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Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250 mg/m2 d-6, etoposide 300 mg/m2 d-5 ~ d-2, cytarabine 500 mg/m2 d-5 ~ d-2, and cyclophosphamide 1200 mg/m2 d-5 ~ d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95% vs 97%, P = 1.000) and complete response rate (66% vs 73%, P = 0.580) between the two cohorts. The 5-year progression-free survival (PFS), 5-year overall survival (OS), and 5-year cumulative incidence of relapse (CIR) for all patients were 72% (95% CI 62%-82%), 92% (95% CI 86%-97%), and 29% (95% CI 17%-38%), respectively. There was no significant difference in the 5-year PFS (80% vs 70%, P = 0.637), 5-year OS (95% vs 91%, P = 0.496), and 5-year CIR (20% vs 30%, P = 0.733) between cohorts. In terms of safety, the CEAC cohort had a lower incidence rate of grade 1-2 gastrointestinal hemorrhage (P = 0.023) and severe nausea (P = 0.007) compared with the BEAM cohort. In conclusion, the CEAC regimen seems to be a suitable alternative to the BEAM regimen for ASCT in DLBCL patients.
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Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Humanos , Carmustina/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/efeitos adversos , Etoposídeo/efeitos adversos , Semustina , Estudos de Coortes , Pontuação de Propensão , Transplante Autólogo/métodos , Recidiva Local de Neoplasia , Ciclofosfamida/efeitos adversos , Citarabina/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The preferred donor (haploidentical donor [HID] versus matched unrelated donor [URD]) choice in patients with acquired severe aplastic anemia (SAA) who lack an HLA-matched sibling donor (MSD) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n = 58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) and 5-year failure-free survival (FFS) were comparable among the URD (n = 8), HID (n = 25), and MSD (n = 25) cohorts (OS: mean, 87.5 ± 11.7% versus 98.0 ± 6.5% versus 83.3 ± 7.6% [P = .926]; FFS: mean, 60.0 ± 18.2% versus 87.0 ± 7.0% versus 78.3 ± 8.6% [P = .222]). Multivariate analysis revealed that primary engraftment failure independently predicted OS and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, but donor type and age were not predictive of these outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Our findings show that an alternative donor SCT is indicated for eligible SAA patients without an MSD even if age ≥40 years.
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Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Adulto , Anemia Aplástica/terapia , Estudos Retrospectivos , Irmãos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-TroncoRESUMO
OBJECTIVE: To explore the clinical and laboratory characteristics of hematological tumors with different types of abnormalities in platelet derived growth factor ß (PDGFRß) gene. METHODS: A retrospective analysis was carried out on 141 patients with abnormal long arm of chromosome 5 (5q) and comprehensive medical history data from Changhai Hospital Affiliated to Naval Medical University from 2009 to 2020, and their clinical data were collected. R-banding technique was used for chromosomal karyotyping analysis for the patient's bone marrow, and fluorescence in situ hybridization (FISH) was used to detect the PDGFRß gene. The results of detection were divided into the amplification group, deletion group, and translocation group based on FISH signals. The three sets of data column crosstabs were statistically analyzed, and if the sample size was n >= 40 and the expected frequency T for each cell was >= 5, a Pearson test was used to compare the three groups of data. If N < 40 and any of the expected frequency T for each cell was < 5, a Fisher's exact test is used. Should there be a difference in the comparison results between the three sets of data, a Bonferroni method was further used to compare the data. RESULTS: In total 98 patients were detected to have PDGFRß gene abnormalities with the PDGFRß probe, which yielded a detection rate of 69.50% (98/141). Among these, 38 cases (38.78%) had PDGFRß gene amplifications, 57 cases (58.16%) had deletions, and 3 (3.06%) had translocations. Among the 98 cases, 93 were found to have complex karyotypes, including 37 cases from the amplification group (97.37%, 37/38), 55 cases from the deletion group (96.49%, 55/57), and 1 case from the translocation group (33.33%, 1/3). Analysis of three sets of clinical data showed no significant gender preponderance in the groups (P > 0.05). The PDGFRß deletion group was mainly associated with myeloid tumors, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (P < 0.001). The PDGFRß amplification group was more common in lymphoid tumors, such as multiple myeloma (MM) (P < 0.001). The PDGFRß translocation group was also more common in myelodysplastic/myeloproliferative tumors (MDS/MPN). CONCLUSION: Tumors with PDGFRß gene rearrangement may exhibit excessive proliferation of myeloproliferative tumors (MPN) and pathological hematopoietic changes in the MDS, and have typical clinical and hematological characteristics. As a relatively rare type of hematological tumor, in addition to previously described myeloid tumors such as MPN or MDS/MPN, it may also cover lymphoid/plasma cell tumors such as multiple myeloma and non-Hodgkin's lymphoma.
