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Impact of Donor Age on Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults with Acute Myeloid Leukemia
Abid, M. B., Estrada-Merly, N., Zhang, M. J., Chen, K., Allan, D., Bredeson, C., Sabloff, M., Guru Murthy, G. S., Badar, T., Hashmi, S., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Allogeneic hematopoietic cell transplant (alloHCT) provides cure for older patients with acute myeloid leukemia (AML); however, disease relapse remains a major concern. Based on recent data suggesting that younger donor age confers the greatest benefit among matched unrelated donors (MUD), we attempted to answer a practical question: which donor type provides the best outcomes when an older patient with AML has a matched sibling donor (MSD, also older) vs the best MUD? METHODS This retrospective cohort registry study accessed data from Center for International Blood and Marrow Transplant Research database (CIBMTR) in patients with AML 50 years or older undergoing alloHCT from older MSD (aged≥50) or younger MUD (aged≤35) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host-disease (GVHD) prophylaxis. The primary outcome was relapse risk. Secondary outcomes included non-relapse mortality (NRM), GVHD, disease-free survival (DFS), and overall survival (OS). RESULTS Among 4684 eligible patients, 1736 underwent alloHCT with an older MSD whereas 2948 received transplant from a younger MUD. In multivariable analysis, compared to an alloHCT from older MSDs, younger MUDs conferred a decreased relapse risk (HR 0.86; p=.005) and a significantly lower adjusted 5-year cumulative incidence of relapse (35% vs 41%; p=.003), but was associated with an increased risk for chronic GVHD (HR 1.18; 95% CI, 1.08-1.29; p=.0002) and greater NRM only in the earlier period from 2011-2015 (HR 1.24; p=.016). The corresponding NRM rates were significantly lower in the more recent period from 2016-2018 (HR 0.78; p=.017). The adjusted 5-year DFS probability was 44% (95% CI, 42%-46%) with an alloHCT from younger MUDs compared to 41% (95% CI, 38%-43%) with an older MSD (p=.04). CONCLUSION In older patients with AML undergoing alloHCT, the use of younger MUDs is associated with a decreased relapse risk and improved DFS compared to older MSDs.
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Younger Matched Unrelated Donors Confer Decreased Relapse Compared to Older Sibling Donors in Older B-cell ALL Patients Undergoing Allogeneic Hematopoietic Cell Transplantation
Abid, M. B., Merly, N. E., Zhang, M. J., Chen, K., Bredeson, C., Allan, D., Sabloff, M., Marks, D. I., Litzow, M., Hourigan, C., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION While allogeneic hematopoietic cell transplant (alloHCT) offers cures for older patients with acute lymphoblastic leukemia (ALL), disease relapse remains a major issue. Whether matched sibling donors (MSD) are still the preferred donor choice compared to younger matched unrelated donors (MUD), in the contemporary era of improved transplant practices, remains unknown. METHODS This retrospective cohort registry study queried the Center for International Blood and Marrow Transplant Research database (CIBMTR) data in B-cell ALL patients 50 years or older, undergoing alloHCT from older MSDs (donor age ≥ 50) or younger MUDs (donor age ≤ 35) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft versus host disease (GVHD) prophylaxis strategies. The primary outcome was relapse risk whereas secondary outcomes included non-relapse mortality (NRM), GVHD, leukemia-free survival (LFS), and overall survival (OS). RESULTS Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median donor age, 58) whereas 539 received transplant from a younger MUD (median donor age, 25). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.68; p=.002) vs older MSDs. The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs compared to older MSDs (26% vs 37%; p=.001). Younger MUDs were associated with a greater risk of chronic GVHD compared to older MSDs (HR 1.33; 95% CI, 1.10-1.61; p=.003). Compared to older MSDs, younger MUDs conferred an increased NRM (HR 1.38; p=.02) and higher adjusted cumulative incidence of NRM at 5 years (31% vs 22%; p=.006). There were no differences in OS or LFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.09; p=.37; DFS: HR 0.95; p=.57). CONCLUSION Younger MUDs could be considered as a possible way to prevent relapse after alloHCT in older adults with ALL. Combining the use of younger MUDs with improved strategies to reduce GVHD is worth further exploration to improve outcomes.
