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INTRODUCTION: Peripheral blood stem cells (PBSCs) are the most common source of stem cell transplantation, which depends on an adequate number of CD34+ cells. Although pre-apheresis CD34+ cell count is a standard guide for the collection, it is not always available. This study aimed to evaluate complete blood count parameters for predicting successful one-day autologous PBSC collection. METHODS: Data from the patients who underwent autologous PBSC collection at a tertiary care hospital were retrospectively reviewed. RESULTS: There were 123 patients (185 leukapheresis procedures). Successful PBSC collection (CD34+ cells ≥4.0 × 106 cells/kg) was obtained in 85 patients (69.1%), of which 55 (44.7%) were successfully obtained on the first day. The median CD34+ collection efficiency was 44.1%. The mean platelet loss during apheresis was 39.9%. The adverse event rate was 18.9%. Patients in whom PBSCs were collected within one day were less likely to experience adverse effects related to leukapheresis. Pre-apheresis CD34+ cells ≥10 cells/µLand combined white blood cell (WBC) counts ≥5 × 109/L and/or monocyte ≥10% were independently associated with the successful one-day PBSC collection (adjusted odds ratio 24.06, 95% confidence interval [CI] 5.30-109.10, p < 0.001; and 6.94, 95% CI 1.35-35.79, p = 0.021, respectively). Only pre-apheresis CD34+ cells had a strong correlation with the total stem cell yield. CONCLUSIONS: To reduce the complication of leukapheresis, the combined pre-apheresis WBC ≥5 × 109/L and/or monocyte ≥10% is a practical parameter to initiate a successfully one-day PBSC collection with or without pre-apheresis CD34+ cell results.
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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease. This review article draws from the expertise of practicing hematologists/oncologists in the region, with the aim of integrating data from current scientific evidence to address the unmet needs and unique socioeconomic challenges faced by challenging high risk patient groups in the Asia-Pacific region.
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ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.
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Neoplasias do Sistema Nervoso Central , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Linfoma de Células T/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/mortalidade , Prognóstico , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/terapia , Fatores de Risco , Recidiva , Células Matadoras Naturais , Adulto JovemRESUMO
AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs. METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes. RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes. CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.
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CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.
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Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Indução de Remissão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Adulto , Idoso , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Adulto Jovem , Receptores de Antígenos Quiméricos/imunologia , Taxa de Sobrevida , Seguimentos , Antígenos CD19/imunologia , Resposta Patológica CompletaRESUMO
The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Biomarcadores , Doença Enxerto-Hospedeiro/tratamento farmacológico , Terapia de Imunossupressão , Transplante HomólogoRESUMO
Several prognostic models have been introduced to predict outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Endothelial activation and stress index (EASIX) is a surrogate of endothelial dysfunction which has been shown to predict outcomes of patients with various hematologic malignancies. However, the prognostic implication of EASIX for DLBCL is limited and warrants exploration. We conducted a retrospective study enrolling adult DLBCL patients including a discovery cohort from the single-centered university hospital database and a validation cohort from the independent nationwide multi-center registry. EASIX scores were calculated using creatinine, lactate dehydrogenase, and platelet levels. The receiver operating characteristic curve analysis was used to determine optimal cutoff. Statistical analysis explored the impact of EASIX on survival outcomes. A total of 323 patients were included in the discovery cohort. The optimal EASIX cutoff was 1.07 stratifying patients into low (53.9%) and high EASIX (46.1%) groups. Patients with high EASIX had worse 2-year progression-free survival (PFS) (53.4% vs. 81.5%, p<0.001) and overall survival (OS) (64.4% vs. 88.7%, p<0.001) than patients with low EASIX. Multivariate analysis revealed that older age, bulky disease, impaired performance status, and high EASIX were associated with an unfavorable OS. In the validation cohort of 499 patients, the optimal EASIX cutoff was 1.04. Similar to the discovery cohort, high EASIX score was associated with high-risk diseases, worse PFS, and inferior OS. In conclusion, EASIX score was significantly associated with survival outcomes and may be used as a simple prognostic tool to better risk-classify DLBCL.
