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BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/µL at hour +1 or greater than 224.5 CAR+EVs/µL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).
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Antígenos CD19 , Vesículas Extracelulares , Inmunoterapia Adoptiva , Linfoma de Células B , Humanos , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Antígenos CD19/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/sangre , Adulto , Anciano , Receptores Quiméricos de Antígenos/inmunología , Estudios ProspectivosRESUMEN
Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). There are no biomarkers that can consistently predict its occurrence. We aimed to evaluate whether numbers of antigen-presenting cell subsets in peripheral blood (PB) or serum chemokine concentrations are biomarkers of cGVHD occurrence. The study cohort comprised 101 consecutive patients undergoing allogeneic HSCT between January 2007 and 2011. cGVHD was diagnosed by both modified Seattle criteria and National Institutes of Health (NIH) criteria. Multicolor flow cytometry was used to determine the number of PB myeloid dendritic cells (DCs), plasmacytoid DCs, CD16+ DCs, and CD16+ and CD16- monocytes, as well as CD4+ and CD8+ T cells, CD56+ natural killer cells, and CD19+ B cells. Serum concentrations of CXCL8, CXCL10, CCL2, CCL3, CCL4, and CCL5 were measured by a cytometry bead array assay. At a median of 60 days after enrollment, 37 patients had developed cGVHD. Patients with cGVHD and those without cGVHD had comparable clinical characteristics. However, previous acute GVHD (aGVHD) was strongly correlated with later cGVHD (57% versus 24%, respectively; P = .0024). Each potential biomarker was screened for its association with cGVHD using the Mann-Whitney U test. Biomarkers that differed significantly (P < .05) between patients with cGVHD and those without cGVHD were analyzed by receiver operating characteristic (ROC) curve analysis to select the variables predicting cGVHD with an area under the ROC curve (AUC) >.5 and a P value <.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 ≥592.650 pg/mL (hazard ratio [HR], 2.655; 95% confidence interval [CI], 1.298 to 5.433; P = .008), pDC ≥2.448/µL (HR, .286; 95% CI, .142 to .577; P < .001) and previous aGVHD (HR, 2.635; 95% CI, 1.298 to 5.347; P = .007). A risk score was derived based on the weighted coefficients of each variable (2 points each), resulting in the identification of 4 cohorts of patients (scores of 0, 2, 4, and 6). In a competing risk analysis to stratify patients at differing risk levels of cGVHD, the cumulative incidence of cGVHD was 9.7%, 34.3%, 57.7%, and 100% in patients with scores of 0, 2, 4, and 6, respectively (P < .0001). The score could nicely stratify the patients based on the risk of extensive cGVHD as well as NIH-based global and moderate to severe cGVHD. Based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of .791 (95% CI, .703 to .880; P < .001). Finally, a cutoff score ≥4 was identified as the optimal cutoff by Youden J index with a sensitivity of 57.1% and a specificity of 85.0%. A multiparameter score including a history of previous aGVHD, serum CXCL10 concentration, and number of pDCs in the PB at 3 months post-HSCT stratify patients at varying risk levels of cGVHD. However, the score needs to be validated in a much larger independent and possibly multicenter cohort of patients undergoing transplantation from different donor types and with distinct GVHD prophylaxis regimens.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Pronóstico , Linfocitos T CD8-positivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Dendríticas , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/epidemiología , Biomarcadores , Factores de Riesgo , Quimiocina CXCL10RESUMEN
PURPOSE OF REVIEW: Several studies showed that age alone should not be used as an arbitrary parameter to exclude patients from allogeneic hematopoietic cell transplantation (HCT). The accessibility to allogeneic HCT programs for older patients with hematological diseases is growing up constantly. The Center for International Blood and Marrow Transplant Research has recently shown that over 30% of allogeneic HCT recipients are at least 60âyears old and that nearly 4% are aged 70 or more. Historically, the use of allogeneic HCT among elderly patients has been limited by age restrictions, reflecting physicians' concerns regarding prohibitive transplant-related mortality and HCT-associated morbidity. RECENT FINDINGS: The introduction of reduced intensity/toxicity conditioning regimens has allowed transplant Centers to carry out allogeneic HCT on patients previously considered not ideal candidates. The integration of specific risk scores could lead to better capture mental and physical frailties of older patients. Older adults less frequently have available medically fit siblings, able to donate, so, unrelated donors, familial haploidentical donors or umbilical cord blood grafts could potentially abrogate such a difficulty, allowing the curative potential of allogeneic HCT. SUMMARY: The appropriate assessing of allogeneic HCT feasibility for elderly patients should be the resonate application of different clinical and biological principles.