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Neoplasias Hematológicas , Mieloma Múltiplo , Síndromes Mielodisplásicas , Humanos , Relevância Clínica , Neoplasias Hematológicas/genética , Hibridização in Situ Fluorescente , Estudos Retrospectivos , Translocação GenéticaRESUMO
Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell disorder, which accounts for ~70% of all PCL. Survival of pPCL remains poor, and is related with early mortality. There is no standard therapy for patients with pPCL. In the present study, a 26-year-old man who was diagnosed with pPCL was reported. The patient achieved stringent complete remission to the successful treatment of intensive chemotherapy combined with sequential autologous and allogeneic stem cell transplantation (SCT) followed by maintenance therapy with oral administration of ixazomib, thalidomide and dexamethasone (IRD regimen). Development of complex treatment algorithms that combine novel agents, SCT and post-transplantation remission strategies may translate into survival in patients with pPCL.
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Parathyroid adenomas are benign proliferative disorders of parathyroid glands. Patients typically exhibit hyperparathyroidism and elevated serum calcium levels due to elevated levels of parathyroid hormone (PTH). We report a newly diagnosed case of a rare pathological osteolytic lesion. Radiological evaluation revealed multiple bony lesions in multiple parts of the pelvis, vertebral body, and spinous process, suggesting hematological neoplasms or bone marrow metastatic carcinoma. The morphology revealed many abnormal cells in the bone marrow smear. Furthermore, serum calcium and PTH levels were significantly increased compared to normal levels. Doppler color ultrasound showed a thyroid mass (left), suspected parathyroid adenoma, thyroid, and isthmus nodular goiter (right). The patient underwent bilateral neck exploration with parathyroidectomy, and serum calcium and PTH levels significantly decreased on the second day after surgery and had a surgical cure.
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As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.
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Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Prognóstico , Mutação , Leucemia Mieloide Aguda/terapiaRESUMO
Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.
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Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR T) therapy. However, patients who receive CAR T therapy in pivotal clinical trials are subjected to restrictive selection criteria, and this means that rare but fatal toxicities are underestimated. Here, we systematically analyzed CAR T-associated hematologic AE using the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC); the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5,112 CAR T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AE (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH; n=136 [2.7%], ROR025 = 21.06), coagulopathy (n=128 [2.5%], ROR025 = 10.43), bone marrow failure (n=112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC; n=99 [1.9%], ROR025 = 9.64), and B-cell aplasia (n=98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly under-reported AE in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43%, and 22 death-related hematologic AE were identified using LASSO regression analysis. These findings could help clinicians in the early detection of those rarely reported but lethal hematologic AE, thus reducing the risk of severe toxicities for CAR T recipients.
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Coagulação Intravascular Disseminada , Linfo-Histiocitose Hemofagocítica , Receptores de Antígenos Quiméricos , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/terapia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/terapia , Farmacovigilância , Estudos Retrospectivos , Terapia Baseada em Transplante de Células e TecidosRESUMO
INTRODUCTION: Genetic landscape, disease characteristics, and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. METHODS: We conducted a multicenter, cross-sectional study to compare the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (>60 years). RESULTS: Of the 1,664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV, and 71 (20.3%) with MF. In multivariate analyses, the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. CONCLUSIONS: We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.
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Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Idoso , Pessoa de Meia-Idade , Humanos , Adulto Jovem , Adolescente , Adulto , Estudos Transversais , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/genética , Policitemia Vera/genética , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Mielofibrose Primária/genética , Medidas de Resultados Relatados pelo PacienteRESUMO
A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.
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Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , PrognósticoRESUMO
Acute myeloid leukemia (AML) patients relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a poor prognosis. Cytogenetic evolution (CGE) has been investigated and found to have an important impact on the prognosis of relapsed leukemia, but its impact on AML patients relapsing after transplantation remains controversial. In this study, we analyzed 34 AML patients relapsing after allo-HSCT, among whom 14 developed additional abnormalities in chromosomal karyotype after leukemia recurrence (CGE group) and 20 patients did not (non-CGE group). We found that the cytogenetic characteristics were much more complex at relapse in the CGE group, and the acquisition of aberrations at relapse most commonly involved chromosome 11. The 6-month post-relapse overall survival (PROS) of the CGE group was significantly lower than that of the non-CGE group (21.4% versus 50.0%, P = 0.004). The CGE group also showed a trend of worse 2-year OS (7.1% versus 28.6%, P = 0.096). In the multivariate analyses, the occurrence of chronic graft-versus-host disease (HR 0.27 [95% CI, 0.11-0.68], P = 0.006) and a reduced-intensity FBA conditioning regimen (HR 0.42 [95% CI, 0.18-0.98], P = 0.045) were found to be two independent factors for a better PROS, whereas CGE (HR 3.16 [95% CI, 1.42-7.05], P = 0.005) was associated with a worse PROS. In conclusion, CGE was associated with a poor prognosis in AML patients who relapsed after allo-HSCT, and the importance of monitoring karyotype changes after transplantation should be noted.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Transplante Homólogo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Doença Crônica , Cariotipagem , Recidiva , PrognósticoRESUMO
Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.
