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Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.
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Transfusion reactions induced by platelet transfusions may be reduced and alleviated by leukocyte reduction of platelets. Although leukoreduction of apheresis platelets can be performed either pre-storage or post-storage, seldom studies directly compare the incidence of transfusion reaction in these two different blood products. We conducted a retrospective study to compare the transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets. We reviewed the general characteristics and the transfusion reactions, symptoms, and categories for inpatients who received pre-storage or post-storage leukoreduced apheresis platelets. Propensity-score matching was performed to adjust for baseline differences between groups. A total of 40,837 leukoreduction apheresis platelet orders were reviewed. 116 (0.53%) transfusion reactions were reported in 21,884 transfusions with pre-storage leukoreduction, and 174 (0.91%) reactions were reported in 18,953 transfusions with post-storage leukoreduction. Before propensity-score matching, the odds ratio for transfusion reactions in the pre-storage group relative to the post-storage group was 0.57 (95% confidence interval [CI] 0.45-0.72, P < 0.01); the odds ratio after matching was 0.63 (95% CI 0.49-0.80, P < 0.01). A two-proportion z-test revealed pre-storage leukoreduction significantly decreases the symptoms of chills, fever, itching, urticaria, dyspnea, and hypertension as compared with those in post-storage leukoreduction. Pre-storage leukoreduced apheresis platelet significantly decreased febrile non-hemolytic transfusion reaction as compared with post-storage groups. This study suggests pre-storage leukoreduction apheresis platelet significantly decreases the transfusion reaction as compared with those in post-storage leukoreduction.
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Remoção de Componentes Sanguíneos , Reação Transfusional , Humanos , Estudos Retrospectivos , Pontuação de Propensão , Plaquetas , Remoção de Componentes Sanguíneos/efeitos adversos , Transfusão de Plaquetas/efeitos adversosRESUMO
Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.
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Progressão da Doença , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Transplante Autólogo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Estudos Retrospectivos , Taxa de Sobrevida , AutoenxertosRESUMO
BACKGROUND/PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. METHODS: Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. RESULTS: Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III-IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III-IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. CONCLUSION: This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Idoso , Estudos de Coortes , Comorbidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Condicionamento Pré-TransplanteRESUMO
BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AACâAAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid substitutions at T315I, F317L, and T315A accounted for the majority of missense mutations and the loss of major molecular response. Mutation analysis is essential for patients receiving TKI therapy who exhibit an unfavourable response. The present study provided a landscape of BCR-ABL mutations in the era of second-generation TKIs.
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Biomarcadores Tumorais/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/uso terapêutico , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
With increasing usage of computed tomography (CT) for lymphoma patients receiving curative-intent treatment, development of secondary primary malignancy (SPM) related to radiation from CT scans becomes an emerging issue in these long-term survivors. We conducted a nationwide population-based study analyzing non-Hodgkin lymphoma (NHL) patients receiving curative-intent treatment between January 1997 and December 2010. Patients were divided into two populations by the medium number of CT performed. The cumulative incidence of SPM in these two groups was compared using the Kaplan-Meier method. Propensity score matching was applied to eliminate potential confounders. Group stratification and multivariate analyses calculated by Cox proportional hazard models using competing risk analyses adjusted for mortality were performed to identify independent predictors for SPM. Patients receiving >8 CT scans had a significantly greater risk for developing SPM (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.61-3.13; p < 0.001) than those with ≤8 scans and this difference remained significant even after correction with propensity score matching. Among the 180 SPM identified, those receiving more CT scans had significantly higher SPM incidence in cancers of the breast (HR 11.22), stomach (HR 5.22) and liver and biliary tract (HR 2.18) in comparison to those with less exposure. The risk of SPM was estimated to increase 3% per one more CT scan performed. Our study demonstrated that after curative-intent treatment, patients with NHL receiving more frequent surveillance CT scans would have an increased risk of SPM.