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Linfoma Difuso de Grandes Células B , População do Sudeste Asiático , Adulto , Humanos , Prognóstico , Estudos Retrospectivos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Intervalo Livre de ProgressãoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) in adults may be idiopathic or secondary to various conditions. Recent studies identified germline hepatitis A virus-cellular receptor 2 (HAVCR2) mutations in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with HLH. The roles of this mutation in HLH, especially in idiopathic group, have never been explored. Of the 65 HLH cases, we detected germline HAVCR2Y82C mutations in nine (13.8%) cases (five SPTCL and four idiopathic HLH). Other causes of HLH were hematologic malignancies excluding SPTCL (32.3%), idiopathic HLH without HAVCR2 mutation (29.2%), infections (15.3%), and autoimmune diseases (9.2%). Germline HAVCR2 mutation was significantly associated with less anemia and better survival. This defines a distinct subgroup of HLH.
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Linfo-Histiocitose Hemofagocítica , Adulto , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Mutação , Células Germinativas , Prognóstico , Receptor Celular 2 do Vírus da Hepatite A/genéticaRESUMO
ABSTRACT Introduction: Relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) leads to dismal outcomes. This study aimed to identify high-risk patients and explore the effects of cytomegalovirus (CMV) reactivation in a high CMV-seropositive population. Methods: The study involved a single-center retrospective cohort in Thailand, analyzing clinical risk factors and CMV-mediated immune responses, correlated with transplant outcomes in AML patients. Results: Eighty-five patients with AML in complete remission (CR) undergoing HLA-matched myeloablative allo-SCT between 2011 and February 2021 were enrolled. The relapse rate was 27.1% with the median time of 7 months after transplantation. The 3-year relapse-free-survival (RFS) and overall-survival (OS) were 72.2% and 80.8%, respectively. The disease status (>CR1) and absence of chronic graft-versus-host disease (cGVHD) were independently significant adverse prognostic factors of RFS and OS. Ninety-two percent of recipient-donor pairs were both CMV seropositive. The CMV reactivation occurred in 54.1% of the patients. The clinically significant CMV infection rate was 49.4%. No CMV syndrome/disease or CMV-related mortality occurred. One-year cumulative incidence of relapse among CMV-reactivation and non-reactivation groups were 14.3% and 25.6%, respectively, without a statistically significant difference. Transplantation-related mortality was 11.1%. Conclusions: The transplantation beyond CR1 and absence of cGVHD are powerful prognostic factors associated with inferior RFS and OS. In a high CMV prevalence country, there appears to be no impact of CMV reactivation on relapse in AML patients undergoing an allo-SCT.
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Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is a challenging condition to treat, and there is an unmet clinical need for effective therapies. Recently, polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADC), combined with bendamustine-rituximab (BR), has been approved for R/R DLBCL patients. However, real-world data on Pola-based regimens in R/R DLBCL patients, especially in Thailand, are limited. This study aimed to evaluate the efficacy and safety of Pola-based salvage treatment in R/R DLBCL patients in Thailand. Thirty-five patients who received Pola-based treatment were included in the study, and their data were compared to 180 matched patients who received non-Pola-based therapy. The overall response rate (ORR) in the Pola group was 62.8%, with complete remission and partial remission rates of 17.1% and 45.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 10.6 months and 12.8 months, respectively. The study found a significantly higher ORR in Pola-based salvage treatments compared to non-Pola-based therapy (62.8% vs. 33.3%). The survival outcomes were also significantly superior in the Pola group, with longer median PFS and OS than the control group. Grades 3-4 adverse events (AEs) were mainly hematological, and they were tolerable. In conclusion, this study provides real-world evidence of the efficacy and safety of Pola-based salvage treatment in R/R DLBCL patients in Thailand. The results of this study are promising and suggest that Pola-based salvage treatment could be a viable option for R/R DLBCL patients who have limited treatment options.
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Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , População do Sudeste Asiático , Tailândia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Imunoconjugados/uso terapêutico , RituximabRESUMO
Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.
