HCT. Notably, detailed observations, including organ function tests every 3-6 months, are recommended during the first two years after allo-HCT because many patients developed PI within 2 years posttransplant. We defined PI as around ≥30% impairment of the whole person in each organ on the same scale because we regarded this level as critical; however, this cutoff point warrants validation. Notably, the quality of life in long-term survivors without PI is, of course, not always good and, conversely, the quality of life in those with PI is not always poor. However, PI can result in recurrent infection or vascular events some day in the subsequent life of recipients of allo-HCT. We believe that this is a critical problem, particularly, in young patients. Because the evaluation of PI is based on the widely accepted guides published by the American Medical Association, retrospective analyses of PI are feasible in most institutes which have long-term follow-up programs. Multi-institutional studies will make it possible to validate the clinical usefulness of PIRFS as an endpoint for long-term success of allo-HCT. Furthermore, exploration of interventions to prevent the development of PI in prospective studies may provide additional well-being for long-term survivors after allo-HCT in the future.
In conclusion, this study demonstrates that PIRFS represented healthy life for survivors after allo-HCT and correlated with disease risk and KPS at transplant. The assessment of PIRFS yields novel information regarding the quality of long-term survival after allo-HCT, which cannot be represented even in well-executed endpoints such as GRFS. Hence, although our assessment method for transplant success warrants further investigation by prospective studies with larger cohorts of patients, this study proposes that PIRFS is a novel composite endpoint to assess long-term transplant success from a perspective different from previous evaluation methods. Acknowledgments The authors thank all the physicians, nurses, and other staff who participated in the care of these patients at the Department of Hematology and Oncology, Konan Kosei Hospital.
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Figure legends Figure 1. The disease-free survival (DFS), GVHD-free/relapse-free survival (GRFS), and permanent impairment-free, relapse-free survival (PIRFS) in the entire cohort. The 5-year DFS, GRFS, and PIRFS rates were 53.8%, 33.8%, and 40.6%, respectively.
Figure 2. The disease-free survival (DFS), GVHD-free/relapse-free survival (GRFS), and permanent impairment-free, relapse-free survival (PIRFS) for patients undergoing non-umbilical cord blood transplantation (UCBT; A) and UCBT (B). The PIRFS curve declined across the GRFS curve at 397 days posttransplant in UCBT recipients (B).
Figure 3. The cumulative incidence of permanent impairment in patients surviving for ≥180 days without relapse. Over 1 of 5 long-term survivors had some permanent impairment (PI; A). The umbilical cord blood (UCB) significantly correlated with the higher cumulative incidence of PI (B).
Table 1. Patients’ characteristics. Factors
Total
Survivors for ≥6 months without relapse
No. of patients Age, median (range)
164
121
50 (16–70)
47 (16–69)
84 (51)
56 (46)
105 (64)
79 (65)
54 (33)
32 (26)
117 (71)
86 (71)
47 (29)
35 (29)
Low
98 (60)
82 (68)
High
66 (40)
39 (32)
<3
120 (73)
94 (78)
≥3
44 (27)
27 (22)
16 (10)
14 (12)
148 (90)
107 (88)
RBM
4 (2)
4 (3)
RPB
29 (18)
20 (17)
URBM
64 (39)
49 (40)
URPB
4 (2)
3 (2)
UCB
63 (38)
45 (37)
4/8
2 (1)
2 (2)
5/8
2 (1)
2 (2)
6/8
1 (1)
1 (1)
7/8
17 (10)
12 (10)
Age at transplant ≥50 years Sex Male KPS (%) ≤90 Disease Myeloid malignancy Others Disease risk
HCT-CI score
Recipient and donor CMV serology Recipient and donor negative Other Donor/Graft type
Non-UCB HLA match status*
8/8
79 (48)
59 (49)
CsA-MTX
19 (12)
13 (11)
TAC-MTX
141 (86)
104 (86)
4 (2)
4 (3)
46 (28)
31 (26)
118 (72)
90 (74)
≤8 mg/kg
117 (71)
89 (74)
>8 mg/kg
47 (29)
32 (26)
≤100 mg/m2
132 (80)
100 (83)
2
32 (20)
21 (17)
≤6 Gy
99 (60)
68 (56)
>6 Gy
65 (40)
53 (44)
16 (10)
13 (11)
18 (11)
13 (11)
FLU-MEL-TBI
4 (2)
1 (1)
Others
9 (5)
4 (3)
CY-TBI (only non-UCBT)
25 (15)
21 (17)
BU-CY (only non-UCBT)
20 (12)
13 (11)
FLU-BU
12 (7)
8 (7)
CA-CY-TBI (only UCBT)
36 (22)
30 (25)
FLU-BU-TBI
10 (6)
7 (6)
Others
15 (9)
11 (9)
GVHD prophylaxis
Post CY-TAC-MMF Conditioning dose-intensity RIC MAC Conditioning regimen BU
MEL >100 mg/m TBI
Conditioning regimen 2 RIC FLU-CY-TBI 2
FLU-MEL (MEL ≤140 mg/m ) (only non-UCBT)
MAC
Follow-up period for surviving patients, median (months, range)
58.6 (12–131)
KPS, Karnofsky performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; CMV, cytomegalovirus; RBM, related donor and bone marrow; RPB, related donor and peripheral blood; URBM, unrelated donor and bone marrow; URPB, unrelated donor and peripheral blood; UCB, umbilical cord blood; CsA, cyclosporine; MTX, methotrexate; TAC, tacrolimus; CY, cyclophosphamide; MMF, mycophenolate mofetil; RIC, reduced intensity conditioning; MAC, myeloablative conditioning; BU, busulfan; MEL, melphalan; TBI, total body irradiation; FLU, fludarabine; CA, cytarabine. Data presented are n (%), unless otherwise indicated. *The four cases in 4/8 and 5/8 HLA match status were from related haploidentical donors. All other cases of mismatched grafts were from unrelated donors.
