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1.
EASIX score predicts inferior survival after allogeneic hematopoietic cell transplantation
Sanchez-Escamilla, M., Flynn, J., Devlin, S., Maloy, M., Fatmi, S. A., Tomas, A. A., Escribano-Serrat, S., Ponce, D., Sauter, C. S., Giralt, S. A., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.
PICO Summary
Population
Adults with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) allogeneic HSCT with uniform GVHD prophylaxis, from a single centre in USA (n=152)
Intervention
Evaluation of the EASIX score pre-transplant between day -30 and day -10
Comparison
Evaluation of the EASIX score post-transplant at day 30 and day 100
Outcome
In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher non-relapse mortality (Hazard ratio (HR) = 1.64) and lower overall survival (HR = 1.33). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65; and HR = 1.65) and decreased OS (HR = 1.27; and HR = 1.49), independent of HCT-CI, disease and conditioning regimen.
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2.
Incidence and impact of fungal infections in post-transplant Cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis and haploidentical hematopoietic cell transplantation: A CIBMTR analysis
Papanicolaou, G. A., Chen, M., He, N., Martens, M. J., Kim, S., Batista, M. V., Bhatt, N. S., Hematti, P., Hill, J. A., Liu, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Fungal infections (FI) after allogeneic hematopoietic cell transplant (HCT) are associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft versus host disease (GVHD), and viral infections are risk factors for FI. OBJECTIVES The objectives of this CIBMTR registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants receiving either calcineurin inhibitor (CNI)-based or PTCy-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplant outcomes. STUDY DESIGN Patients who received their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes and received related haploidentical transplant with PTCy (HaploCy, N = 757) or Sib transplant with PTCy (SibCy, N = 403) or CNI (SibCNI, N = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as a cumulative incidence with death as the competing risk. The association of FI on overall survival (OS), non-relapse mortality (NRM), chronic GVHD, and relapse at 2 years post HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS By Day 180 post HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI developed ≥1 FI (<0.001). The cumulative incidence (99% confidence interval) of yeast FI was 5.2% (3.3-7.3), 2.2% (0.7-4.5), and 1.9% (1.1-2.9) (p=.001), and mold FI was 2.9% (1.5-4.7). 3.7% (91.7-6.6) and 1.7% (1.0-2.6) (p=0.040) for HaploCy, SibCy, and SibCNI, respectively. FI were associated with an increased risk of death with an adjusted hazard ratio [HR] (99% confidence interval) of 4.06 (2.2-7.6); 4.7(2.0-11.0) and 3.4 (1.8-6.4) for HaploCy; SibCy and SibCNI compared with SibCNI without FI, respectively (p<.0001; for all). Similar associations were noted for transplant-related mortality. FI did not impact relapse or chronic GVHD. CONCLUSIONS Rates of FI by Day 180 ranged between 1.9-5.2% for yeast and 1.7%-3.7% for molds across the 3 cohorts. Use of PTCy was associated with higher rates of yeast infections only in Haplo HCT and mold infections in Haplo and Sib HCT. Presence of FI by Day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor or PTCy. While rates of FI were low with PTCy, FI were associated with increased risk of death, underscoring the need for improved management strategies.
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3.
Application of the CIBMTR One Year Survival Outcomes Calculator as a tool for retrospective analysis
Cho, C., Devlin, S., Maloy, M., Horowitz, M. M., Logan, B., Rizzo, J. D., Giralt, S. A., Perales, M. A.
Bone marrow transplantation. 2023
Abstract
The Web-based One Year Survival Outcomes Calculator developed by the Center for International Blood and Marrow Transplant Research (CIBMTR) applies large-scale registry data to generate individualized estimates of overall survival (OS) probability 1 year after first allogeneic hematopoietic cell transplant (HCT) and can therefore provide a data-driven foundation for personalized patient counseling. We assessed the calibration of the CIBMTR One Year Survival Outcomes Calculator when applied to retrospective data among adult recipients of first allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) with peripheral blood stem cell transplant (PBSCT) from a 7/8- or 8/8-matched donor from 2000 through 2015 at a single center. Predicted 1 year OS was estimated for each patient using the CIBMTR Calculator. Corresponding observed 1 year OS was estimated for each group by the Kaplan-Meier method. A weighted Kaplan-Meier estimator was used to visually display the average of observed 1 year survival estimates over the continuous range of predicted OS. In the first analysis of its kind, we demonstrated that the CIBMTR One Year Survival Outcomes Calculator could be applied to larger patient cohorts and predicted 1 year prognosis with general agreement between predicted and observed survival.