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Trasplante de Células Madre Hematopoyéticas , Anciano , Humanos , Persona de Mediana Edad , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de Riesgo , Donante no Emparentado , Acondicionamiento PretrasplanteRESUMEN
PURPOSE: To evaluate changes in the ocular surface microbiome (OSM) between pre- and post-haemopoietic stem cell transplant (HSCT) in the same patient, and to assess the potential impact of these changes in ocular graft-versus-host disease (o)GVHD development. METHODS: Lower fornix conjunctival swabs of 24 patients were obtained before and after HSCT and subjected to DNA extraction for amplification and sequencing of the V3-V4 regions of the bacterial 16S rRNA gene. The obtained reads were reconstructed, filtered, and clustered into zero-radius operational taxonomic units (zOTUs) at 97% identity level before taxonomic assignment, and biodiversity indexes were calculated. Transplant characteristics were recorded, and dry eye was diagnosed and staged 1-4 according to the Dry Eye WorkShop (DEWS) score. RESULTS: No significant difference in OSM alpha diversity between pre- and post-transplant was found. A significant difference in beta diversity was observed between patients with a DEWS score of 1 versus 3 (p = 0.035). Increased corneal damage between pre- and post-HSCT was significantly associated with a decrease in alpha diversity. The changes in OSM were not associated with oGVHD, nor with any transplant parameter. CONCLUSIONS: This preliminary study is the first study to analyse changes in the OSM before and after HSCT longitudinally. No trend in OSM biodiversity, microbial profile, or overall composition changes before and after HSCT was significant or associated with oGVHD onset. The great variability in the observed OSM profiles seems to suggest the absence of a patient-specific OSM "signature".
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Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way.
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Introduction: Minimal residual disease (MRD) is commonly assessed in bone marrow (BM) aspirate. However, sample quality can impair the MRD measurement, leading to underestimated residual cells and to false negative results. To define a reliable and reproducible method for the assessment of BM hemodilution, several flow cytometry (FC) strategies for hemodilution evaluation have been compared. Methods: For each BM sample, cells populations with a well-known distribution in BM and peripheral blood - e.g., mast cells (MC), immature (IG) and mature granulocytes (N) - have been studied by FC and quantified alongside the BM differential count. Results: The frequencies of cells' populations were correlated to the IG/N ratio, highlighting a mild correlation with MCs and erythroblasts (R=0.25 and R=0.38 respectively, with p-value=0.0006 and 0.0000052), whereas no significant correlation was found with B or T-cells. The mild correlation between IG/N, erythroblasts and MCs supported the combined use of these parameters to evaluate BM hemodilution, hence the optimization of the ALLgorithMM. Once validated, the ALLgorithMM was employed to evaluate the dilution status of BM samples in the context of MRD assessment. Overall, we found that 32% of FC and 52% of Next Generation Sequencing (NGS) analyses were MRD negative in samples resulted hemodiluted (HD) or at least mildly hemodiluted (mHD). Conclusions: The high frequency of MRD-negative results in both HD and mHD samples implies the presence of possible false negative MRD measurements, impairing the correct assessment of patients' response to therapy and highlighs the importance to evaluate BM hemodilution.