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Linfoma não Hodgkin/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Tomografia Computadorizada por Raios X , Adulto , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Razão de Chances , Vigilância da População , Risco , Taiwan/epidemiologia , Fatores de Tempo , Tomografia Computadorizada por Raios X/efeitos adversosRESUMO
The relationship between chronic myeloid leukemia (CML) and tuberculosis (TB) has not been determined. We conducted a national survey including 1,082 CML patients identified from the Taiwan National Health Insurance database covering a period between 1998 and 2011; the matched non-exposed cohort included 10,820 subjects without CML that were matched for age, sex and comorbidities. The impact of TB was measured by the overall mortality, and the risk factors were identified by a multivariate Cox proportional hazards model. We found the risk of TB was higher in the CML cohort, with an adjusted hazard ratio (aHR) of 3.76 (p = 0.001) for both pulmonary (aHR 3.23, p < 0.001) and extrapulmonary (aHR 9.77, p = 0.001) TB. Specific risk factors were: aged ≥ 60 (aHR 3.24, p = 0.022), being male (aHR 13.49, p = 0.012), receiving stem cell transplantation (aHR 10.50, p = 0.001) and interferon-α therapy (aHR 3.34, p = 0.011). CML patients with TB had a higher mortality rate than those without (aHR 2.04, p = 0.043). We conclude that the incidence of TB is significantly higher in CML patients of male sex, aged ≥ 60, having received either stem cell transplantation or interferon-α treatment. Careful screening strategies for TB should be considered for CML patients with high risk of the infection.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Tuberculose/epidemiologia , Tuberculose/etiologia , Adulto , Comorbidade , Feminino , Humanos , Incidência , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Fatores de Risco , Taiwan , Tuberculose/mortalidadeRESUMO
Pericardial effusion (PE) is a rare but potentially life-threatening complication for allogeneic haematopoietic stem cell transplantation (HSCT) recipients. The risk factors, aetiology, incidence and therapy are largely unclear. To investigate this issue, we reviewed 391 adult patients undergoing allogeneic HSCT between January 2003 and December 2013. Twelve out of 391 patients (3·1%) developed PE of moderate to large amounts, including 9 out of 12 patients (75%) identified as late-onset PE. Two out of the nine patients with late-onset PE experienced recurrent effusion. The median age at HSCT was 44·5 years (range: 22-63 years) among the 12 patients with PE and 47 years in the late-onset patients. Multivariate analysis revealed that multiple transplant procedures was a significant risk factor for PE (P = 0·036) and a trend as risk factor in patients aged>50 years (P = 0·066). For late-onset PE, pre-transplant age>50 years (P = 0·032) and extensive chronic graft-versus-host disease (cGVHD) (P = 0·006) remained statistically significant on multivariate analysis. Currently, there are no published data exploring the risk factors for post-transplant PE in adult patients of allogeneic HSCT. Our study determined the risk factors and incidence for the post-transplant PE, especially in the late-onset group.
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Derrame Pericárdico/epidemiologia , Derrame Pericárdico/etiologia , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Derrame Pericárdico/mortalidade , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Cancer patients are at risk of thromboembolism. However, studies investigating the relationship between ovarian cancer and ischemic stroke are lacking. The objectives of this study were to assess the association between ovarian cancer and ischemic stroke, and to determine the predictive risk factors. METHODS: Ovarian cancer patients aged 20 years and older without antecedent cerebrovascular events and who were followed up for more than 1 year between 1 January 2003 and 31 December 2011 were recruited from the Taiwan National Health Insurance database. Hazard ratios (HRs) of stroke risk for ovarian cancer patients compared with an age- and comorbidity-matched cohort were calculated by Cox proportional regression analysis. The difference in cumulative ischemic stroke incidence between ovarian cancer patients and the matched cohort was analyzed with the Kaplan-Meier method and tested with the log-rank test. RESULTS: Each cohort (ovarian cancer and matched cohort) consisted of 8,810 individuals, with a median age of 49 years. After a median follow-up of 2.68 and 3.85 years, respectively, the ischemic stroke incidence was 1.38-fold higher in the ovarian cancer cohort than in the comparison cohort (9.4 versus 6.8 per 1,000 person-years), with an age- and comorbidity-adjusted HR of 1.49 (P <0.001). The ischemic stroke risk imposed by ovarian cancer was more prominent in patients under 50 years old (HR 2.28; P <0.001) compared with patients 50 years and older (HR 1.33; P = 0.005). Significant risk factors predicting stroke development were age 50 years and older (HR 2.21; P <0.001), hypertension (HR 1.84; P <0.001), diabetes mellitus (HR 1.71; P <0.001), and treatment with chemotherapy (HR 1.45; P = 0.017), especially platinum-based regimens. CONCLUSIONS: Ovarian cancer patients were at an increased risk of developing ischemic stroke. Age, hypertension, diabetes, and chemotherapy treatment were independent risk factors.
