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1.
Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
Prockop, S. E., Hasan, A., Doubrovina, E., Dahi, P. B., Rodriguez-Sanchez, I., Curry, M., Mauguen, A., Papanicolaou, G. A., Su, Y., Yao, J., et al
The Journal of clinical investigation. 2023;133(10)
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Editor's Choice
Abstract
BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.
PICO Summary
Population
Adults and children with cytomegalovirus (CMV) viremia or disease arising after HSCT, treated in a single centre in USA (n=67)
Intervention
Adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs).
Comparison
None
Outcome
T cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.
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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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Outcomes and Management of SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation (HCT) and Chimeric Antigen Receptor T cell (CART) therapy
Infante, M. S., Nemirovsky, D., Devlin, S., DeWolf, S., Tamari, R., Dahi, P. B., Lee, Y. J., Chung, D. J., Politikos, I., Barker, J., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CART) recipients who develop COVID-19 can have decreased overall survival, likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19 directed therapies and vaccines have improved COVID-19 related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of SARS-CoV-2 variant infections, including Omicron and its sublineages, particularly in transplant recipients, are yet to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CART recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March-June 2020). STUDY DESIGN Retrospective analysis adult HCT/CART recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center (MSKCC), New York, between July 2021 and July 2022. RESULTS We identified 353 patients (172 auto, 49%; 152 allo, 43%; 29 CART, 8%) with a median time from HCT/CART to SARS-CoV-2 infection of 1010 days (IQR, 300 to 2046). Forty-one (12%) patients were diagnosed with COVID-19 during the delta wave and 312 (88%) patients during the Omicron wave. Risk factors associated with increased odds of COVID-19 related hospitalization were the presence of 2 or more comorbidities (OR, 4.9; 95% CI 2.4-10.7, p< 0.001), CART therapy compared to allogeneic HCT (OR 7.7; 95% CI 3.0-20.0, p<0.001), hypogammaglobulinemia (OR 2.71; 95% CI 1.06-6.40, p=0.027), and age at COVID-19 diagnosis (OR 1.03; 95% CI 1.0-1.05, p= 0.04). In contrast, infection during Omicron variant BA5/BA4 dominant period compared to variant BA1 (OR 0.21; 95% CI 0.03-0.73, p =0.037), and more than 3 years from HCT/CART therapy to COVID-19 diagnosis, compared to early infection < 100 days (OR 0.31; 95% CI 0.12-0.79, p=0.011) were associated with a decreased odds for hospitalization. The overall survival (OS) at 12 months from COVID-19 diagnosis was 89% (95% CI: 84-94%), with 6/26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower overall survival at 12 months, with 73% (95% CI: 62-84%) vs 89% (95% CI: 84-94%), (p<0.001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients, being 90% (95% CI: 86-95%) vs 82% (95% CI: 72-94%) at 12 months, respectively (p=0.003). No significant difference in OS was observed in patients infected with the Omicron vs with Delta variant (p=0.4) or treated with specific COVID-19 treatments vs those not treated (p=0.2). CONCLUSIONS We observed higher overall survival in HCT and CART recipients infected with the Omicron variants compared to the ancestral strain of SARS-CoV2. Use of COVID-19 antivirals, monoclonal antibodies, and vaccines may have contributed to improved outcomes.