Table 2. Univariate and multivariate analyses of risk factors for GRFS and PIRFS.
GRFS
Variables
PIRFS Multivariate
Univariate HR (95% CI)
P
HR (95% CI)
Multivariate
Univariate P
HR (95% CI)
P
Age ≥50 years
1.47 (1.00–2.15)
0.049
1.02 (0.63–1.68)
0.92
1.56 (1.04–2.34)
0.03
Sex: male vs. female
1.42 (0.94–2.13)
0.09
1.21 (0.80–1.83)
0.37
0.93 (0.62–1.42)
0.75
Disease: myeloid vs. other 1.23 (0.80–1.89)
0.35
1.10 (0.70–1.72)
0.68
Disease risk: high vs. low 2.17 (1.48–3.17)
<0.01
KPS ≤90%
1.29 (0.87–1.93)
HCT-CI (≥3)
0.057
<0.01 2.10 (1.40–3.14)
<0.01 1.91 (1.26–2.88)
<0.01
0.20
2.03 (1.35–3.05)
<0.01 1.73 (1.14–2.63)
0.01
1.30 (0.85–1.97)
0.22
1.64 (1.05–2.55)
0.03
1.52 (0.97–2.37)
0.07
1.31 (0.66–2.60)
0.44
1.16 (0.59–2.31)
0.67
0.82 (0.54–1.23)
0.34
0.73 (0.48–1.12)
0.15
1.56 (1.04–2.33)
0.03
1.13 (0.73–1.76)
0.59
1.20 (0.75–1.90)
0.45
0.99 (0.59–1.65)
0.97
0.60 (0.40–0.90)
0.01
0.82 (0.54–1.24)
0.34
2.16 (1.48–3.16)
Conditioning intensity MAC vs. RIC Conditioning regimen BU: >8 mg/kg MEL: >100 mg/m TBI: > 6Gy
2
P
1.49 (0.99–2.25)
CMV serology Recipient or donor (+)
HR (95% CI)
1.11 (0.70–1.78)
0.78 (0.50–1.20)
0.65
0.26
Donor: related vs unrelated 1.36 (0.86–2.14)
0.19
Graft: non-UCB vs UCB
1.75 (1.16–2.70)
<0.01
1.24 (0.69–2.21)
0.47
1.75 (1.16–2.70)
0.98 (0.59–1.64)
0.95
<0.01 0.85 (0.57–1.28)
0.45
0.78 (0.39–1.55)
0.47
Graft type Mismatch (non-UCB)
GRFS, graft-versus-host disease-free relapse-free survival; PIRFS, permanent impairment-free relapse-free survival; KPS, Karnofsky performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; CMV, cytomegalovirus; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; BU, busulfan; MEL, melphalan; TBI, total body irradiation UCB, umbilical cord blood.
Table 3. Univariate and multivariate analyses of risk factors for the cumulative incidence of permanent impairment. Cumulative incidence of permanent impairment
Variables
Multivariate
Univariate HR (95% CI) KPS ≤90%
P
HR (95% CI)
P
2.34(1.09–5.03)
0.03
2.19 (0.98–4.89)
0.06
Conditioning regimen: MEL >100 mg/m 0.16 (0.02–1.26)
0.08
0.24 (0.03–1.99)
0.18
Graft: UCB vs other
2.57 (1.20–5.50)
0.02
2.35 (1.11–4.99)
0.03
Acute GVHD grade 3–4 by day 180
3.61 (1.08–12.0)
0.04
3.59 (1.04–12.4)
0.04
TMA by day 180
2.78 (1.05–7.34)
0.04
2.74 (1.10–6.87)
0.03
2
KPS, Karnofsky performance status; MEL, melphalan; UCB, umbilical cord blood; GVHD, graft-versus-host disease; TMA, thrombotic microangiopathy.
Table 4. Types of permanent impairment.
Organ
Disease
Causes
N
Kidney
Chronic kidney disease
Unknown
2
TMA
5
AKI (HC)
1
AKI (HC) + Unknown
2
AKI (HZ) + Unknown
1
BO
Chronic GVHD
5
BO + ALS
Chronic GVHD
1
COP
Immune reaction
1
COP + ALS
Immune reaction
1
Only DLCO decline
Unknown
3
Heart
Chronic heart failure
Cardiomyopathy
2
CNS
Leukoencephalopathy
TMA + Viral infection
1
Post-encephalitis
Idiopathic Encephalitis
1
Lung
TMA, thrombotic microangiopathy; AKI, acute kidney injury; HC, hemorrhagic cystitis; HZ, herpes zoster; BO, bronchiolitis obliterans; ALS, air leak syndrome; COP, cryptogenic organizing pneumonia; DLCO, carbon monoxide diffusing capacity; CNS, central nervous system
Journal Pre-proof
Permanent impairment-free, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant Yoshitaka Adachi MD , Kazutaka Ozeki MD, PhD , Shun Ukai MD , Ken Sagou MD , Nobuaki Fukushima MD, PhD , Akio Kohno MD, PhD PII: DOI: Reference:
S1083-8791(20)30058-6 https://doi.org/10.1016/j.bbmt.2020.01.025 YBBMT 55918
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
25 October 2019 28 January 2020
Please cite this article as: Yoshitaka Adachi MD , Kazutaka Ozeki MD, PhD , Shun Ukai MD , Ken Sagou MD , Nobuaki Fukushima MD, PhD , Akio Kohno MD, PhD , Permanent impairmentfree, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant, Biology of Blood and Marrow Transplantation (2020), doi: https://doi.org/10.1016/j.bbmt.2020.01.025
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
Highlights
We estimated permanent impairment of six vital organs in allogeneic transplant.