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Relapse and Disease-Free Survival in Patients With Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation Using Older Matched Sibling Donors vs Younger Matched Unrelated Donors
Guru Murthy, G. S., Kim, S., Hu, Z. H., Estrada-Merly, N., Abid, M. B., Aljurf, M., Bacher, U., Badawy, S. M., Beitinjaneh, A., Bredeson, C., et al
JAMA oncology. 2022
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Editor's Choice
Abstract
IMPORTANCE Matched sibling donors (MSDs) are preferred for allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic syndrome even if they are older. However, whether older MSDs or younger human leukocyte antigen-matched unrelated donors (MUDs) are associated with better outcomes remains unclear. OBJECTIVE To investigate whether allo-HCT for myelodysplastic syndrome using younger MUDs would be associated with improved disease-free survival and less relapse compared with older MSDs. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study assessed data reported to the Center for International Blood and Marrow Transplant Research database from 1761 adults 50 years or older with myelodysplastic syndrome who underwent allo-HCT using an older MSD or younger MUD between January 1, 2011, and December 31, 2017, with a median follow-up of 48 months. Data analysis was performed from January 8, 2019, to December 30, 2020. INTERVENTIONS/EXPOSURES Allo-HCT from an older MSD (donor age ≥50 years) or a younger MUD (donor age ≤35 years). MAIN OUTCOMES AND MEASURES The primary outcome was disease-free survival. Secondary outcomes were overall survival, relapse, nonrelapse mortality, acute graft-vs-host disease (GVHD), chronic GVHD, and GVHD-free relapse-free survival. RESULTS Of 1761 patients (1162 [66%] male; median [range] age, 64.9 [50.2-77.6] years in the MSD cohort and 66.5 [50.4-80.9] years in MUD cohort), 646 underwent allo-HCT with an older MSD and 1115 with a younger MUD. In multivariable analysis, the rate of disease-free survival was significantly lower in allo-HCTs with older MSDs compared with younger MUDs (hazard ratio [HR], 1.17; 95% CI, 1.02-1.34; P = .02), whereas the difference in overall survival rate of allo-HCT with younger MUDs vs older MSDs was not statistically significant (HR, 1.13; 95% CI, 0.98-1.29; P = .07). Allo-HCT with older MSDs was associated with significantly higher relapse (HR, 1.62; 95% CI, 1.32-1.97; P < .001), lower nonrelapse mortality (HR, 0.76; 95% CI, 0.59-0.96; P = .02), lower acute GVHD (HR, 0.52; 95% CI, 0.42-0.65; P < .001), chronic GVHD (HR, 0.77; 95% CI, 0.64-0.92; P = .005), and a lower rate of GVHD-free relapse-free survival beyond 12 months after allo-HCT (HR, 1.42; 95% CI, 1.02-1.98; P = .04). CONCLUSIONS AND RELEVANCE This cohort study found higher disease-free survival and lower relapse for allo-HCT in myelodysplastic syndrome using younger MUDs compared with older MSDs. The risk of nonrelapse mortality and GVHD was lower with older MSDs. These results suggest that the use of younger MUDs should be considered in the donor selection algorithm for myelodysplastic syndrome, in which it is pivotal to minimize relapse given limited treatment options for managing relapsed disease.
PICO Summary
Population
People 50 years and older with myelodysplastic syndrome, identified from the CIBMTR database (n=1761)
Intervention
Matched sibling donor transplantation from an older donor 50 years and over (older MSD, n=646)
Comparison
Matched unrelated donor transplantation from a younger donor 35 years and under (younger MUD, n=1115)
Outcome
In multivariable analysis, the rate of disease-free survival was significantly lower in allo-HCTs with older MSDs compared with younger MUDs (hazard ratio [HR], 1.17; 95% CI, 1.02-1.34), whereas the difference in overall survival rate of allo-HCT with younger MUDs vs older MSDs was not statistically significant (HR, 1.13; 95% CI, 0.98-1.29). Allo-HCT with older MSDs was associated with significantly higher relapse (HR, 1.62; 95% CI, 1.32-1.97;), lower nonrelapse mortality (HR, 0.76; 95% CI, 0.59-0.96;), lower acute GVHD (HR, 0.52; 95% CI, 0.42-0.65), chronic GVHD (HR, 0.77; 95% CI, 0.64-0.92), and a lower rate of GVHD-free relapse-free survival beyond 12 months after allo-HCT (HR, 1.42; 95% CI, 1.02-1.98).
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Primary preventative care of hematopoietic stem cell transplant survivors: time to educate and empower recipients and providers
Fulcher, J., Blanchard, A. P., Bredeson, C., van Walraven, C.