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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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SARS-CoV-2 vaccination in the first year after allogeneic hematopoietic cell transplant: a prospective, multicentre, observational study
Hill, J. A., Martens, M. J., Young, J. H., Bhavsar, K., Kou, J., Chen, M., Lee, L. W., Baluch, A., Dhodapkar, M. V., Nakamura, R., et al
EClinicalMedicine. 2023;59:101983
Abstract
BACKGROUND The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. METHODS We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations <4 months versus 4-12 months after HCT using a propensity-adjusted analysis. We also evaluated factors associated with high-level anti-S IgG titers (≥2403 U/mL) in logistic regression models. FINDINGS Between April 22, 2021 and November 17, 2021, 175 allogeneic HCT recipients were enrolled in the study, of whom all but one received mRNA SARS-CoV-2 vaccines. SARS-CoV-2 anti-S IgG titers, neutralizing antibody titers, and TCR breadth and depth did not significantly differ at all tested time points following the second vaccination among those initiating vaccinations <4 months versus 4-12 months after HCT. Anti-S IgG ≥2403 U/mL correlated with neutralizing antibody levels similar to those observed in a prior study of non-immunocompromised individuals, and 57% of participants achieved anti-S IgG ≥2403 U/mL at the end-of-study time point. In models adjusted for SARS-CoV-2 infection pre-enrollment, SARS-CoV-2 vaccination pre-HCT, CD19+ B-cell count, CD4+ T-cell count, and age (as applicable to the model), vaccine initiation timing was not associated with high-level anti-S IgG titers at the post-V2, post-V3, or end-of-study time points. Notably, prior graft-versus-host-disease (GVHD) or use of immunosuppressive medications were not associated with high-level anti-S IgG titers. Grade ≥3 vaccine-associated adverse events were infrequent. INTERPRETATION These data support starting mRNA SARS-CoV-2 vaccination three months after HCT, irrespective of concurrent GVHD or use of immunosuppressive medications. This is one of the largest prospective analyses of vaccination for any pathogen within the first year after allogeneic HCT and supports current guidelines for SARS-CoV-2 vaccination starting three months post-HCT. Additionally, there are few studies of mRNA vaccine formulations for other pathogens in HCT recipients, and these data provide encouraging proof-of-concept for the utility of early vaccination targeting additional pathogens with mRNA vaccine platforms. FUNDING National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.
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Patterns of CMV Infection After Letermovir Withdrawal in Recipients of Post-Transplant Cyclophosphamide Based Transplant
Lin, A., Brown, S., Chinapen, S., Lee, Y. J., Seo, S. K., Ponce, D. M., Shahid, Z., Giralt, S. A., Papanicolaou, G. A., Perales, M. A., et al
Blood advances. 2023
Abstract
Reactivation of latent cytomegalovirus (CMV) is increased in CMV seropositive (CMV+) recipients of allogeneic hematopoietic cell transplantation (allo HCT) using post-transplant cyclophosphamide (PT-Cy) based graft versus host disease prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy based allo HCT, including 157 CMV+ patients of whom 80 completed letermovir prophylaxis without csCMVi, and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range (IQR): 160 - 250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (14.3 - 32.8). There were no episodes of CMV end-organ disease. Hypo-gammaglobulinemia prior to letermovir discontinuation was predictive of csCMVi (hazard ratio: 0.33, 95% confidence interval: 0.12-0.93, p = 0.03), whereas T-cell and B-cell reconstitution prior to letermovir withdrawal were not predictive of csCMVi. Higher numbers of NK cells were found prior to letermovir withdrawal in patients that experienced csCMVi (median 202 versus 160, p = 0.03). In CMV+ recipients, CD3+CD4-CD8+ T-cell reconstitution was faster in CMV+ patients regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV specific adaptive immunity in patients with persistent hypo-gammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.
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7.