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BACKGROUND: Extranodal involvement is recognized as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, the prognostic differences of patients with refractory/relapsed (R/R) nodal and extranodal DLBCL in the chimeric antigen receptor T cell (CART) therapy era are still unclear. MATERIALS AND METHODS: In this study, 18 R/R nodal DLBCL (R/R N-DLBCL) and 19 R/R extranodal DLBCL (R/R EN-DLBCL) were enrolled to compare clinical outcomes. RESULTS: The median follow-up time was 13 (range, 1-47) months and one-year progression-free survival (PFS; 83.3% vs. 42.1%, P = 0.008) and one-year overall survival (OS; 94.4% vs. 63.2%, P = 0.020) were significantly different between nodal and extranodal patients. In the multivariable Cox regression analysis, R/R EN-DLBCL was associated with worse PFS (hazard ratio [HR] = 4.263, P = 0.018) and OS (HR = 9.589, P = 0.034) compared to R/R N-DLBCL. Additionally, autologous hematopoietic stem cell transplantation (ASCT) combined with CART therapy (ASCT + CART) was correlated with better PFS (HR = 0.164, P = 0.003) compared to CART treatment alone. CONCLUSIONS: The clinical outcomes of R/R EN-DLBCL were worse than R/R N-DLBCL in patients receiving CART therapy and ASCT + CART therapy is a promising alternative treatment for patients with R/R EN-DLBCL.
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Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêuticoRESUMO
The pathogenesis of central nervous system involvement (CNSI) in patients with acute lymphoblastic leukaemia (ALL) remains unclear and a robust biomarker of early diagnosis is missing. An untargeted cerebrospinal fluid (CSF) metabolomics analysis was performed to identify independent risk biomarkers that could diagnose CNSI at the early stage. Thirty-three significantly altered metabolites between ALL patients with and without CNSI were identified, and a CNSI evaluation score (CES) was constructed to predict the risk of CNSI based on three independent risk factors (8-hydroxyguanosine, l-phenylalanine and hypoxanthine). This predictive model could diagnose CNSI with positive prediction values of 95.9% and 85.6% in the training and validation sets respectively. Moreover, CES score increased with the elevated level of central nervous system (CNSI) involvement. In addition, we validated this model by tracking the changes in CES at different stages of CNSI, including before CNSI and during CNSI, and in remission after CNSI. The CES showed good ability to predict the progress of CNSI. Finally, we constructed a nomogram to predict the risk of CNSI in clinical practice, which performed well compared with observed probability. This unique CSF metabolomics study may help us understand the pathogenesis of CNSI, diagnose CNSI at the early stage, and sequentially achieve personalized precision treatment.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Biomarcadores , Sistema Nervoso Central/patologia , Líquido Cefalorraquidiano , Humanos , Metabolômica , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
NPM1mut acute myeloid leukemia (AML) has been identified as a distinct entity of myeloid neoplasms according to the 2017 European LeukemiaNet (ELN) guidelines. It confers a favorable prognosis regardless of cytogenetic abnormalities. We evaluated 418 newly diagnosed AML patients to test the validity of this hypothesis. Seventy-four patients with NPM1mut AML showed a good response to induction and a relatively favorable prognosis. Abnormal karyotypes were observed in 15 patients. Chromosomal abnormalities were significantly associated with a worse prognosis in NPM1mut AML patients (5-year overall survival (OS): 38.9 ± 12.9%, p = .037; event-free survival (EFS): 33.3 ± 12.2%, p = .043, respectively). Four patients with abnormal karyotypes who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) during CR1 had longer survival than those who received chemotherapy only. Multivariable analysis revealed abnormal karyotypes independently predicted OS and EFS among NPM1mut AML patients. In summary, cytogenetic abnormalities are strong prognostic indicators in NPM1mut AML. Therefore, they should be classified accordingly, and alloHSCT should be performed on selected patients during CR1.