The 5-year permanent impairment-free, relapse-free survival (PIRFS) was 40.6%.
PIRFS is an endpoint to assess long-term transplant success from a novel perspective.
Permanent impairment-free, relapse-free survival: A novel composite endpoint to evaluate long-term success in allogeneic transplant Yoshitaka Adachi1)2), MD, Kazutaka Ozeki2), MD, PhD, Shun Ukai2), MD, Ken Sagou2), MD, Nobuaki Fukushima2), MD, PhD, Akio Kohno2), MD, PhD 1) Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan 2) Department of Hematology and Oncology, Konan Kosei Hospital, Konan, Japan Corresponding author: Yoshitaka Adachi, MD Department of Hematology and Oncology, Nagoya University Graduate School of Medicine 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan Phone No: +81-52-744-2145 Fax No: +81-52-744-2157 E-mail: [email protected] Short title: Permanent impairment after allogeneic transplant Financial Disclosure Statement The authors declare no conflict of interest.
Abstract Permanent impairment (PI) of vital organs is one of the transplant-related health problems affecting the quality of life and morbidity even in patients who do not develop graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT), but no data are available on PI of multiple organs. This retrospective study aims to estimate a novel composite endpoint of PI-free, relapse-free survival (PIRFS) in 164 allo-HCT recipients. We defined PI as >26%–30% impairment of the whole person in six vital organs using the whole person impairment rating. Conventional GVHD-free/relapse-free survival (GRFS) and PIRFS at 5 years were 33.8% (95% CI: 26.5%–41.3%) and 40.6% (95% CI: 32.6%–48.4%). In the whole cohort, PIRFS was higher than GRFS at any time after allo-HCT. However, PIRFS was lower than GRFS after day 397 posttransplant in patients who underwent umbilical cord blood transplantation (UCBT). In UCBT recipients, 5-year GRFS and PIRFS were 47.6% (95% CI: 34.3%–59.7%) and 39.2% (95% CI: 26.6%–51.5%). The cumulative incidence of PI after 5 years was 20.9% (95% CI: 13.7%–29.0%) in patients surviving for ≥6 months without relapse. The multivariate analysis revealed that high disease risk (HR, 1.91; 95% CI: 1.26–2.88; P < 0.01) and Karnofsky performance status ≤90% at transplant (HR, 1.73; 95% CI: 1.14–2.63; P = 0.01) correlated with the lower PIRFS, whereas
UCBT (HR, 2.35; 95% CI: 1.11–4.99; P = 0.03), grade III–IV acute GVHD by day 180 (HR, 3.59; 95% CI: 1.04–12.4; P = 0.04), and thrombotic microangiopathy by day 180 (HR, 2.74; 95% CI: 1.10–6.87; P = 0.03) significantly correlated with the higher incidence of PI. Over 1 of 5 long-term survivors had PI. Hence, this study proposes that PIRFS is a useful endpoint to assess long-term transplant success from a perspective different from those established previously. Keywords permanent impairment; graft-versus-host disease-free relapse-free survival; permanent impairment-free relapse-free survival; umbilical cord blood; thrombotic microangiopathy; long-term transplant success
Introduction Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a promising treatment procedure for patients with hematological diseases. Remarkable advances in transplantation techniques and supportive care practices have enhanced the long-term survival after allo-HCT, and transplant-related health problems affecting the quality of life have garnered considerable interest lately [1-4]. Graft-versus-host disease (GVHD) is the leading cause of mortality and late morbidity after
allo-HCT. GVHD-free, relapse-free survival (GRFS), a composite endpoint incorporating the occurrence of GVHD as an event, has been extensively used to assess transplant success in clinical studies [5-7]. Recently, “current GRFS” and “refractory GRFS” were developed to measure transplant success more precisely because GVHD could resolve completely or partially posttreatment [8,9]. However, even allo-HCT recipients who do not develop GVHD are at risks for several complications, including infectious diseases, thrombotic microangiopathy (TMA), and organ failure after allo-HCT [10-14], which can often cause permanent impairment (PI). PI worsens the quality of life and, sometimes, results in non-relapse death [15,16]. Hence, it is imperative to assess the proportion of allo-HCT recipients who survive without PI to evaluate transplant success. Although several studies have focused on single organ impairment after allo-HCT [12,14,15,17-23], no data are available on PI of multiple vital organs. Hence, this study aims to investigate the cumulative incidence of PI and the likelihood of survival after allo-HCT without PI, relapse, or death, which we termed “PI-free, relapse-free survival (PIRFS).” Furthermore, this study compares PIRFS with conventional GRFS. Materials and Methods Patients
A total of 167 adult patients underwent first allo-HCT for the treatment of hematological diseases at the Konan Kosei Hospital (Konan, Japan) between January 2008 and December 2017. Of these, we excluded 3 patients who already had organ impairment as defined in this study at transplant. Hence, we analyzed 164 patients. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Konan Kosei Hospital. Furthermore, we obtained written informed consent from all patients before undergoing allo-HCT. Donor selection and treatment procedures Although the first choice for a donor was a human leukocyte antigen (HLA)–matched sibling, in the absence of a suitable HLA-matched sibling donor, we selected bone marrow or peripheral blood from an HLA-matched unrelated donor, peripheral blood from an HLA-haploidentical related donor, or single-unit umbilical cord blood (UCB) as a graft source. Sometimes, we used UCB for patients in urgent need of allo-HCT. A UCB donor was selected on the basis of cell dose and HLA-A, HLA-B, and HLA-DR matching at the antigen level. We evaluated the HLA-matching between the recipient and unrelated donors of the bone marrow or peripheral blood based on the compatibility of HLA-A, HLA-B, HLA-C, and HLA-DRB1 at the allelic level. In addition, based on the patients’ age, disease risk,