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Neoplasias Ovarianas/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Isquemia Encefálica/etiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Incidência , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Neoplasias Ovarianas/tratamento farmacológico , Análise de Regressão , Projetos de Pesquisa , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Taiwan/epidemiologiaRESUMO
PURPOSE: A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II. RESULTS: The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05-0.48; P = 0.001). CONCLUSIONS: Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694.
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Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Receptores de Antígenos Quiméricos , Humanos , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Linfócitos T/imunologia , Linfoma de Células B/tratamento farmacológico , Antígenos CD19/imunologiaRESUMO
BACKGROUND: Adoptive transfer of CD19-specific chimeric antigen receptor (CD19CAR) T cells can induce dramatic disease regression in patients with B cell malignancies. CD19CAR T cell therapy may be limited by insufficient engraftment and persistence, resulting in tumor relapse. We previously demonstrated a proof of principle that cytomegalovirus (CMV)-specific T cells can be isolated and enriched prior to CD19CAR transduction to produce CMV-CD19CAR T cells, and that these CMV-CD19CAR T cells can be expanded in vivo through CMV vaccination, resulting in better tumor control in a murine model. Here we developed a clinical platform for generating CMV-CD19CAR T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) collected from CMV-seropositive healthy donors were stimulated with a good manufacturing practices-grade PepTivator overlapping CMVpp65 peptide pool and enriched for CMV-responsive interferon γ (IFNγ)+T cells using IFNγ Catchmatrix, within the CliniMACS Prodigy Cytokine Capture System (Miltenyi Biotec). Resulting CMV-specific T cells were transduced with a lentiviral vector encoding a second generation CD19R:CD28:ζ/EGFRt CAR and expanded with interleukin 2 (IL-2) and IL-15 for 15 days before characterization. RESULTS: CMV-specific T cells were enriched from 0.8%±0.5 of input PBMC to 76.3%±11.6 in nine full-scale qualification runs (absolute yield of 4.2±3.3×106 IFNγ+T cells from an input of 1×109 PBMCs). Average CD19CAR transduction efficiency of CMV-specific T cells was 27.0%±14.2 in the final products, which underwent rapid expansion, resulting in a total cell dose of 6.2±0.9 × 106 CD19CAR-tranduced T cells with CMV specificity (ie, functionally bispecific). CMV-CD19CAR T cells were polyclonal, expressed memory markers but had low expression of exhaustion markers, responded to both CD19 and CMVpp65 stimulation with rapid proliferation and exhibited antigen-specific effector functions against both CD19-expressing tumors and CMVpp65 antigen. The final products passed release criteria for clinical use. CONCLUSIONS: We demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application. We plan to initiate a clinical trial at City of Hope using CMV-CD19CAR T cells for patients with intermediate/high-grade B cell non-Hodgkin's lymphoma immediately after autologous hematopoietic cell transplantation followed by vaccination with a novel CMV vaccine based on Modified Vaccinia Ankara (Triplex) 28 days and 56 days post-T cell infusion.
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Imunidade Adaptativa/imunologia , Citomegalovirus/imunologia , Leucócitos Mononucleares/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
Thalassemia and iron deficiency are the most common etiologies for microcytic anemia and there are indices discriminating both from common laboratory simple automatic counters. In this study a new classifier for discriminating thalassemia and non-thalassemia microcytic anemia was generated via combination of exciting indices with machine-learning techniques. A total of 350 Taiwanese adult patients whose anemia diagnosis, complete blood cell counts, and hemoglobin gene profiles were retrospectively reviewed. Thirteen prior established indices were applied to current cohort and the sensitivity, specificity, positive and negative predictive values were calculated. A support vector machine (SVM) with Monte-Carlo cross-validation procedure was adopted to generate the classifier. The performance of our classifier was compared with original indices by calculating the average classification error rate and area under the curve (AUC) for the sampled datasets. The performance of this SVM model showed average AUC of 0.76 and average error rate of 0.26, which surpassed all other indices. In conclusion, we developed a convenient tool for primary-care physicians when deferential diagnosis contains thalassemia for the Taiwanese adult population. This approach needs to be validated in other studies or bigger database.
