Grade 3-4 cytokine release syndrome is associated with poor survival in haploidentical peripheral blood stem cell transplantation
Leukemia & lymphoma. 2021;:1-11
The information on the impact of cytokine release syndrome (CRS) on haploidentical donor peripheral blood stem cell transplant (haploPBSCT) outcomes is limited. We retrospectively evaluated 98 patients who underwent haploPBSCT between June 2012 and June 2019 for the onset and severity of CRS per the ASTCT guidelines. The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%, p<.001), inferior relapse-free survival (64.0% vs. 20%, p<.001), and higher non-relapse mortality (NRM) (16.4% vs. 60%, p<.001) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71, p=.04), and higher NRM (SHR 4.51, p=.006) with grade 3-4 CRS. Our study shows that grade 3-4 CRS was adversely associated with survival. Therefore, early identification and preventive strategies are warranted.
Patients who underwent haploidentical peripheral blood stem cell transplantation (haploPBSCT) between June 2012 and June 2019 (n=98)
Evaluation of the onset and severity of cytokine release syndrome (CRS)
The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%), inferior relapse-free survival (64.0% vs. 20%), and higher non-relapse mortality (NRM) (16.4% vs. 60%) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71), and higher NRM (SHR 4.51) with grade 3-4 CRS.
Predictors of a short hospitalization in bone marrow transplantation patients presenting to the emergency department
The American journal of emergency medicine. 2021;45:117-123
BACKGROUND Despite the advantages of bone marrow transplantation (BMT), patients receiving this intervention visit the emergency department (ED) frequently and for various reasons. Many of those ED visits result in hospitalization, and the length of stay varies. OBJECTIVES The objective of our study was to identify the patients who were only briefly hospitalized and were thus eligible for safe discharge from the ED. METHODS This was a retrospective cohort study conducted on all adult patients who have completed a successful BMT and had an ED visit that resulted in hospitalization. RESULTS Our study included 115 unique BMT with a total number of 357 ED visits. Around half of those visits resulted in a short hospitalization. We found higher odds of a short hospitalization among those who have undergone autologous BMT (95%CI [1.14-2.65]). Analysis of the discharge diagnoses showed that patients with gastroenteritis were more likely to have a shorter hospitalization in comparison to those diagnosed with others (95%CI [1.10-3.81]). Furthermore, we showed that patients who presented after a month from their procedure were more likely to have a short hospitalization (95%CI [1.04-4.87]). Another significant predictor of a short of hospitalization was the absence of Graft versus Host Disease (GvHD) (95%CI [2.53-12.28]). Additionally, patients with normal and high systolic blood pressure (95%CI [2.22-6.73] and 95%CI [2.81-13.05]; respectively), normal respiratory rate (95%CI [2.79-10.17]) and temperature (95%CI [2.91-7.44]) were more likely to have a shorter hospitalization, compared to those presenting with abnormal vitals. Likewise, we proved higher odds of a short hospitalization in patients with a quick Sepsis Related Organ Failure Assessment score of 1-2 (95%CI [1.29-5.20]). Moreover, we demonstrated higher odds of a short hospitalization in patients with a normal platelet count (95%CI [1.39-3.36]) and creatinine level (95%CI [1.30-6.18]). CONCLUSION In our study, we have shown that BMT patients visit the ED frequently and many of those visits result in a short hospitalization. Our study showed that patients presenting with fever/chills are less likely to have a short hospitalization. We also showed a significant association between a short hospitalization and BMT patients without GvHD, with normal RR, normal T °C and a normal platelet count.
IgM Autoantibodies to Complement Factor H in Atypical Hemolytic Uremic Syndrome
Journal of the American Society of Nephrology : JASN. 2021
BACKGROUND Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class. METHODS In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein. RESULTS We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant-related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b. CONCLUSIONS Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H's active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.