Transplantation and cellular therapy. 2022
Abstract
Increased use of hematopoietic stem cell transplantation (HCT) and improvements in recipient outcomes has led to a steady increase in the number of allogeneic HCT survivors. In addition to complications specific to the transplant process, HCT recipients are at increased risk of developing cardiovascular disease (CVD) and subsequent neoplasms (SN). Strict adherence to general population CVD risk factor and cancer surveillance is recommended as an essential component of long-term follow-up (LTFU) care of HCT survivors but implementation of this has been suboptimal. Models to improve the provision of survivorship care have been proposed including a hybrid/combined care approach where the HCT providers manage transplant-specific complications and the primary care physician (PCP) provides general medical care including surveillance and aggressive management of CVD risk factors and screening for subsequent neoplasm (SN). This model also offers a practical approach to LTFU care for HCT survivors who live at a distance from the HCT center which is a reality for many recipients of HCT at the Ottawa hospital (TOH). As the success of such a hybrid approach to survivorship care is dependent on the engagement of HCT recipients with their PCP and compliance with recommended general population surveillance, the aim of the study reported here was to assess the rates of PCP attendance and adherence to recommended preventive-medicine interventions in the years immediately prior to and following HCT. We hypothesized that rates would be sub-optimal and planned to use these results as a baseline for an educational initiative aimed at increasing awareness of HCT recipients and their PCPs about embracing a preventative survivorship care. This was a single center cohort study of allogeneic HCT recipients transplanted at TOH with linkage to population-based health administrative data. Published clinical practice guidelines were used to define recommended screening for CVD risk factors and cancer. In the 5 years prior to and following HCT, the rates of annual PCP visits and utilization of recommended preventative care interventions were calculated for all eligible patients. Between 2014 and 2020, 409 patients with provincial health care coverage underwent allogeneic HCT at TOH. Median age was 51 (range 15-73) with a male predominance (60.9%). Approximately one quarter of recipients did not attend their PCP in the five years before and after transplant and this proportion increased to one third in the 5(th) year post-HCT. For those recipients who were eligible, only 20-25% underwent recommended screening for dyslipidemia and diabetes. Cancer screening rates were also low at 16-18% for cervical cancer, 18-22% for colon cancer and 30-31% for breast cancer. Results highlight the need to increase awareness of HCT recipients and their PCPs about the risk of developing CVD and SN post-transplant, and to emphasize the potential to mitigate this risk by adhering to recommendations for surveillance to enable prompt intervention. Patient education should incorporate this information and empower HCT survivors to actively engage in their follow-up care and optimize their long-term outcomes.
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A Portrait of SARS-CoV-2 Infection in Patients Undergoing Hematopoietic Cell Transplantation: A Systematic Review of the Literature
Bailey, A. J. M., Kirkham, A. M., Monaghan, M., Shorr, R., Buchan, C. A., Bredeson, C., Allan, D. S.
Current oncology (Toronto, Ont.). 2022;29(1):337-349
Abstract
The management of COVID-19 in hematopoietic cell transplant (HCT) recipients represents a special challenge given the variable states of immune dysregulation and altered vaccine efficacy in this population. A systematic search (Ovid Medline and Embase on 1 June 2021) was needed to better understand the presenting features, prognostic factors, and treatment options. Of 897 records, 29 studies were identified in our search. Most studies reporting on adults and pediatric recipients described signs and symptoms that were typical of COVID-19. Overall, the mortality rates were high, with 21% of adults and 6% of pediatric HCT recipients succumbing to COVID-19. The factors reported to be associated with increased mortality included age (HR = 1.21, 95% CI 1.03-1.43, p = 0.02), ICU admission (HR = 4.42, 95% CI 2.25-8.65, p < 0.001 and HR = 2.26, 95% CI 1.22-4.20, p = 0.01 for allogeneic and autologous HCT recipients), and low platelet count (OR = 21.37, 95% CI 1.71-267.11, p = 0.01). Performance status was associated with decreased mortality (HR = 0.83, 95% CI 0.74-0.93, p = 0.001). A broad range of treatments was described, although no controlled studies were identified. The risk of bias, using the Newcastle-Ottawa scale, was low. Patients undergoing HCT are at a high risk of severe morbidity and mortality associated with COVID-19. Controlled studies investigating potential treatments are required to determine the efficacy and safety in this population.
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Can GCSF-stimulated donor lymphocyte infusions improve outcomes for relapsed disease following allogeneic hematopoietic cell transplantation? A systematic review and meta-analysis
Kirkham, A. M., Bailey, A. J. M., Masurekar, A., Shorr, R., Bredeson, C., Sabloff, M., Allan, D. S.