significant comorbidities, and donor types, we decided the type of conditioning regimens. Typically, the GVHD prophylaxis contained tacrolimus or cyclosporine and short-term methotrexate. However, tacrolimus, mycophenolate mofetil, and posttransplantation cyclophosphamide were used in cases of allo-HCT from haploidentical related donors. Furthermore, patients who developed GVHD, requiring systemic treatment, were primarily treated with prednisolone at 0.5–1 mg/kg/day. Definitions Regarding the disease risk, low-risk diseases included acute leukemia in the first or second complete remission, chronic myeloid leukemia in the first or second chronic phase, myelodysplastic syndrome in refractory anemia or refractory anemia with ring sideroblasts, chemotherapy-sensitive lymphoma or multiple myeloma, and non-malignant hematological diseases. Notably, high-risk diseases included all other diagnoses [24]. We defined regimens with a total busulfan dose of >9 mg/kg, melphalan dose of >140 mg/m2, total body irradiation (TBI) of >5 Gy for a single dose, or TBI of >8 Gy fractionated as myeloablative conditioning [25]. In addition, reduced-intensity conditioning was fludarabine-based with or without low-dose TBI (≤4 Gy). Our institute does not use non-myeloablative regimens. We evaluated hematopoietic cell transplantation–specific comorbidity index scores as described previously
by Sorror et al. [24]. In addition, acute GVHD was graded according to the established criteria [26], and we diagnosed chronic GVHD as reported previously [27]. The DFS was defined as the time from transplantation to relapse of the underlying malignancy for which allo-HCT was performed or death. GRFS was defined as the time from transplantation to the onset of grade III–IV acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death as described previously by Holtan et al. [5]. PIRFS events were defined as PI diagnosis described below, relapse, or death from any cause after allo-HCT. That is, we defined PIRFS as the time from transplantation to PI diagnosis, relapse or death. Permanent impairment assessment We assessed PI of multiple vital organs. In this study, we assessed the function of the following organs: heart, lungs, liver, digestive tracts, kidneys, and central nervous system. Using “The American Medical Association’s Guides to the Evaluation of Permanent Impairment,” we assessed the degree of PI on the same scale in different organs [28]. In addition, we defined PI as around ≥26%–30% impairment of the whole person for >6 months to consider the impairment as permanent. The date of PI diagnosis was defined as 180 days after the onset of impairment. We excluded the impairment in the first 6 months after allo-HCT to avoid misclassifying reversible impairment as permanent. The renal function was assessed
by calculating the estimated glomerular filtration rate (GFR) as reported previously [29]. Moreover, renal impairment was defined as an estimated GFR ≤45 mL/min/1.73 m2 (≥30% impairment of the whole person). We defined liver impairment as follows: (1) progressive chronic liver disease with objective evidence or history of jaundice, ascites, or bleeding esophageal or gastric varices within past year; and (2) possibly affected nutrition and strength; or (3) intermittent hepatic encephalopathy (≥30% impairment of the whole person). Pulmonary impairment was defined as follows: (1) measured forced vital capacity ≤59% of predicted; or (2) measured forced expiratory volume in the first second ≤59% of predicted; or (3) diffusing capacity for carbon monoxide ≤59% of predicted (around ≥26% impairment of the whole person). However, we did not assess the maximum oxygen consumption and metabolic equivalents. Cardiac, gastrointestinal, and central nervous system impairments were evaluated based on each disease (≥30% impairment of the whole person). Notably, we had a long-term follow-up program to provide lifelong support to patients who underwent allo-HCT. We assessed the severity and activity of chronic GVHD and the function of vital organs for survivors without relapse after allo-HCT semiannually in the first year and annually from the second year on. We also evaluated renal function at least every 3 months. After a patient developed some kind of organ impairment or GVHD, we assessed relevant
organ function at least every 3 months. Furthermore, we ascertained whether the recovery of organ function was noted during the follow-up period after the PI diagnosis. Endpoints and statistical analysis
Using the Fisher’s exact test and the Wilcoxon rank-sum test, we compared categorized and continuous variables, respectively. We estimated the univariate probabilities of GRFS and PIRFS using the Kaplan–Meier curves and compared using log-rank tests [30]. The occurrence of PI was estimated by cumulative incidence curves using landmark analysis at 6 months after transplant because we aimed to evaluate PI in patients surviving ≥6 months after allo-HCT. Death and relapse were the competing events for the analysis of PI [31]. Gray’s test was used to assess the difference between various subgroups for the cumulative incidence of PI. Then, Cox regression models [32] were developed to determine the independent effect of variables on GRFS and PIRFS. Using proportional hazard models of Fine and Gray [33], we examined the independent effect of variables on the cumulative incidence of PI. We included pretransplant variables when a significant level of P <0.1 and proportionality were detected in the univariate Cox regression analysis for GRFS and PIRFS. We included not only pretransplant variables but also posttransplant variables within 6 months on the landmark analysis for the cumulative incidence of PI. Notably, a significance level of P <0.05
(two-sided) was needed in the multivariate analysis. All statistical analyses in this study were performed using EZR on R commander version 1.32 [34]. Results Patients’ characteristics In this study, we enrolled 164 patients [median age: 50 (range: 16–70) years] with various hematological diseases. Table 1 summarizes the patients’ clinical characteristics. We did not use T-cell depletion as GVHD prophylaxis in this study. The most UCB units were 4/6-matched to patients for HLA-A, -B, and -DR antigens. In addition, the majority of patients, including all patients undergoing umbilical cord blood transplantation (UCBT), received tacrolimus in combination with short-term methotrexate as GVHD prophylaxis, while the remaining received cyclosporine instead of tacrolimus, and four who underwent haploidentical
allo-HCT received
tacrolimus
and
mycophenolate
mofetil
besides
posttransplantation cyclophosphamide. The majority of UCBT recipients received the TBI-containing conditioning regimen. In addition, high-dose cytarabine was added to the conventional cyclophosphamide and TBI regimen as myeloablative conditioning in UCBT. For the landmark analysis, we excluded 25 patients with relapse or progression disease, and 18 patients with non-relapse death within 180 days after allo-HCT. Hence, we included the