Pre-transplant use of tyrosine kinase inhibitors and transplant associated thrombotic microangiopathy - a single centre analysis of incidence, risk factors and outcomes
Bone marrow transplantation. 2021
Transplant associated thrombotic microangiopathy (TA-TMA) is life-threatening complication post allogeneic stem cell transplant (ASCT). Risk factors and prognosis of TA-TMA are not well defined. We retrospectively studied consecutive ASCT patients with AML, ALL, and CML from January 2008 to March 2019 to study the incidence, risk factors, and outcomes of TMA. Definitive and probable TA-TMA was defined using Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) and Cho criteria, respectively. Risk factors explored were age, gender, diagnosis, type of transplant, use of tyrosine kinase inhibitors (TKI) pre transplant, conditioning regimen, and acute GVHD. Standard statistical methods were used. Total 241 patients, 179 (74.2 %) males, median age of 29 years were studied. Diagnoses were AML in 104, ALL in 85 (Ph+ve 23) and CML 52. Total 26 (10.7%) patients (22 males) developed TA-TMA at median of day+102. On multivariate analysis, pre-HSCT TKI (OR 2.7, p?=?0.028), haplo-HSCT (OR 3.16, p?=?0.018) and presence of acute GVHD (OR 4.17, p?=?0.003) were significant risk factors. With a median follow up of 60 months, median OS with and without TA-TMA was 18 and 97 months respectively (p?=?0.021). The association of pre-HSCT with TKI with TA-TMA merits further exploration in prospective studies.
Genetic Predictors for Sinusoidal Obstruction Syndrome-A Systematic Review
Journal of personalized medicine. 2021;11(5)
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts.
Validation of Healthcare Professional Proxy-Reported Children's International Mucositis Evaluation Scale
Oral diseases. 2021
OBJECTIVE The objective was to describe the reliability and validity of the healthcare professional proxy-report version of the Children's International Mucositis Evaluation Scale (ChIMES). METHODS We included pediatric patients who were between 4 and 21 years of age and scheduled to undergo hematopoietic cell transplantation. Mucositis was evaluated by trained healthcare professionals who scored ChIMES, the World Health Organization oral toxicity scale, mouth and throat pain visual analogue scale, National Cancer Institute - Common Terminology Criteria and the Oral Mucositis Daily Questionnaire. Measures were completed daily and evaluated on days 7-17 post stem cell infusion for this analysis. Psychometric properties examined were internal consistency, test re-test reliability (days 13 and 14) and convergent construct validity. RESULTS There were 192 participants included. Cronbach's alpha were 0.90 for ChIMES Total Score and 0.93 for ChIMES Percentage Score. Test re-test reliability were as follows: intraclass correlation coefficient (ICC) 0.82 (95% confidence interval (CI) 0.77-0.85) for ChIMES Total Score and ICC 0.82 (95% CI 0.77-0.86) for ChIMES Percentage Score. In terms of construct validation, all correlations between measures met or exceeded those hypothesized (all P < 0.05). CONCLUSIONS The healthcare professional proxy-report version of ChIMES is reliable and valid for children and adolescents undergoing hematopoietic cell transplantation.
Serial Changes in Cardiac Strain and Contractility After Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies
International heart journal. 2021
Hematopoietic stem cell transplantation (HSCT) is occasionally associated with cardiac dysfunction during long-term follow-up. Global longitudinal strain (GLS) has emerged as an early predictor of cardiotoxicity associated with cancer therapy; however, the serial changes in GLS before and after HSCT have not been elucidated. To clarify the association between HSCT and GLS, we investigated serial changes in GLS before and after HSCT. We evaluated cardiac function before and 1, 3, and 6 months after HSCT in 38 consecutive HSCT patients enrolled in this study. Overall, GLS and left ventricular (LV) ejection fraction (EF) temporally decreased 1 month post-HSCT. LVEF completely recovered to baseline at 3 months after HSCT, whereas GLS partially recovered 6 months after HSCT. Except for five patients who died within 6 months, GLS values in the low EF group (LVEF = 55% at 6 months post-HSCT, n = 6) were significantly and consistently lower than those in the normal EF group (LVEF > 55% at 6 months post-HSCT, n = 27) at any time during follow-up. These findings suggest that GLS before HSCT might be associated with a decrease in LVEF after HSCT in patients with hematologic malignancies. Further prospective and long-term data will be important for understanding the management of HSCT-associated cardiac dysfunction.