Leukemia & lymphoma. 2022;:1-12
Abstract
Donor lymphocyte infusions (DLI) can produce graft-versus tumor effects to treat relapse after allogeneic hematopoietic cell transplantation, however, durable responses remain uncommon. A systematic review and meta-analysis are needed to clarify whether DLI collected after stimulation with granulocyte colony-stimulating factor (GCSF; G-DLI) can improve clinical outcomes. Sixteen studies (4 controlled) involving 585 patients were identified in a systematic search up to 17 September 2020. A meta-analysis demonstrated no significant difference in the risk of all-cause mortality (RR: 0.94, 95% CI 0.52-1.68, p = 0.82; n = 3 studies) or relapse-related mortality (RR: 0.72, 0.44-1.18, p = 0.19; n = 3 studies) between G-DLI and conventional DLI (C-DLI) groups. G-DLI products had similar mean CD3+ cells compared to C-DLI products, but median CD34+ cells/kg were increased. No improvement in disease progression, complete response rates, or risk of developing GVHD was observed with G-DLI, however, greater non-relapse mortality was observed compared to C-DLI. Alternative approaches to enhancing graft-versus-tumor effects are needed.
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Outcomes of Allogeneic Hematopoietic Cell Transplantation in T-cell Prolymphocytic Leukemia: A Contemporary Analysis from the Center for International Blood and Marrow Transplant Research
Murthy, H. S., Ahn, K. W., Estrada-Merly, N., Alkhateeb, H. B., Bal, S., Kharfan-Dabaja, M. A., Dholaria, B., Foss, F., Gowda, L., Jagadeesh, D., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy with limited treatment options and poor long-term survival. Previous studies of allogeneic hematopoietic cell transplantation (alloHCT) for T-PLL are limited by small numbers, and descriptions of patient and transplant characteristics and outcomes after alloHCT are sparse. OBJECTIVE To describe outcomes of alloHCT in T-PLL and identify predictors of post-transplant relapse and survival. STUDY DESIGN We conducted an analysis of data using the Center for International Blood and Marrow Transplant Research (CIBMTR) database on 266 patients with T-PLL who underwent alloHCT during 2008-2018. RESULTS The 4-year rates of overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) were 30.0% (95% CI, 23.8-36.5%), 25.7% (95% CI, 20-32%), 41.9% (95% CI, 35.5-48.4%), and 32.4% (95% CI, 26.4-38.6%), respectively. In multivariable analyses, three variables were associated with inferior OS: myeloablative conditioning (MAC) (hazard ratio [HR] 2.18, p<0.0001); age older than 60 years (HR 1.61, p=0.0053); and suboptimal performance status defined by Karnofsky Performance Status (KPS) <90 (HR 1.53, p=0.0073). MAC also was associated with increased TRM (HR 3.31, p<0.0001), increased cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) (HR 2.94, p=0.0011) and an inferior disease-free survival (HR 1.86, p=0.0004). Conditioning intensity was not associated with relapse; however stable disease/progression correlated with increased risk of relapse (HR 2.13, p=0.0072). Both in vivo T cell depletion (TCD) as part of conditioning and KPS <90 were associated with worse TRM and inferior DFS. Total Body Irradiation was not found to have any significant effect on OS, DFS or TRM. CONCLUSION Our data showed that reduced-intensity conditioning without in vivo T-cell depletion (that is, without ATG or alemtuzumab) prior to alloHCT was associated with long-term disease-free survival in patients with T-PLL who were 60 or younger or who had KPS >90 or had chemo-sensitive disease.
PICO Summary
Population
People with T-cell prolymphocytic leukaemia (T-PLL), identified from the CIBMTR database (n=266)
Intervention
Allogeneic haematopoietic stem cell transplantation
Comparison
None
Outcome
The 4-year rates of overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) were 30.0% (95% CI, 23.8-36.5%), 25.7% (95% CI, 20-32%), 41.9% (95% CI, 35.5-48.4%), and 32.4% (95% CI, 26.4-38.6%), respectively. In multivariable analyses, three variables were associated with inferior OS: myeloablative conditioning (MAC) (hazard ratio [HR] 2.18); age older than 60 years (HR 1.61); and suboptimal performance status defined by Karnofsky Performance Status (KPS) <90 (HR 1.53). MAC also was associated with increased TRM (HR 3.31), increased cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) (HR 2.94) and an inferior disease-free survival (HR 1.86). Conditioning intensity was not associated with relapse; however stable disease/progression correlated with increased risk of relapse (HR 2.13). Both in vivo T cell depletion (TCD) as part of conditioning and KPS <90 were associated with worse TRM and inferior DFS. Total Body Irradiation was not found to have any significant effect on OS, DFS or TRM.