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Antigen-directed target therapy for B-cell acute lymphoblastic leukemia (B-ALL) is now the standard of care for relapsed/refractory (R/R) disease. A comprehensive determination of the target itself is mandatory to aid physician's choice. We determined baseline Cluster of differentiation 22 (CD22) expression percentage and fluorescent intensity on lymphoblasts of 30 patients with R/R B-ALL treated with anti-CD22 immunoconjugate drug Inotuzumab Ozogamicin (INO) and analyzed the impact of both parameters on patient outcome. Most patients (24/30, 80%) had a high leukemic blast CD22-positivity defined as ≥90%. We did not observe a benefit in terms of complete remission, overall survival (OS) and duration of response (DoR) for patients with CD22 ≥ 90% versus CD22 < 90%. Concerning CD22-FI quartile analysis we appreciated a trend for superior response rates in higher quartiles (Q2 -Q4 ) compared to Q1 and a significant benefit in terms of OS and DoR for patients with higher CD22-FI. INO demonstrates to be effective also in patients with lower CD22 expression, but therapeutical benefits are more evident in patients with higher CD22-FI. The evaluation of both CD22 percentage and CD22-FI of the leukemic blast may help physicians in therapeutic choices for R/R B-ALL patients when multiple treatment options are available, although no CD22 expression threshold can currently be identified below which INO should be considered not effective.
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Inmunoconjugados , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Inmunoconjugados/uso terapéutico , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inducción de Remisión , Resultado del TratamientoAsunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Trasplante de Células Madre de Sangre Periférica , Enfermedad Injerto contra Huésped/etiología , Humanos , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Estudios Prospectivos , Acondicionamiento Pretrasplante/métodosRESUMEN
The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Busulfano/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia/terapia , Estudios Prospectivos , Recurrencia , Tiotepa/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Background: Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS. Methods: This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation. Results: Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients. Discussion: Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.
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MicroARNs , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Interleucina-10 , Linfocitos T CD8-positivos , Inmunoterapia Adoptiva , Estudios ProspectivosRESUMEN
Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (µg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (µg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (µg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.
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Vesículas Extracelulares , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Humanos , Conejos , Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Anticuerpos/uso terapéutico , Linfocitos , RecurrenciaRESUMEN
Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3+/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n = 71; 75%) or lymphoblastic (n = 23; 25%) leukemia in complete remission who underwent matched related donor (n = 35; 37%) or unrelated donor (n = 59; 63%) allo-PBSCT. The median graft CD3+ cell, Treg, and gCD3/TregsR values were 196 × 106/kg body weight (range, 17 to 666 × 106/kg), 3 × 106/kg (range, 0.1 to 35 × 106/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P = .002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n = 48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n = 46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P = .015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P = .017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P = .135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Trasplante de Células Madre de Sangre Periférica , Humanos , Leucemia Mieloide Aguda/terapia , Estudios Prospectivos , Linfocitos T ReguladoresRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.
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Imidazoles/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Médula Ósea/patología , Proteínas de Fusión bcr-abl/genética , Humanos , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Resultado del TratamientoAsunto(s)
Inotuzumab Ozogamicina/uso terapéutico , Transfusión de Linfocitos/métodos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia Recuperativa , Trasplante de Células Madre/métodos , Adolescente , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
PURPOSE: The purpose of this research was to evaluate the incidence, risk factors, and complications of ocular graft-versus-host disease (GVHD) in a large single-center study. DESIGN: Retrospective observational case series. METHODS: This study included 283 patients who underwent hematopoietic stem cell transplantation (HSCT) between 2005 and 2020. Ocular GVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group criteria. Potential risk factors for ocular GVHD were evaluated using the Cox proportional hazards model. RESULTS: The cumulative incidence of ocular GVHD was 19.7% at 1 year, 29.3% at 2 years, 40.7% at 3 years, 47.2% at 4 years, and 49.7% at 5 years. Ocular GVHD was significantly associated with recipient age (hazard ratio [HR]: 1.228; 95% confidence interval [CI]: 1.033-1.459; P = .020); female sex (HR: 1.797; 95% CI: 1.195-2.703; P = .005); peripheral blood stem cell use (PBSC) (HR: 2.079; 95% CI: 1.268-3.411; P = .004); and previous acute GVHD (HR: 1.276; 95% CI: 1.073-1.518; P = .006). Ocular complications after HSCT included cataract, corneal ulcer, corneal perforation, lacrimal obstruction, herpetic keratitis, and cytomegalovirus retinitis. CONCLUSIONS: Half of patients developed ocular GVHD in the 5 years following HSCT. Older age, female sex, use of PBSC, and acute GVHD disease were significant predictors of ocular GVHD. Hematologists and ophthalmologists should be aware of its vision threating complications.