Head-to-head Comparison of Qualitative Radiologist Assessment With Automated Quantitative Computed Tomography Analysis for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation
Journal of thoracic imaging. 2021
PURPOSE Computed tomography (CT) findings of bronchiolitis obliterans syndrome (BOS) can be nonspecific and variable. This study aims to measure the incremental value of automated quantitative lung CT analysis to clinical CT interpretation. A head-to-head comparison of quantitative CT lung density analysis by parametric response mapping (PRM) with qualitative radiologist performance in BOS diagnosis was performed. MATERIALS AND METHODS Inspiratory and end-expiratory CTs of 65 patients referred to a post-bone marrow transplant lung graft-versus-host-disease clinic were reviewed by 3 thoracic radiologists for the presence of mosaic attenuation, centrilobular opacities, airways dilation, and bronchial wall thickening. Radiologists' majority consensus diagnosis of BOS was compared with automated PRM air trapping quantification and to the gold-standard diagnosis of BOS as per National Institutes of Health (NIH) consensus criteria. RESULTS Using a previously established threshold of 28% air trapping on PRM, the diagnostic performance for BOS was as follows: sensitivity 56% and specificity 94% (area under the receiver operator curve [AUC]=0.75). Radiologist review of inspiratory CT images alone resulted in a sensitivity of 80% and a specificity of 69% (AUC=0.74). When radiologists assessed both inspiratory and end-expiratory CT images in combination, the sensitivity was 92% and the specificity was 59% (AUC=0.75). The highest performance was observed when the quantitative PRM report was reviewed alongside inspiratory and end-expiratory CT images, with a sensitivity of 92% and a specificity of 73% (AUC=0.83). CONCLUSIONS In the CT diagnosis of BOS, qualitative expert radiologist interpretation was noninferior to quantitative PRM. The highest level of diagnostic performance was achieved by the combination of quantitative PRM measurements with qualitative image feature assessments.
Characterizing Immune-Mediated Cytopenias After Allogeneic Hematopoietic Cell Transplantation for Pediatric Nonmalignant Disorders
Transplantation and cellular therapy. 2021;27(4):316.e1-316.e8
Immune-mediated cytopenias (IMC)-isolated or combined hemolytic anemia, thrombocytopenia, or neutropenia-are increasingly recognized as serious complications after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant disorders (NMD). However, IMC incidence, duration, response to therapy, and risk factors are not well defined. This retrospective chart review identified cases of IMC with serologic confirmation among patients who underwent HCT for NMD at a single institution between 2010 and 2017. IMC after HCT for NMD in a large pediatric cohort (n = 271) was common with a cumulative incidence of 18%, identified at a median of 136 days after HCT. Treatment included prolonged immune suppression (>3 months) in 58% of all IMC cases, 91% when multiple cell lines were affected. Multiple therapeutic agents were used for the majority affected, and median time to resolution of IMC was 118 days from diagnosis. Fine-Gray competing risk multivariate regression analysis identified a combined risk factor of younger age (<3 years) and inherited metabolic disorder, as well as hemoglobinopathy (at any age) associated with 1-year incidence of IMC (P < .01). We expand these findings with the observation of declining donor T-lymphoid chimerism from day 60 to 100 and lower absolute CD4+ counts at day 100 (P < .01), before median onset of IMC, for patients with IMC compared to those without. In this cohort, 4 deaths (8%) were associated with IMC, including 2 requiring second transplantation for secondary graft failure. Although the pathogenesis of IMC post-HCT for NMD remains elusive, further research may identify approaches to prevent and better treat this HCT complication.
Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation
Annals of hematology. 2021
BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.