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4.
Emergence of human CMV-induced NKG2C+ NK cells is associated with CD8+ T-cell recovery after allogeneic HCT
van der Ploeg, K., Sottile, R., Kontopoulos, T., Shaffer, B. C., Papanicolaou, G. A., Maloy, M. A., Cho, C., Robinson, K. S., Perales, M. A., Le Luduec, J. B., et al
Blood advances. 2023;7(19):5784-5798
Abstract
Cytomegalovirus (CMV) infection is associated with the expansion of a mature NKG2C+FcεR1γ- natural killer (NK) cell population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T-cell-depleted (TCD) allografts. We analyzed peripheral blood lymphocytes from 119 patients at serial time points after infusion of their TCD allograft and compared immune recovery with that in samples obtained from recipients of T-cell-replete (T-replete) (n = 96) or double umbilical cord blood (DUCB) (n = 52) allografts. NKG2C+ NK cells were detected in 92% (45 of 49) of recipients of TCD HCT who experienced CMV reactivation. Although NKG2A+ cells were routinely identifiable early after HCT, NKG2C+ NK cells were identified only after T cells could be detected. T-cell reconstitution occurred at variable times after HCT among patients and predominantly comprised CD8+ T cells. In patients with CMV reactivation, recipients of TCD HCT expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared with patients who received T-replete HCT or DUCB transplantation. NKG2C+ NK cells after TCD HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared with the adaptive the NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of a CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.
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5.
Utility of routine pulmonary function test after autologous hematopoietic cell transplantation in lymphoma
Dahi, P. B., Kenny, S., Flynn, J., Devlin, S. M., Ruiz, J. D., Chinapen, S. A., Lahoud, O. B., Matasar, M. J., Moskowitz, C. H., Perales, M. A., et al
Leukemia & lymphoma. 2023;:1-7
Abstract
This study aims to evaluate the predictive value of routine pulmonary function testing (PFT) at the 12-month mark post-autologous hematopoietic cell transplant (AHCT) in identifying clinically significant lung disease in lymphoma survivors. In 247 patients, 173 (70%) received BEAM (carmustine, etoposide, cytarabine, melphalan), and 49 (20%) received TBC (thiotepa, busulfan, cyclophosphamide) conditioning regimens. Abnormal baseline PFT was noted in 149 patients (60%). Thirty-four patients had a significant decline (reduction of ≥ 20% in DLCO or FEV1 or FVC) in post-AHCT PFT, with the highest incidence in the CNS lymphoma group (39%). The incidence of clinically significant lung disease post-transplant was low at 2% and there was no association between abnormal pre- and 1-year post-transplant PFTs with the development of clinical lung disease. While this study illustrates the impact of treatment regimens on PFT changes, it did not demonstrate a predictive value of scheduled PFTs in identifying clinically significant post-AHCT lung disease.
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Prognostic Biomarkers for Hepatic Veno-occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) in Myeloablative Allogeneic Hematopoietic Cell Transplantation: Results from the BMT CTN 1202 Study
Putta, S., Young, B. A., Levine, J. E., Reshef, R., Nakamura, R., Strouse, C., Perales, M. A., Howard, A., Pine, P., Shi, J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). OBJECTIVES To determine a blood biomarker signature early after HCT that identifies patients at high risk for VOD/SOS. STUDY DESIGN A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on Days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using Bonferroni-adjusted Wilcoxon rank sum (P≤0.002). RESULTS 33 patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, eight, and five biomarkers measured from the plasma of these patients were significantly associated with development of VOD/SOS at Days 0, 7, and 14, respectively, with the strongest associations being on Days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiving operator curve (AUC) of 0.81 on Day 7 and 0.79 on Day 14. Multivariate models of up to five biomarkers generated AUCs ranging from 0.82 to 0.85. All associations with VOD/SOS risk were independent of clinical risk factors. CONCLUSIONS This study confirmed previously identified biomarkers of VOD/SOS risk and identified novel, prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to five of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.