remaining 121 patients who survived for ≥6 months without relapse in the landmark analysis for the cumulative incidence of PI. The median follow-up period for surviving patients was 58.6 (range: 12–131) months. DFS, GRFS, and PIRFS In the entire cohort, 2-year DFS, GRFS, and PIRFS were 59.5% (95% CI: 51.5%–66.6%), 37.0% (95% CI: 29.7%–44.4%), and 47.9% (95% CI: 40.0%–55.4%), respectively. In addition, 5-year DFS, GRFS, and PIRFS were 53.8% (95% CI: 45.6%–61.4%), 33.8% (95% CI: 26.5%–41.3%), and 40.6% (95% CI: 32.6%–48.4%), respectively (Fig. 1). PIRFS was higher than GRFS at any time after allo-HCT in the entire cohort. We also observed this tendency in patients who underwent non-UCBT (Fig. 2A). However, in patients who underwent UCBT, the PIRFS curve declined across the GRFS curve at 397 days posttransplant (Fig. 2B). In patients who underwent UCBT, 5-year DFS, GRFS, and PIRFS were 57.1% (95% CI: 43.4%–68.7%), 47.6% (95% CI: 34.3%–59.7%), and 39.2% (95% CI: 26.6%–51.5%), respectively. Univariate and multivariate analyses of risk factors for GRFS and PIRFS Both univariate and multivariate analyses were performed to detect the pretransplant variables related to GRFS and PIRFS. Among various variables listed in Table 2, the
univariate analysis revealed that age ≥50 years, high-risk disease, BU >8 mg/kg, TBI ≤6 Gy, and non-UCBT significantly correlated with lower GRFS (Table 2). The adjustment of potential variables by the multivariate analysis revealed that high-risk disease (HR, 2.16; 95% CI: 1.48–3.16; P <0.01) and non-UCBT (HR, 1.75; 95% CI: 1.16–2.70; P <0.01) significantly correlated with lower GRFS. Conversely, age ≥50 years, high-risk disease, Karnofsky performance status (KPS) ≤90%, and hematopoietic cell transplantation–specific comorbidity index scores ≥3 significantly correlated with lower PIRFS by the univariate analysis. Furthermore, the multivariate analysis revealed that high-risk disease (HR, 1.91; 95% CI: 1.26–2.88; P < 0.01) and KPS ≤90% (HR, 1.73; 95% CI: 1.14–2.63; P = 0.01) correlated with lower PIRFS. Cumulative incidence of permanent impairment We analyzed 121 patients in the landmark analysis for the cumulative incidence of PI (Table 1). Figure 3 shows the cumulative incidence of PI in patients who survived for ≥6 months without relapse posttransplant. The cumulative incidence of PI by 5 years after allo-HCT was 20.9% (95% CI: 13.7%–29.0%) in the entire cohort (Fig. 3A). The cumulative incidence of PI was significantly higher in patients who underwent UCBT than in those who underwent non-UCBT in the Gray test—30.6% (95% CI: 17.2%–45.1%) for UCBT and 15.1% (95% CI:
7.6%–25.0%) for non-UCBT (P = 0.016; Fig. 3B). The cumulative incidence of respiratory PI by 5 years after allo-HCT was 10.4% (95% CI: 5.4%–17.3%). The cumulative incidence of renal PI 5 years after allo-HCT was 10.7% (95% CI: 5.8%–17.3%). The median period from transplantation to PI diagnosis was 17 (range: 12–83) months. Twenty out of 26 patients who were diagnosed as having PI developed PI within 2 years after allo-HCT. In addition, we assessed the degree of impairment precisely in all patients with persistent impairment from our electronic medical chart. Of note, the organ impairment did not recover in all patients who were diagnosed with PI during the follow-up period. The median follow-up period after the PI diagnosis was 28.5 (range: 2.2–108) months. Moreover, we assessed the risk factors for the cumulative incidence of PI in patients who survived for ≥6 months without relapse after allo-HCT. Besides the pretransplant variables shown in Table 2, we included the following posttransplant complications within 6 months after allo-HCT: grade II–IV acute GVHD; grade III–IV acute GVHD; cytomegalovirus antigenemia; veno-occlusive disease; TMA; and sepsis. Table 3 presents variables with a P < 0.1 in the univariate analysis. The univariate analysis revealed that KPS ≤90%, MEL ≤100 mg/m2, UCB, grade III–IV acute GVHD, and TMA significantly correlated with the higher cumulative incidence of PI. The adjustment of potential variables by the multivariate analysis revealed that UCB (HR, 2.35;
95% CI: 1.11–4.99; P = 0.03), grade III–IV acute GVHD (HR, 3.59; 95% CI: 1.04–12.4; P = 0.04), and TMA (HR, 2.74; 95% CI: 1.10–6.87; P = 0.03) significantly correlated with the higher cumulative incidence of PI. Types of PI Table 4 shows the types of PI. If a patient developed multiple PI of different organs, PI that developed earliest after allo-HCT was described. We observed PI in 26 patients. The leading cause of chronic kidney disease (CKD) as renal PI was TMA. After the development of hemorrhagic cystitis, a patient was diagnosed with renal PI. In three patients with mild kidney failure, the renal function was aggravated by viral infectious diseases. The leading cause of respiratory PI was bronchiolitis obliterans. In addition, recurrent pneumothorax (air leak syndrome) was one of the causes of respiratory PI in two patients. Moreover, two patients who were diagnosed with cardiomyopathy had fatigue on exertion and required diuretics regularly to alleviate symptoms. Besides, we observed a decline in the cognitive function and dysgraphia in a patient who developed leukoencephalopathy. Furthermore, a patient who developed encephalitis had a persistent disturbance of consciousness and became bedridden. Discussion
This study estimated PIRFS in 164 patients and the cumulative incidence of PI in 121 patients who survived for ≥6 months without relapse. We observed that 5-year PIRFS was 40.6% and that over 1 of 5 long-term survivors had some PI. To date, several studies have reported complications after allo-HCT focusing on each organ [12,14,15,17-23,35]. Unlike other studies, this study focused on irreversible impairment rather than temporary impairment because we assumed that irreversible impairment causes adverse effects on the quality of life and late morbidity in long-term survivors. A study proposed GRFS as a composite endpoint that measured freedom from ongoing morbidity and denoted ideal allo-HCT recovery [5]. Considering that PI caused by complications other than cGVHD could exert a considerable negative impact on health and quality of life after allo-HCT, we proposed PIRFS as a novel composite endpoint that reflected deterioration in the quality of life and non-lethal morbidity more realistically in long-term survivors of allo-HCT. This study revealed that PIRFS was higher than GRFS at any time after allo-HCT in the entire cohort, suggesting that patients who developed severe acute GVHD or systemic therapy-requiring chronic GVHD did not necessarily have PI of vital organs. In UCBT recipients, however, PIRFS was lower than GRFS after around 1-year posttransplant, revealing that many patients had PI, although they did not develop severe
