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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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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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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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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.
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Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improves Transplant Outcomes in Older MDS Patients
Oran, B., Ahn, K. W., Fretham, C., Beitinjaneh, A., Bashey, A., Pawarode, A., Wirk, B., Scott, B. L., Savani, B. N., Bredeson, C., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Reduced-intensity conditioning (RIC) regimens developed to extend allogeneic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the two most commonly used RIC regimens, intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in myelodysplastic syndrome (MDS). Through CIBMTR, we identified 1045 MDS patients aged = 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using RIC. CIBMTR's definition of RIC was used: a regimen that incorporated an intravenous busulfan total dose = 7.2 mg/kg, or a low-dose melphalan total dose of = 150 mg/m(2). The two groups, FluBu (n=697) and FluMel (n=448), were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44% (p=0.0001). Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%, p=0.0001). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, p=0.02, and 35% vs. 27% at 3 years, p=0.01). Overall survival (OS) was comparable at 1 year (63% vs. 61%, p=0.4) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%, p=0.03). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
PICO Summary
Population
Patients with myelodysplastic syndrome aged >/=60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor, and were reported to the CIBMTR registry (n=1045)
Intervention
Reduced intensity regimen incorporating an intravenous busulfan total dose = 7.2 mg/kg (FluBu, n=697)
Comparison
Reduced intensity regimen incorporating a low-dose melphalan total dose of = 150 mg/m(2) (FluMel, n=448)
Outcome
The two groups were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44%. Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, and 35% vs. 27% at 3 years). Overall survival (OS) was comparable at 1 year (63% vs. 61%) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
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9.
Does Lymphocyte Count Impact Dosing of Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplantation?
Heelan, F., Mallick, R., Bryant, A., Radhwi, O., Atkins, H., Huebsch, L., Bredeson, C., Allan, D., Kekre, N.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg of ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single centre study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (Thymoglobulin(R)) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analysis were used to determine if any patient or transplant related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. One hundred and eleven patients met inclusion, with a median age of 50 years (range 19-70). The most common diagnoses were AML (43%), MDS/MPN (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range 45-216). The median ALC on the first day of ATG administration was 0.1 x 10(9)/L (range 0-190). The median total dose of ATG received was 201 mg (range 112-540). The incidence of acute and chronic GVHD was 35.1% and 21.6% respectively. In multivariate model, the actual dose of ATG given to patients was not associated with GVHD (HR=1.11, 95% CI 0.99-1.25, p=0.07), relapse (HR=1.13, 95% CI 0.98-1.30, p=0.1) or mortality (HR= 1.09, 95% CI 0.92-1.28, p=0.32). Similarly, the pre-transplant ALC was not associated with GVHD (HR=1, p=0.82), relapse (HR=1, p=0.90) or mortality (HR=1, p=0.39). If patients had received ALC based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than five times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.
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10.
Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy: Guidelines for Hematopoietic Transplantation and Cellular Therapy
Kanate, A. S., Majhail, N. S., Savani, B. N., Bredeson, C., Champlin, R. E., Crawford, S., Giralt, S. A., LeMaistre, C. F., Marks, D. I., Omel, J. L., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years, the field has not only seen an improvement in transplantation technology thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells including chimeric antigen receptor T-cell (CART-cell) and T-cell receptors (TCRs) has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established multi-stakeholder task force consisting of transplant experts, payer representatives and a patient advocate to provide guidance on indications for HCT and IECT. This manuscript presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence, (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but has been shown to be effective therapy, (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exist but large clinical trials and observational studies are not feasible, (4) Developmental, for diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option, and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.