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Outcomes of refractory cytomegalovirus (CMV) infection in the first year after allogeneic hematopoietic cell transplantation
Karantoni, E., Zavras, P. D., Su, Y., Fang, J., Tamari, R., Cho, C., Perales, M. A., Stern, A., Papanicolaou, G. A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Outcomes of refractory (Rf) cytomegalovirus infection (CMVi) after hematopoietic cell transplantation (HCT) are poor due to limited treatment options and related toxicities. Maribavir, an orally bioavailable CMV antiviral was recently approved for treatment of Rf-CMVi. Real-world studies, quantifing the burden of Rf-CMVi prior to maribavir provide a benchmark for evaluation of the net value of novel treatments. OBJECTIVES We report the incidence, clinical outcomes and healthcare resource utilization (HRU) associated with Rf-CMVi in the first year after HCT in a cohort of CMV seropositive HCT from a single center. METHODS The retrospective cohort study included adult CMV seropositive (R+) HCT recipients between 1/1/2014 and 12/31/2017 at Memorial Sloan Kettering Cancer Center (MSKCC) managed exclusive by preemptive therapy. CMVi was defined as CMV viremia treated preemptively. Rf-CMVi was defined as <1 log(10) decrease and CMV viral load (VL) >1,000 U/mL after ≥14 days of appropriately dosed therapy. Well-days were calculated as alive days not hospitalized and off CMV antivirals by 1 year post-HCT. The impact of Rf-CMVi on EOD, mortality and HRU was examined in multivariable models. RESULTS Of 286 R+ patients, 145 (50.7%) developed CMVi (99 no Rf-CMVi and 46 Rf-CMVi). Compared with no Rf-CMVi, more patients with Rf-CMVi had CMV EOD (23.9% versus 10.1%, p=0.030); CMV-related mortality (9.5% versus 0.0%, p=0.002) and all-cause mortality (33.3% versus 15.6%, adjusted p=0.049). Rf-CMVi was an independent predictor for readmissions (adjusted odds ratio [aOR] [95% confidence interval, CI] 3.24 [2.19-4.87]; p<0.0001); CMV-related readmissions (aOR [95 CI] 9.48 [5.83-15.80]; p<0.0001) and decreased well days (adjusted arithmetic mean ratio [aAMR] [95% CI] 0.72 [0.58-0.89], p=0.001) in the first-year post-HCT. CONCLUSIONS Rf-CMVi is associated with increased mortality and increased HRU at 1 year after HCT. Improved therapies for Rf-CMVi have the potential of improving HCT outcomes and reducing HRU.
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8.
MAIT and Vδ2 unconventional T cells are supported by a diverse intestinal microbiome and correlate with favorable patient outcome after allogeneic HCT
Andrlová, H., Miltiadous, O., Kousa, A. I., Dai, A., DeWolf, S., Violante, S., Park, H. Y., Janaki-Raman, S., Gardner, R., El Daker, S., et al
Science translational medicine. 2022;14(646):eabj2829
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Abstract
Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells.
Clinical Commentary
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9.
Analysis of Disparities in Time to Allogeneic Transplantation in Adults with Acute Myelogenous Leukemia
Fingrut, W. B., Gyurkocza, B., Flynn, J. R., Davis, E., Devlin, S. M., Scaradavou, A., Chinapen, S., Quach, S., Cho, C., Giralt, S. A., et al
Blood advances. 2022
Abstract
While alternative donors extend transplant access, whether recipient ancestry impacts the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 transplanted adult acute myelogenous leukemia (AML) patients. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% versus 24%, p < 0.001). Overall, the median time from transplant indication to allograft was 127 days (range 57-1,683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication-transplant time > 180 days (OR 2.1, 95%CI:1.4-5.6, p = 0.012) due to significant delays in indication-consult > 90 days (OR 2.8, 95%CI:1.3-4.5, p = 0.005) and consult-transplant > 120 days (OR 2.4, 95%CI:1.2-3.7, p = 0.005). Compared to recipients of HLA-matched unrelated donors (URD), HLA-mismatched adult donor recipients were at increased risk of delayed indication-transplant whereas matched sibling and cord blood recipients were at lower risk. Sub-analysis showed more indication-transplant delays in non-European versus European 8/8 URD recipients (44% versus 19% > 180 days, p = 0.004). Finally, the pandemic further exacerbated delays for non-Europeans. In summary, while non-European AML patients are less likely to receive 8/8 URDs as expected, if they do their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and utilize all alternative donor sources are critical to ensure timely transplantation for AML patients.
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10.
Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant
Miltiadous, O., Waters, N. R., Andrlová, H., Dai, A., Nguyen, C. L., Burgos da Silva, M., Lindner, S., Slingerland, J., Giardina, P., Clurman, A., et al
Blood. 2022;139(18):2758-2769
Abstract
Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.