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Linfo-Histiocitose Hemofagocítica , Paniculite , Humanos , Masculino , Adolescente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Paniculite/genética , Paniculite/complicações , Paniculite/patologia , Mutação em Linhagem Germinativa , Células Germinativas/patologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Estudos Multicêntricos como AssuntoRESUMO
INTRODUCTION: CD19-directed chimeric antigen receptor (CAR) T-cell therapy is a highly effective therapy for patients with relapsed/refractory large B-cell lymphoma (LBCL) and three CD19 CAR T-cell products (axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel) are currently approved for this indication. Despite the clinical benefit of CD19 directed CAR T-cell therapy, this treatment is associated with significant morbidity from treatment-emergent toxicities. AREAS COVERED: This Review discusses the safety considerations of axicabtagene ciloleucel in patients with LBCL. This includes discussion of the frequently observed immune-mediated toxicities of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Additionally, we review CAR T-cell therapy related cytopenias, infection, organ dysfunction and the more recently described hemophagocytic lymphohistiocytosis. EXPERT OPINION: A thorough understanding of the toxicities associated with CD19-directed CAR T-cell therapy will facilitate the optimal selection of patients for this therapy. Furthermore, knowledge of preventative measures of CAR T-cell related complications, and early recognition and appropriate intervention will lead to the safe administration of these therapies, and ultimately improved outcomes for our patients.
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Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Resultado do Tratamento , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Antígenos CD19/efeitos adversosRESUMO
BACKGROUND: Cytokine-induced killer (CIK) cells are a heterogeneous group of immune cells that exert potent MHC-unrestricted cytotoxicity toward various cancer cells in both solid and hematological malignancies. OBJECTIVE: The purposes of this study were to compare the expansion and characteristics of cytokine-induced killer cells between a standard culture method and a gas-permeable culture method and to develop a clinical-scale expansion protocol for cytokine-induced killer cells using a gas-permeable culture method. METHODS: We compared the absolute cell number, fold change, cell subsets, activation markers, cytokine concentrations, and cytotoxicity toward myeloid leukemia cell lines between cytokine-induced killer cells expanded using two different culture methods. Then, we determined the ability to achieve clinical-scale expansion of cytokine-induced killer cells using the gas-permeable culture method. RESULTS: Cytokine-induced killer cells in the gas-permeable culture method group exhibited significantly better expansion but maintained similar cell subsets, activation markers, and cytotoxicity to those in the standard culture method group. In addition, we successfully manufactured cytokine-induced killer cells for clinical use using the gas-permeable culture method. We also showed the clinical efficacy of allogeneic cytokine-induced killer cells produced by the gas-permeable culture method in a patient with acute myeloid leukemia that relapsed after allogeneic hematopoietic stem cell transplantation. This patient maintained ongoing disease remission for 2 years with minimal side effects after cytokine-induced killer cell infusion. CONCLUSIONS: We successfully developed a simple and effective protocol for the ex vivo expansion of cytokine-induced killer cells using the gas-permeable culture method for clinical application.
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Autologous stem cell transplantation (ASCT) is an important treatment that can offer a cure for patients with lymphoma. However, advanced age is an important factor that determines eligibility and outcomes after ASCT. Over the past decade, attributed to improved supportive care, ASCT for older patients has become more feasible. In this study, we report the single-center outcomes of older patients with lymphoma undergoing ASCT at Mayo Clinic Rochester to highlight its interval improvement over time and to help redefine the implications of ASCT in the chimeric antigen receptor T cell therapy era. This single-center retrospective study evaluated the characteristics and outcomes of older patients with lymphoma who underwent ASCT between 2000 and 2021. We report various relevant transplantation-related outcomes, including progression-free survival, overall survival (OS), relapse incidence, and nonrelapse mortality (NRM) in older patients with various lymphoma histologic subtypes. The main outcome was NRM, defined as the time from ASCT to non-lymphoma-related death, with relapse as a competing event. Of 492 patients age ≥65 years were analyzed. The median age at ASCT was 68.8 years. The most common indication for ASCT was diffuse large B cell lymphoma, accounting for 59.3% of cases. In multivariate analyses, patients undergoing ASCT in 2009 to 2021, an Eastern Cooperative Oncology Group Performance Status of 0, and low Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) (0 to 3) had a significantly lower NRM. Factors associated with OS included age, lactate dehydrogenase level, and HCT-CI. The 1-year NRM in older patients was low at 6.0%, in concordance with previous reports. Age should not be the sole factor determining a patient's ASCT eligibility. With the proper patient selection, ASCT remains a reasonable option for older patients with lymphoma.