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Leucemia Mieloide Aguda , Proteínas Nucleares , Cariótipo Anormal , Aberrações Cromossômicas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Prognóstico , Tirosina Quinase 3 Semelhante a fmsRESUMO
Aim: To characterize the actionable biomarker for leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) at the DNA damage repair promoter methylation level. Materials & methods: Bioinformatic analysis and experimental validation were performed to identify the MPNs-LT specific biomarker out of the promoter methylation of 236 DNA damage repair genes with GSE42042 dataset and an in-house cohort of 80 MPNs. Results: Hypermethylation of BRCA2 promoter was characterized as the JAK2 mutation-independent epigenetic marker for MPNs-LT and repressed mRNA and protein expression, leading to olaparib hypersensitivity in the leukemic cells from MPNs-LT. Conclusion: Expressional silence of BRCA2 by promoter methylation compels the homologous recombination deficiency and vulnerability to PARP inhibition and serves as an actionable marker for targeted therapy for MPNs-LT.
Leukemic transformation is a difficulty of myeloproliferative tumors, known as myeloproliferative neoplasms (MPNs). It is possible that DNA damage repair (DDR) dysregulation plays a very important role during the change process. To show the leukemic transformation-related change in DDR-related genes, the authors compared the promoter methylation patterns of DDR genes between leukemic transformed MPNs and long-lasting MPNs in two independent MPN associates/groups of people. The authors identified BRCA2 as the most significantly epigenetically silenced DDR gene during the leukemic transformation phase of disease. The study found that promoter hypermethylation of BRCA2 is an epigenetic marker for the leukemic transformation of MPNs, although its clinical use awaits further experimentation.
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Transtornos Mieloproliferativos , Neoplasias , Proteína BRCA2/genética , Biomarcadores , Metilação de DNA , Humanos , Mutação , Transtornos Mieloproliferativos/genética , Neoplasias/genética , Regiões Promotoras GenéticasRESUMO
Autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CART) are salvage therapies that are utilised for treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, whether the combination therapy of ASCT and CART (ASCT-CART) can improve the survival of R/R DLBCL remains unknown. Overall, 67 R/R DLBCL patients were included, among which 21 patients underwent ASCT-CART therapy and 46 patients underwent ASCT therapy. The median number of mononuclear cells numbers that were infused in the ASCT-CART and ASCT groups was 4.71 × 108 /kg and 5.36 × 108 /kg, respectively (p = 0.469). The median number of CD34+ cell numbers that were infused in the ASCT-CART and ASCT groups was 2.41 × 106 /kg and 3.05 × 106 /kg, respectively (p = 0.663). The median number of CART cells that were infused was 2.63 × 106 /kg with a median transduction rate of 59.83%. The objective response rates to ASCT-CART and ASCT therapy were 90% and 89%, respectively (p = 1.000). However, the ASCT-CART group showed higher complete remission (CR) rates than the ASCT group (71% vs. 33%; p = 0.003). The ASCT-CART group demonstrated superior 3 year progression-free survival (PFS) (80% vs. 44%; p = 0.036) and lower 3 year relapse/progression rate (15% vs. 56%; p = 0.015) compared to the ASCT group. However, the 3 year overall survival results indicated that there were no differences between the two groups (80% vs. 69%; p = 0.545). For R/R DLBCL patients, ASCT-CART therapy is associated with higher CR rate, better PFS, and lower relapse/progression rate. These data support that ASCT-CART therapy can be used as a salvage therapy for R/R DLBCL patients.
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Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Estudos Retrospectivos , Rituximab , Transplante de Células-Tronco , Transplante AutólogoRESUMO
This study focused genetic pathogenesis and tumor microenvironment of Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCL) in patients without immunodeficiency. DNA samples from these cases were sequenced by next generation sequencing (NGS) using a selected gene panel. Results revealed that most gene mutations were not specific for EBV positive DLBCL. However, B2M (ß2-microglobulin) mutations were significantly increased and HLA-I or HLA-II expression was decreased in these cases, which was related to patient's poor outcome. B2M mutations and deregulation of B2M expression were further confirmed by Sanger sequencing and immunohistochemistry. Reducing the infiltration of CD8+ T lymphocytes, related to decreased expression of HLA-I or HLA-II was found in these patients. These results suggest that the mutations of B2M could cause the disruption of the expression and functions of this important subunit of HLA, leading to decreased expression of HLA-I or HLA-II and subsequently to reduce T lymphocyte infiltration in tumor tissues. The consequence of this event lessens the recognition and elimination of EBV+ tumor cells by host immunity and paves the way for the host immune tolerance to EBV+ tumor cells by evading immune recognition and escaping the T lymphocyte killing.