acute GVHD or systemic therapy-requiring chronic GVHD particularly in the UCBT setting. Tong et al. reported that UCBT without antithymocyte globulin reported higher 3-year GRFS than unrelated peripheral blood stem cell transplantation [36]. Moreover, in this study, multivariate analysis revealed that UCBT was markedly correlated with higher GRFS, but 5-year PIRFS in UCBT recipients was a bit lower than that in non-UCBT recipients. In addition, UCBT markedly correlated with the higher cumulative incidence of PI in patients surviving for ≥6 months without relapse. Although the cause of elevated incidence of PI in UCBT recipients remains unclear, it could be attributable to various factors. We added high-dose cytarabine to the conventional cyclophosphamide and TBI regimen to augment the antitumor effect [37], and added low-dose TBI (2–4 Gy) to decreased-intensity conditioning regimen to prevent graft failure, for patients receiving UCBT. In UCBT setting, multiple nephrotoxic antibiotics or antiviral drugs are often needed for a long time because of delayed neutrophil engraftment or high incidence of viral infection. We did not validate assumed risk factors mentioned above due to the small sample size and the heterogeneity in our cohort; therefore, further validation in the prospective study with larger cohorts of patients will be required to explore what we can do to prevent PI in advance. Furthermore, age at transplant did not markedly correlate with PIRFS and cumulative incidence of PI in the multivariate
analysis, suggesting that many of PI were markedly affected by the posttransplant complications, including TMA, viral infection, or GVHD, rather than aging changes in organs at transplant. In addition, the multivariate analysis revealed that grade III–IV acute GVHD and TMA, as well as UCBT, markedly correlated with the higher cumulative incidence of PI. Reportedly, TMA is clinically represented by a combination of microangiopathic hemolytic anemia, neurologic dysfunction, renal impairment, and fever [38,39]. Endothelial damage is crucial for the TMA pathogenesis and is induced by multiple factors, including immunosuppressants, high-dose chemotherapy as conditioning, GVHD, infection, and irradiation [40-43]. Neurological and renal damage sometimes results in irreversible impairment. A study reported that TMA was one of the risk factors for CKD after allo-HCT [44]. In this study, a patient who developed TMA needed maintenance dialysis. Hence, we need to develop appropriate prevention and treatment strategy against TMA to prevent PI. Of note, the kidneys were the most frequently impaired organ persistently after allo-HCT. Reportedly, the cumulative incidence of CKD at 10 years after allo-HCT was 25%–35% [45,46]. A study with a large, community-based population reported a graded correlation between a decreased estimated GFR and the risk of death, cardiovascular events, and hospitalization [47], thus; we
need to prevent the development of CKD for long-term survivors after allo-HCT. This study suggests that only assessment of GVHD is inadequate to estimate morbidity and quality of life for the long-term survivors because multiple causes of PI were complications other than GVHD (Table 4). We also think that both GRFS and PIRFS can be used as complementary endpoints in terms of both GVHD and PI. In addition, we assessed PI in all patients with persistent impairment, probably, because renal and respiratory impairment, which were assessed by only objective data, accounted for the majority of PI. Nevertheless, the efficacy of assessment of PI in a prospective study warrants further investigation. This study has several limitations. First, while we defined PI as impairment present >6 months, CKD is normally defined as abnormalities of the kidney structure or function, present for >3 months. We considered that 3 months was too short to consider impairment as permanent in the posttransplant setting; however, whether 6 months is optimal as the duration of impairment remains unclear. The duration necessary to regard impairment as permanent might differ by each organ. In addition, it remains unclear whether 5 years after allo-HCT is appropriate as the follow-up period to evaluate PI. We might underestimate PI when the follow-up period is too short. Conversely, we might overestimate PI because of the incorporation of factors with which allo-HCT is not directly related, such as aging, lifestyle,
and newly developed disease after allo-HCT, when the follow-up period is too long. PI could develop even in very late phases, such as 7 years after allo-HCT, suggesting the importance of long-term follow-up for survivors after allo-HCT. Notably, detailed observations, including organ function tests every 3-6 months, are recommended during the first two years after allo-HCT because many patients developed PI within 2 years posttransplant. We defined PI as around ≥30% impairment of the whole person in each organ on the same scale because we regarded this level as critical; however, this cutoff point warrants validation. Notably, the quality of life in long-term survivors without PI is, of course, not always good and, conversely, the quality of life in those with PI is not always poor. However, PI can result in recurrent infection or vascular events some day in the subsequent life of recipients of allo-HCT. We believe that this is a critical problem, particularly, in young patients. Because the evaluation of PI is based on the widely accepted guides published by the American Medical Association, retrospective analyses of PI are feasible in most institutes which have long-term follow-up programs. Multi-institutional studies will make it possible to validate the clinical usefulness of PIRFS as an endpoint for long-term success of allo-HCT. Furthermore, exploration of interventions to prevent the development of PI in prospective studies may provide additional well-being for long-term survivors after allo-HCT in the future.