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BACKGROUND: Extranodal natural killer/T cell lymphoma, nasal type, is one of the more common subtypes of mature T cell lymphoma, especially in the Far East Asian population. This aggressive histologic subtype of peripheral T cell lymphomas is frequently susceptible to exposure of Epstein-Barr virus infection. The optimal treatment is not well elucidated. For stage IV disseminated extranodal natural killer/T cell lymphoma, induction chemotherapy with consolidative autologus or allogeneic hematopoietic stem cell transplantation is recommended as the major first-line treatment. However, there is controversy over which type of chemotherapy is most appropriate and effective as a bridge to autologus or allogeneic hematopoietic stem cell transplantation in patients with newly diagnosed disseminated advanced-stage or relapsed extranodal natural killer/T cell lymphoma because of cancer chemoresistance or associated complications. Pralatrexate is the first US Food and Drug Administration-approved novel agent for the treatment of refractory/recurrent peripheral T cell lymphomas. In our case, pralatrexate was used as a successful bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage disseminated extranodal natural killer/T cell lymphoma refractory to first-line chemotherapy. CASE PRESENTATION: We presented a case report of a 29-year-old Asian man diagnosed as having stage IV disseminated extranodal natural killer/T cell lymphoma, nasal type, with skin and bone marrow involvement, whose disease was primary refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy, but obviously responded to treatment with two cycles of single-agent pralatrexate treatment. Monitoring Epstein-Barr virus viremia revealed dramatic downregulation. In addition to complete remission of the involvement of bone marrow and nasal cavity, skin involvement also obtained partial remission. The extranodal natural killer/T cell lymphoma successfully achieved complete remission after a bridge to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: This is the first study to present pralatrexate as a successful bridge to allogeneic hematopoietic stem cell transplantation in a 29-year-old Asian male patient with advanced-stage extranodal natural killer/T cell lymphoma refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy. This case provides a novel treatment opinion for extranodal natural killer/T cell lymphoma, especially for the Far East Asian population.
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Aminopterina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Linfoma Extranodal de Células T-NK/terapia , Condicionamento Pré-Transplante , Adulto , Aloenxertos/efeitos dos fármacos , Aminopterina/uso terapêutico , Humanos , Masculino , Estadiamento de Neoplasias , Indução de Remissão , Taiwan/epidemiologiaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are hematological diseases predominantly occurring in older patients. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for refractory AML or high-risk MDS, old age is often a hurdle to the procedure. We conducted a retrospective study to analyze the prognostic factors predicting outcomes of older patients undergoing allo-HSCT for acute leukemia and MDS. METHODS: We collected data from patients diagnosed with acute leukemia or MDS, who underwent allo-HSCT at >50 years of age and reviewed clinical characteristics, including age, sex, underlying disease, European Group for Blood and Bone Marrow Transplantation (EBMT) risk score, and presence of acute graft-versus-host disease (aGVHD) or chronic GVHD (cGVHD). The Cox proportional hazard model was adopted to explore the independent prognostic factors for overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM). RESULTS: A total of 85 older patients were included, with the median age at allo-HSCT being 55 years. The significant prognostic factors for worse OS or PFS were an EBMT risk score > 3 and grade III-IV aGVHD, while patients with moderate to severe cGVHD would have better OS or PFS. Interestingly, it is not cGVHD but grade III-IV aGVHD that significantly correlated with NRM. CONCLUSION: This cohort study suggests that an EBMT risk score >3 and grade III-IV aGVHD predict poor outcomes, and careful management of GVHD may allow better survival for older patients undergoing allo-HSCT.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Transplante HomólogoRESUMO