Post-transplantation cyclophosphamide is associated with increased bacterial infections
Ustun, C., Chen, M., Kim, S., Auletta, J. J., Batista, M. V., Battiwalla, M., Cerny, J., Gowda, L., Hill, J. A., Liu, H., et al
Bone marrow transplantation. 2023
Abstract
Post-transplant cyclophosphamide (PTCy) is increasingly used to reduce graft-versus-host disease after hematopoietic cell transplantation (HCT); however, it might be associated with more infections. All patients who were ≥2 years old, receiving haploidentical or matched sibling donor (Sib) HCT for acute leukemias or myelodysplastic syndrome, and either calcineurin inhibitor (CNI)- or PTCy-based GVHD prophylaxis [Haploidentical HCT with PTCy (HaploCy), 757; Sibling with PTCy (SibCy), 403; Sibling with CNI-based (SibCNI), 1605] were included. Most bacterial infections occurred within the first 100 days; 953 patients (34.5%) had at least 1 infection and 352 patients (13%) had ≥2 infections. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 [HaploCy 46%; SibCy 48%; SibCNI 35%; p < 0.001]. Compared with the SibCNI without infection cohort, 1.99-fold, 3.33-fold, 2.78-fold, and 2.53-fold increased TRM was seen for the HaploCy cohort without infection and HaploCy, SibCy, and SibCNI cohorts with infection, respectively. Bacterial infections increased mortality [HaploCy (HR1.84, 99% CI: 1.45-2.33, p < 0.0001), SibCy cohort (HR,1.68, 99% CI: 1.30-2.19, p < 0.0001), and SibCNI cohort (HR,1.76, 99% CI: 1.43-2.16, p < 0.0001). PTCy was associated with increased bacterial infections regardless of donor, and bacterial infections were associated with increased mortality irrespective of GVHD prophylaxis. Patients receiving PTCy should be monitored carefully for bacterial infections following PTCy.
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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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Impact of letermovir primary Cytomegalovirus (CMV) prophylaxis on 1-year mortality after allogeneic hematopoietic cell transplantation (HCT): a retrospective cohort study
Su, Y., Stern, A., Karantoni, E., Nawar, T., Han, G., Zavras, P., Dumke, H., Cho, C., Tamari, R., Shaffer, B., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022
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Abstract
BACKGROUND CMV seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV seronegative recipient/donor (R-D-) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1year post-HCT. METHODS In this retrospective cohort study, we included adult R-D- or R+ patients who received HCT pre-LET (between January 1, 2013 through December 15, 2017) and post-LET (between December 16, 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at one-year post-transplantation. RESULTS Of 848 patients analyzed, 305 were R-D-, 364 R+/no-LET and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR] [95% confidence interval]); 1.29 [0.76-2.18; p=0.353] between pre-LET/R-D- and post-LET/R-D-, R-D- were combined into one group. Compared with R-D-, the aHR for mortality was 1.40 [1.01-1.93] for R+/no-LET and 0.89 [0.57-1.41] for R+/LET. Among R+, LET was associated with decreased risk of death (aHR 0.62 [0.40-0.98]); when conventional and T-cell depleted HCT were analyzed separately, the aHR was 0.86 [0.51-1.43] and 0.21 [0.07-0.65] respectively. CONCLUSIONS At one-year post HCT, LET was associated with closing the mortality disparity between R-D- and R+. Among all R+, LET was associated with decreased mortality; driven by 79% reduced incidence of death in T-cell depleted HCT.
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The incidence and impact of clostridioides difficile infection on transplant outcomes in acute leukemia and MDS after allogeneic hematopoietic cell transplant-a CIBMTR study
Ramanathan, M., Kim, S., He, N., Chen, M., Hematti, P., Abid, M. B., Rotz, S. J., Williams, K. M., Lazarus, H. M., Wirk, B., et al
Bone marrow transplantation. 2022
Abstract
Clostridioides difficile infection (CDI) is common after allogeneic hematopoietic cell transplantation (alloHCT). The determination of incidence, risk factors, and impact of CDI on alloHCT outcomes is an unmet need. The study examines all patients aged 2 years and older who received first alloHCT for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS) between 2013 and 2018 at US centers and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) data registry. In total, 826 patients with CDI and 6723 controls from 127 centers were analyzed. The cumulative incidence of CDI by day 100 was 18.7% (99% CI: 15-22.7%) and 10.2% (99% CI: 9.2-11.1%) in pediatric and adult patients, respectively, with a median time to diagnosis at day +13. CDI was associated with inferior overall survival (OS) (p = 0.0018) and a 2.58-fold [99% CI: 1.43-4.66; p < 0.001] increase in infection-related mortality (IRM). There was a significant overlap in the onset of acute graft versus host disease (aGVHD) and CDI. IRM increased to >4 fold when CDI + aGVHD was considered. Despite advances in the management of CDI, increased IRM and decreased OS still results from CDI.