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Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Humanos , Idoso , Estudos Retrospectivos , Transplante Autólogo , Recidiva Local de Neoplasia , Linfoma não Hodgkin/terapiaRESUMO
INTRODUCTION: Relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) leads to dismal outcomes. This study aimed to identify high-risk patients and explore the effects of cytomegalovirus (CMV) reactivation in a high CMV-seropositive population. METHODS: The study involved a single-center retrospective cohort in Thailand, analyzing clinical risk factors and CMV-mediated immune responses, correlated with transplant outcomes in AML patients. RESULTS: Eighty-five patients with AML in complete remission (CR) undergoing HLA-matched myeloablative allo-SCT between 2011 and February 2021 were enrolled. The relapse rate was 27.1% with the median time of 7 months after transplantation. The 3-year relapse-free-survival (RFS) and overall-survival (OS) were 72.2% and 80.8%, respectively. The disease status (>CR1) and absence of chronic graft-versus-host disease (cGVHD) were independently significant adverse prognostic factors of RFS and OS. Ninety-two percent of recipient-donor pairs were both CMV seropositive. The CMV reactivation occurred in 54.1% of the patients. The clinically significant CMV infection rate was 49.4%. No CMV syndrome/disease or CMV-related mortality occurred. One-year cumulative incidence of relapse among CMV-reactivation and non-reactivation groups were 14.3% and 25.6%, respectively, without a statistically significant difference. Transplantation-related mortality was 11.1%. CONCLUSIONS: The transplantation beyond CR1 and absence of cGVHD are powerful prognostic factors associated with inferior RFS and OS. In a high CMV prevalence country, there appears to be no impact of CMV reactivation on relapse in AML patients undergoing an allo-SCT.
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CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), inducing sustained remissions in these patients. However, CAR T cells can result in significant toxicities. Preinfusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel, and 24 received tisagenlecleucel. There was no severe (grade ≥3) cytokine release syndrome, and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at the time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted.
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Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Intervalo Livre de Progressão , Indução de Remissão , Antígenos CD19RESUMO
CD19-targeted chimeric antigen receptor (CAR) T-cell becomes a breakthrough therapy providing excellent remission rates and durable disease control for patients with relapsed/refractory (R/R) hematologic malignancies. However, CAR T-cells have several potential side effects including cytokine release syndrome, neurotoxicities, cytopenia, and hypogammaglobulinemia. Infection has been increasingly recognized as a complication of CAR T-cell therapy. Several factors predispose CAR T-cell recipients to infection. Fortunately, although studies show a high incidence of infection post-CAR T-cells, most infections are manageable. In contrast to patients who undergo hematopoietic stem cell transplant, less is known about post-CAR T-cell immune reconstitution. Therefore, evidence regarding antimicrobial prophylaxis and vaccination strategies in these patients is more limited. As CAR T-cell therapy becomes the standard treatment for R/R B lymphoid malignancies, we should expect a larger impact of infections in these patients and the need for increased clinical attention. Studies exploring infection and immune reconstitution after CAR T-cell therapy are clinically relevant and will provide us with a better understanding of the dynamics of immune function after CAR T-cell therapy including insights into appropriate strategies for prophylaxis and treatment of infections in these patients. In this review, we describe infections in recipients of CAR T-cells, and discuss risk factors and potential mitigation strategies.
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Neoplasias Hematológicas , Reconstituição Imune , Receptores de Antígenos Quiméricos , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunoterapia Adotiva/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
INTRODUCTION: Myelodysplastic syndromes (MDS) predominantly present with varying degrees of cytopenia, while myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) exhibit proliferative features. Genetic defects underlying different complete blood count (CBC) alterations remain to be defined. OBJECTIVE: We aimed to evaluate mutations and impacts on abnormal blood counts in MDS and MDS/MPN. METHOD: MDS and MDS/MPN patients were recruited and sequenced by targeted next-generation sequencing. Clinical parameters, especially CBC, were evaluated for the association with genetic abnormalities and clinical outcomes. RESULTS: A total of 168 patients with myeloid neoplasms were recruited (92 cases of low-risk MDS, 57 cases of high-risk MDS and 19 cases of MDS/MPN). Compared to low-risk MDS and MDS/MPN, patients with high-risk MDS were presented with more severe neutropenia with 17.5% showing absolute neutrophil counts (ANC) lower than 0.5 × 109/L. Patients with MDS/MPN more commonly harboured mutations and had a higher number of mutations per case than low-risk MDS (94.7% vs. 56.5%; p < 0.001 and 3 vs. 1; p < 0.001, respectively). Patients with SF3B1 mutations showed lower haemoglobin levels than wild-type (7.9 vs. 8.4â g/dL, p = 0.02), but were associated with normal platelet counts (286 vs. 93 × 109/L; p < 0.001). Patients with U2AF1 mutations were associated with more severe leukopenia than wild-type (3 vs. 4.18 × 109/L; p = 0.02). KRAS mutations were associated with monocytosis (p < 0.001). Multivariate analysis revealed high-risk MDS, MDS/MPN, severe neutropenia (ANC < 0.5 × 109/L), and mutations in ASXL1 and SETBP1 were associated with inferior survival outcomes. CONCLUSION: Certain mutations were related to more severe anaemia, lower white blood cell count or monocytosis in Asian MDS and MDS/MPN patients.