BACKGROUND: Mycobacterial infections are important and potentially life-threatening complications after organ transplantations. Notably, for the recipients of allogeneic hematopoietic stem cell transplantation (HSCT), there are a few supporting results to explore post-transplant mycobacterial infections. Taiwan is a high endemic area of the infection. We aim to investigate the incidence, risk factors, and survival of post-transplant mycobacterial infections, including mycobacterium tuberculosis (MTB) and non-tuberculous mycobacterium (NTM). METHODS: We included 422 adult patients undergoing allogeneic HSCT at an Asian tertiary medical center between January 2003 and December 2014. A total 26 subjects developed post-transplant mycobacterial infections. Risk factors, clinical features, and survival for post-transplant mycobacterial infections were collected and analyzed. RESULTS: Post-transplant mycobacterial infections occurred in 26 (6.2%) of 422 HSCT patients. Two-year cumulative incidences in MTB and NTM were 1.4% and 5.4%. In the multivariate analysis, being age >45 years (adjusted HR 2.21, 95% CI 1.01-4.83) and extensive chronic graft-versus-host disease (cGVHD) (adjusted HR 4.95, 95% CI 2.14-11.46) were identified as independent risk factors of infections. There was a trend as a risk factors in relapsed patients (P = 0.088). For patients with cGVHD, there was a significant difference of post-transplant survival between mycobacterial infections and none (P = 0.036). Pneumonia contributed most to mortality (n = 11, 42.3%). CONCLUSION: Mycobacterial infections are worth to note in a high endemic area. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection and treatment of infections.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Mycobacterium/complicações , Infecções por Mycobacterium/epidemiologia , Adulto , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mycobacterium , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Cerebrovascular complications after hematopoietic stem cell transplantation (HSCT) cause serious morbidity and often contribute to mortality. The incidence, risk factors, and outcome of cerebrovascular disease (CVD) after allogeneic HSCT remain poorly defined. We retrospectively evaluated 459 adult patients who underwent allogeneic HSCT at a tertiary medical center between January 2003 and December 2015. A total of 20 patients (4.4%) developed post-transplant CVD. All cerebrovascular accidents occurred in the first two years post-transplant. The two-year incidences of post-transplant CVD, intracranial hemorrhage, and cerebrovascular infarction were 6.1%, 3.2%, and 3.2%, respectively. The incidence rate of CVD within two years after HSCT was 34.7 (95% CI 22.3 to - 53.7) per 1000 person-years, which was about tenfold higher than the general Taiwanese population. The only significant risk factor associated with post-transplant CVD is prior exposure to three or more courses of high-dose cytarabine. Post-transplant CVD is associated with dismal outcome and early mortality. The median overall survival of patients with post-transplant CVD was markedly reduced compared with those without CVD (8.0 vs. 60.6 months). Most patients with post-transplant CVD died within two months after the CVD events. Our study demonstrates that CVD remains a devastating complication after allogeneic HSCT in the modern era.
Assuntos
Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/mortalidade , Transplante de Células-Tronco Hematopoéticas , Adulto , Aloenxertos , Feminino , Seguimentos , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND/PURPOSE: Patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to high risk of developing invasive fungal infections, and the invasive mold infections (IMIs) are becoming more and more common after transplantation. Here, we conducted a retrospective study to analyze demographics, microbiology, and risk factors for IMIs development in adult acute leukemia patients undergoing allo-HSCT. METHODS: We reviewed 245 adult acute leukemia patients undergoing allo-HSCT from January 2003 to December 2014. Clinical characteristics including age, sex, conditioning regimens, European Group for Blood and Bone marrow Transplantation (EBMT) risk score, and presence of acute graft-versus-host disease (aGVHD) or chronic GVHD (cGVHD) were collected and analyzed. Cox proportional hazard model was adopted to explore the independent risk factors for IMIs developments. RESULTS: Seventeen of 245 patients developed IMIs during the study period. The cumulative incidence of IMIs in this cohort was 8.7% and 16.8% at 6 and 12 months, respectively, with Aspergillus species being the most common pathogen. The significant risk factors predicting IMIs were unrelated donor transplantation (hazard ratio [HR] 5.11), smoking (HR 3.55), EBMT risk score > 2 (HR 4.22), and moderate to severe cGVHD (HR 3.76). CONCLUSIONS: We identified four risk factors-unrelated donor transplantation, smoking, EBMT risk score >2 and moderate to severe cGVHD to predict IMIs among acute leukemia patients undergoing allo-HSCT. This cohort study suggests early identification of high-risk patients and to provide better prevention strategies would reduce the incidence and severity of IMIs in these patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Fúngicas Invasivas/microbiologia , Leucemia Mieloide Aguda/complicações , Doença Aguda , Adulto , Aspergilose/etiologia , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Infecções Fúngicas Invasivas/etiologia , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de RiscoRESUMO