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Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Complicaciones Intraoperatorias , Complicaciones Posoperatorias , Adolescente , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Humanos , Incidencia , Leucemia/terapia , Linfoma/terapia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Recently, many reports were published supporting the clinical use of adoptively transferred natural killer (NK) cells as a therapeutic tool against cancer, including acute myeloid leukemia (AML). Our group demonstrated promising clinical response using adoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cells in AML patients. Moreover, the antileukemic effect was correlated with the dose of infused alloreactive NK cells ("functional NK cell dose"). Herein, we update the results of our previous study on a cohort of adult AML patients (median age at enrollment 64) in first morphological complete remission (CR), not eligible for allogeneic stem cell transplantation. After an extended median follow-up of 55.5 months, 8/16 evaluable patients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2 × 105/kg).
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Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Anciano , Femenino , Antígenos de Histocompatibilidad/inmunología , Prueba de Histocompatibilidad , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate longitudinally corneal endothelial cell changes in patients undergoing hematopoietic stem cell transplantation (HSCT) and to further investigate possible correlations with hematological and ocular characteristics. METHODS: Prospective observational study conducted at a single center. All patients underwent a comprehensive ophthalmological examination, before and after HSCT, including slitlamp examination, Schirmer test, tear breakup time, ocular surface staining, specular microscopy of corneal endothelium, and Ocular Surface Disease Index questionnaire. RESULTS: Twenty-five patients undergoing HSCT and 25 age- and sex-matched controls were included. At baseline, hematological patients showed significantly lower values of endothelial cell density (ECD) compared with those of controls (2514.5 ± 390.2 vs. 2723.7 ± 298.0 cells/mm, P = 0.038). After HSCT, ocular surface disease index score significantly increased (P = 0.020) and tear breakup time significantly decreased (P = 0.036). Conversely, no significant changes were found in Schirmer test and corneal fluorescein staining (always P > 0.05). Eight patients (32%) developed ocular graft-versus-host disease (GVHD). ECD values significantly decreased after HSCT (from 2514.5 ± 390.2 to 2409.5 ± 330.9 cells/mm, P = 0.009). The decrease in ECD values after HSCT was more pronounced in patients with ocular GVHD compared with those without (231.1 ± 188.8 vs. 45.6 ± 156.5, P = 0.016). No significant correlations between the changes in ECD and hematological and ocular characteristics were found (always P > 0.05). CONCLUSIONS: Hematological patients showed a lower endothelial cell count already before HSCT, compared with controls. After HSCT, the endothelial cell count further significantly decreased, particularly in patients who developed ocular GVHD.
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Enfermedades de la Córnea/etiología , Endotelio Corneal/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia/terapia , Adulto , Recuento de Células , Enfermedades de la Córnea/diagnóstico , Femenino , Fluorofotometría , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Estudios Prospectivos , Microscopía con Lámpara de Hendidura , Encuestas y Cuestionarios , Lágrimas/fisiologíaRESUMEN
Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) is a rare complication characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites, occurring after high-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and, less commonly, other conditions. We review pathogenesis, clinical appearance and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD occurring post-HSCT. The injury of the sinusoidal endothelial cells with loss of wall integrity and sinusoidal obstruction is the basis of development of postsinusoidal portal hypertension responsible for clinical syndrome. Risk factors associated with the onset of VOD and diagnostic tools have been recently updated both in the pediatric and adult settings and here are reported. Treatment includes supportive care, intensive management, and specific drug therapy with defibrotide. Because of its severity, particularly in VOD with associated multiorgan disease, prophylaxis approaches are under investigation. During the last years, decreased mortality associated to VOD/SOS has been reported being it attributable to a better intensive and multidisciplinary approach.
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Fibrinolíticos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática/terapia , Polidesoxirribonucleótidos/uso terapéutico , Complicaciones Posoperatorias/terapia , Animales , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Cuidados Paliativos , Factores de Riesgo , Trasplante HomólogoRESUMEN
INTRODUCTION: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen. METHODS AND PATIENTS: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000). CONCLUSION: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.