In conclusion, this study demonstrates that PIRFS represented healthy life for survivors after allo-HCT and correlated with disease risk and KPS at transplant. The assessment of PIRFS yields novel information regarding the quality of long-term survival after allo-HCT, which cannot be represented even in well-executed endpoints such as GRFS. Hence, although our assessment method for transplant success warrants further investigation by prospective studies with larger cohorts of patients, this study proposes that PIRFS is a novel composite endpoint to assess long-term transplant success from a perspective different from previous evaluation methods. Acknowledgments The authors thank all the physicians, nurses, and other staff who participated in the care of these patients at the Department of Hematology and Oncology, Konan Kosei Hospital.
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Figure legends Figure 1. The disease-free survival (DFS), GVHD-free/relapse-free survival (GRFS), and permanent impairment-free, relapse-free survival (PIRFS) in the entire cohort. The 5-year DFS, GRFS, and PIRFS rates were 53.8%, 33.8%, and 40.6%, respectively.
Figure 2. The disease-free survival (DFS), GVHD-free/relapse-free survival (GRFS), and permanent impairment-free, relapse-free survival (PIRFS) for patients undergoing non-umbilical cord blood transplantation (UCBT; A) and UCBT (B). The PIRFS curve declined across the GRFS curve at 397 days posttransplant in UCBT recipients (B).
Figure 3. The cumulative incidence of permanent impairment in patients surviving for ≥180 days without relapse. Over 1 of 5 long-term survivors had some permanent impairment (PI; A). The umbilical cord blood (UCB) significantly correlated with the higher cumulative incidence of PI (B).
Table 1. Patients’ characteristics. Factors
Total
Survivors for ≥6 months without relapse
No. of patients Age, median (range)
164
121
50 (16–70)
47 (16–69)
84 (51)
56 (46)
105 (64)
79 (65)
54 (33)
32 (26)
117 (71)
86 (71)
47 (29)
35 (29)
Low
98 (60)
82 (68)
High
66 (40)
39 (32)
<3
120 (73)
94 (78)
≥3
44 (27)
27 (22)
16 (10)
14 (12)
148 (90)
107 (88)
RBM
4 (2)
4 (3)
RPB
29 (18)
20 (17)
URBM
64 (39)
49 (40)
URPB
4 (2)
3 (2)
UCB
63 (38)
45 (37)
4/8
2 (1)
2 (2)
5/8
2 (1)
2 (2)
6/8
1 (1)
1 (1)
7/8
17 (10)
12 (10)
Age at transplant ≥50 years Sex Male KPS (%) ≤90 Disease Myeloid malignancy Others Disease risk
HCT-CI score
Recipient and donor CMV serology Recipient and donor negative Other Donor/Graft type
Non-UCB HLA match status*
8/8
79 (48)
59 (49)
CsA-MTX
19 (12)
13 (11)
TAC-MTX
141 (86)
104 (86)
4 (2)
4 (3)
46 (28)
31 (26)
118 (72)
90 (74)
≤8 mg/kg
117 (71)
89 (74)
>8 mg/kg
47 (29)
32 (26)
≤100 mg/m2
132 (80)
100 (83)
2
32 (20)
21 (17)
≤6 Gy
99 (60)
68 (56)
>6 Gy
65 (40)
53 (44)
16 (10)
13 (11)
18 (11)
13 (11)
FLU-MEL-TBI
4 (2)
1 (1)
Others
9 (5)
4 (3)
CY-TBI (only non-UCBT)
25 (15)
21 (17)
BU-CY (only non-UCBT)
20 (12)
13 (11)
FLU-BU
12 (7)
8 (7)
CA-CY-TBI (only UCBT)
36 (22)
30 (25)
FLU-BU-TBI
10 (6)
7 (6)
Others
15 (9)
11 (9)
GVHD prophylaxis
Post CY-TAC-MMF Conditioning dose-intensity RIC MAC Conditioning regimen BU
MEL >100 mg/m TBI
Conditioning regimen 2 RIC FLU-CY-TBI 2
FLU-MEL (MEL ≤140 mg/m ) (only non-UCBT)
MAC
Follow-up period for surviving patients, median (months, range)
58.6 (12–131)
KPS, Karnofsky performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; CMV, cytomegalovirus; RBM, related donor and bone marrow; RPB, related donor and peripheral blood; URBM, unrelated donor and bone marrow; URPB, unrelated donor and peripheral blood; UCB, umbilical cord blood; CsA, cyclosporine; MTX, methotrexate; TAC, tacrolimus; CY, cyclophosphamide; MMF, mycophenolate mofetil; RIC, reduced intensity conditioning; MAC, myeloablative conditioning; BU, busulfan; MEL, melphalan; TBI, total body irradiation; FLU, fludarabine; CA, cytarabine. Data presented are n (%), unless otherwise indicated. *The four cases in 4/8 and 5/8 HLA match status were from related haploidentical donors. All other cases of mismatched grafts were from unrelated donors.