Assuntos
Síndromes Mielodisplásicas , Doenças Mieloproliferativas-Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Neutropenia , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/genéticaRESUMO
Programmed cell death (PD)/PD-ligands (PD-Ls) pathway plays an important role in the regulation of physiologic immune response. Several cancers, including lymphoma exhibit abnormal PD-1/PD-Ls expression, which may contribute to treatment failure, progression, and inferior outcomes. PD-1/PD-Ls expression has predominantly been described in B-cell lymphoma; such data in peripheral T-cell lymphoma (PTCL) is limited. We described PD-1/PD-Ls expression patterns and associations with clinical characteristics and outcomes, in patients with systemic PTCLs. Correlation between PD-1/PD-Ls expression and outcomes was analyzed in patients who received lymphoma-specific therapy. PD-1/PD-Ls expression was observed across all common PTCL histologies at different proportions (PD-1 0%-76.9%, PD-L1 38.5%-62.5%, and PD-L2 62.5%-100%) with PD-1 being highly expressed in angioimmunoblastic T-cell lymphoma. Baseline characteristics were comparable between PD-1/PD-Ls expression status. Of 47 patients who received lymphoma-specific therapy, outcomes were similar across all PD-L1/PD-L2 subgroups. In the Cox proportional hazard analysis, treatment response was the only factor associated with survival outcomes. However, PD-1/PD-Ls expression, either in lymphoma or stroma, was not a predictor for survival outcomes. In conclusion, differential PD-1/PD-Ls expressions were observed among various histological PTCL subtypes. In this study, we were unable to demonstrate an association between PD-1/PD-Ls expression, clinical characteristics, treatment response, and outcomes of PTCL patients.
Assuntos
Antígeno B7-H1 , Linfoma de Células T Periférico , Apoptose , Antígeno B7-H1/metabolismo , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Novel monoclonal antibody (mAb)-based therapies targeting CD19 and CD22 (blinatumomab and inotuzumab) have shown high rates of complete remission (CR) and been used as a bridging treatment to potentially curative allogeneic hematopoietic stem cell transplantation (alloHSCT) in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, limited data exist on the outcome of patients resistant to both mAbs as well as responses to each agent when progressed after the alternate antigen-targeted mAb. Herein, we report outcomes of 29 patients with R/R B-ALL previously treated with both blinatumomab and inotuzumab. Twenty-five patients (86.2%) received blinatumomab as first mAb (mAb1), and CD19-negative/dim relapses were observed in 44% of the patients. Inotuzumab induced CR in 68% of the patients for post-blinatumomab relapse regardless of CD19 expression status. The median time between mAb1 and mAb2 was 99 days. Twelve (63.2%) of 19 patients who achieved remission after mAb2 underwent alloHSCT. The median time from mAb2 to alloHSCT was 37.5 days. Acute graft-versus-host disease and nonrelapse mortality were observed in 58.3% (grade 3 or higher, 25%) and 41.7%, respectively. With a median follow-up of 16.8 months after mAb2, 19 patients (65.5%) relapsed, and 21 patients (72.4%) have died. Overall survival was not different between alloHSCT and non-alloHSCT patients. In conclusion, patients with B-ALL who relapsed after blinatumomab could be successfully rescued by inotuzumab as a bridge to alloHSCT but represent an ultra-high-risk group with poor overall survival. Further studies, including novel consolidation and treatment sequence, may improve outcomes of these patients.