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The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis
Mei, M., Pillai, R., Kim, S., Estrada-Merly, N., Afkhami, M., Yang, L., Meng, Z., Abid, M. B., Aljurf, M., Bacher, U., et al
Haematologica. 2022
Abstract
Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (alloHCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry (CIBMTR) database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range: 28-77) who underwent alloHCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, p=0.049) or high (HR=3.22, p=0.0004) correlated significantly with overall survival (OS). When the molecularly informed CPSS-Mol was applied, a high CPSS-Mol score (HR=2 p=0.0079) correlated significantly with OS. The most common somatic mutations were ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased OS (HR=1.70 [95%CI: 1.11-2.60], p=0.0147 and HR=2.72 [95%CI: 1.37-5.39], p=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (DFS) (HR=1.66 [95%CI: 1.11-2.49], p=0.0138, HR=1.79 [95%CI: 1.06- 3.03], p=0.0293, and HR=2.94 [95%CI: 1.50-5.79], p=0.0018 respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, p=0.0201). Nonetheless, the impact specifically of TP53 mutations should be interpreted cautiously given its rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have provided the mutational landscape in patients with CMML who underwent alloHCT, and we demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond the CPSS.
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9.
Impact of Pretransplantation Renal Dysfunction on Outcomes after Allogeneic Hematopoietic Cell Transplantation
Farhadfar, N., Dias, A., Wang, T., Fretham, C., Chhabra, S., Murthy, H. S., Broglie, L., D'Souza, A., Gadalla, S. M., Gale, R. P., et al
Transplantation and cellular therapy. 2021
Abstract
Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age =40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age <40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR =90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR <45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR <60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR =90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR <45 mL/min group. Compared with the eGFR =90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P < .0001) and the eGFR <45 mL/min group (HR, 3.09; P < .0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR <45 mL/min was associated with an increased overall mortality (HR, 1.63; P < .0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.
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10.
Early warning of infection in patients undergoing hematopoietic stem cell transplantation using heart rate variability and serum biomarkers
Buchan, C. A., Li, H. O., Herry, C., Scales, N., MacPherson, P., Faller, E., Bredeson, C., Huebsch, L., Hodgins, M., Seely, A. J.
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Early warning of infection is critical to reduce risk of deterioration and mortality, especially in neutropenic patients following hematopoietic stem cell transplantation (HCT). Given that heart rate variability (HRV) is a sensitive and early marker for infection and serum inflammatory biomarkers can have high specificity for infection, we hypothesized their combination may be useful for accurate early warning of infection. PURPOSE Develop and evaluate a composite predictive model utilizing continuous HRV with daily serum biomarker measurements to provide risk stratification of future deterioration in HCT patients. METHODS 116 ambulatory outpatients about to undergo HCT consented to collection of prospective demographic, clinical (daily vital signs), HRV (continuous electrocardiogram (ECG) monitoring, laboratory (daily serum samples frozen -80°C) and infection outcome variables (defined as the time of escalation of antibiotics), all from 24 hours (h) pre-transplant until infection or 14 days post-transplant. Indications for antibiotic escalation were adjudicated as "true infection" or not by two blinded HCT clinicians. A composite time series of 8 HRV metrics was created for each patient and the probability of deterioration within the next 72h was estimated using logistic regression modelling of composite HRV and serum biomarkers using a rule-based Naïve-Bayes model, if the HRV-based probability exceeded a median threshold. RESULTS 35(30%) patients withdrew within <24h due to intolerability of ECG monitoring, leaving 81 patients, of which 48(59%) had antibiotic escalation adjudicated as true infection. The combined HRV and biomarker (TNFa, IL6 and IL7) predictive model started increasing ~48 hours on average prior to diagnosis of infection, could distinguish between high risk of impending infection (>90% incidence of subsequent infection within 72h), average risk (~50%) and low risk (<10%), with an area under the receiver operating characteristic curve (AUC-ROC) of 0.87. CONCLUSION We derived a predictive model using HRV and serum biomarker to predict being diagnosed with infection within 72h combined in patients at high risk of infection. As prophylactic predictive ECG monitoring and daily serum collection proved challenging for many patients, further refinement in measurement is necessary for further study.