Table 2. Univariate and multivariate analyses of risk factors for GRFS and PIRFS.
GRFS
Variables
PIRFS Multivariate
Univariate HR (95% CI)
P
HR (95% CI)
Multivariate
Univariate P
HR (95% CI)
P
Age ≥50 years
1.47 (1.00–2.15)
0.049
1.02 (0.63–1.68)
0.92
1.56 (1.04–2.34)
0.03
Sex: male vs. female
1.42 (0.94–2.13)
0.09
1.21 (0.80–1.83)
0.37
0.93 (0.62–1.42)
0.75
Disease: myeloid vs. other 1.23 (0.80–1.89)
0.35
1.10 (0.70–1.72)
0.68
Disease risk: high vs. low 2.17 (1.48–3.17)
<0.01
KPS ≤90%
1.29 (0.87–1.93)
HCT-CI (≥3)
0.057
<0.01 2.10 (1.40–3.14)
<0.01 1.91 (1.26–2.88)
<0.01
0.20
2.03 (1.35–3.05)
<0.01 1.73 (1.14–2.63)
0.01
1.30 (0.85–1.97)
0.22
1.64 (1.05–2.55)
0.03
1.52 (0.97–2.37)
0.07
1.31 (0.66–2.60)
0.44
1.16 (0.59–2.31)
0.67
0.82 (0.54–1.23)
0.34
0.73 (0.48–1.12)
0.15
1.56 (1.04–2.33)
0.03
1.13 (0.73–1.76)
0.59
1.20 (0.75–1.90)
0.45
0.99 (0.59–1.65)
0.97
0.60 (0.40–0.90)
0.01
0.82 (0.54–1.24)
0.34
2.16 (1.48–3.16)
Conditioning intensity MAC vs. RIC Conditioning regimen BU: >8 mg/kg MEL: >100 mg/m TBI: > 6Gy
2
P
1.49 (0.99–2.25)
CMV serology Recipient or donor (+)
HR (95% CI)
1.11 (0.70–1.78)
0.78 (0.50–1.20)
0.65
0.26
Donor: related vs unrelated 1.36 (0.86–2.14)
0.19
Graft: non-UCB vs UCB
1.75 (1.16–2.70)
<0.01
1.24 (0.69–2.21)
0.47
1.75 (1.16–2.70)
0.98 (0.59–1.64)
0.95
<0.01 0.85 (0.57–1.28)
0.45
0.78 (0.39–1.55)
0.47
Graft type Mismatch (non-UCB)
GRFS, graft-versus-host disease-free relapse-free survival; PIRFS, permanent impairment-free relapse-free survival; KPS, Karnofsky performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; CMV, cytomegalovirus; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; BU, busulfan; MEL, melphalan; TBI, total body irradiation UCB, umbilical cord blood.
Table 3. Univariate and multivariate analyses of risk factors for the cumulative incidence of permanent impairment. Cumulative incidence of permanent impairment
Variables
Multivariate
Univariate HR (95% CI) KPS ≤90%
P
HR (95% CI)
P
2.34(1.09–5.03)
0.03
2.19 (0.98–4.89)
0.06
Conditioning regimen: MEL >100 mg/m 0.16 (0.02–1.26)
0.08
0.24 (0.03–1.99)
0.18
Graft: UCB vs other
2.57 (1.20–5.50)
0.02
2.35 (1.11–4.99)
0.03
Acute GVHD grade 3–4 by day 180
3.61 (1.08–12.0)
0.04
3.59 (1.04–12.4)
0.04
TMA by day 180
2.78 (1.05–7.34)
0.04
2.74 (1.10–6.87)
0.03
2
KPS, Karnofsky performance status; MEL, melphalan; UCB, umbilical cord blood; GVHD, graft-versus-host disease; TMA, thrombotic microangiopathy.
Table 4. Types of permanent impairment.
Organ
Disease
Causes
N
Kidney
Chronic kidney disease
Unknown
2
TMA
5
AKI (HC)
1
AKI (HC) + Unknown
2
AKI (HZ) + Unknown
1
BO
Chronic GVHD
5
BO + ALS
Chronic GVHD
1
COP
Immune reaction
1
COP + ALS
Immune reaction
1
Only DLCO decline
Unknown
3
Heart
Chronic heart failure
Cardiomyopathy
2
CNS
Leukoencephalopathy
TMA + Viral infection
1
Post-encephalitis
Idiopathic Encephalitis
1
Lung
TMA, thrombotic microangiopathy; AKI, acute kidney injury; HC, hemorrhagic cystitis; HZ, herpes zoster; BO, bronchiolitis obliterans; ALS, air leak syndrome; COP, cryptogenic organizing pneumonia; DLCO, carbon monoxide diffusing capacity; CNS, central nervous system