Post-transplant thoracic air-leak syndrome (ALS) is rare but potentially life-threatening in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT). Nevertheless, papers on thoracic ALS are limited, and this complication remains largely unknown. We reviewed 423 adult patients undergoing allogeneic HSCT from 2003 to 2014. Risk factors, clinical features and survival for thoracic ALS were collected and analysed. Thirteen out of 423 patients (3.1%) developed post-transplant thoracic ALS, including two ALS patients in the early phase. The median age at HSCT was 33 years among 13 patients with thoracic ALS. Male patients were predominant (69%). The median onset time was 253 days (range: 40-2680) after HSCT. Multivariate analysis revealed that grade III-IV acute graft-versus-host disease (GVHD) (p = 0.017), extensive chronic GVHD (cGVHD) (p = 0.019) and prior history of pulmonary invasive fungal infection (p = 0.007) were significant risk factors for thoracic ALS. In patients with cGVHD, those with thoracic ALS had a significantly worse survival than those without thoracic ALS (p = 0.04). Currently, published data analysing and exploring post-transplant thoracic ALS are limited. Our study employed a large patient cohort and determined the risk factors and clinical features for post-transplant thoracic ALS.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Fúngicas Invasivas/microbiologia , Transplante Homólogo/efeitos adversos , Adulto , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/microbiologia , Humanos , Infecções Fúngicas Invasivas/etiologia , Infecções Fúngicas Invasivas/patologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Torácicas/etiologia , Neoplasias Torácicas/microbiologia , Neoplasias Torácicas/patologiaRESUMO
Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare form of cytotoxic T-cell lymphoma. It is believed that SPTL in patients without hemophagocytic syndrome (HPS) follows an indolent course; in contrast, SPTL in patients with HPS has been associated with unfavorable survival. To provide more clinical data on SPTL in Asian populations and to identify optimal therapeutic strategies for SPTL, we assessed the clinicopathological features and long-term follow-up data of 10 Taiwanese SPTL patients diagnosed at a single center. Our study demonstrates a group of patients with high incidence of HPS (50%), rather aggressive courses, and early progression. A total of eight patients underwent hematopoietic stem cell transplant (HSCT), including one autologous HSCT and seven allogeneic HSCT. Seven of eight patients receiving HSCT achieved durable remission and maintained in remission for over 30 months (range 30-132 months). There was no difference in 3-year survival of patients with HPS (80%) compared with patients without HPS (80%). Of long-term survivors in the HPS group, three of four received HSCT (autologous HSCT, n = 1; allogeneic HSCT, n = 2). Our study indicated that HSCT is a curative option for eligible SPTL patients with HPS.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células T/terapia , Paniculite/terapia , Adulto , Povo Asiático , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Linfoma de Células T/complicações , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Paniculite/complicações , Paniculite/mortalidade , Indução de Remissão , Análise de SobrevidaRESUMO
BACKGROUND: Currently, the role of dacarbazine (DTIC) based chemotherapy in neuroendocrine tumors (NETs) in Asia is unclear. Here, we report the outcomes of dacarbazine (DTIC)-based chemotherapy in Taiwan population. METHODS: DTIC alone (250 mg/m2/day), or 5-fluorouracil (5-FU, 500 mg/m2/day) and DTIC (200 mg/m2/day) with or without epirubicin (200 mg/m2/day), for 3 days, every 3-4 weeks. Subgroups were analyzed by grading, and by Ki-67 index. RESULTS: 48 patients were reviewed in this study, including 3 had grade 1 tumors, 23 had grade 2, while 22 were grade 3. In grade 3 NEC patients, the tumor Ki-67 index of 21-55% were noted in 8 patients, and >55% in 14 patients. Progression-free survival (PFS) was 5.1 months, and overall survival (OS) was 31.6 months. The PFS (in months) were 12.5 and 1.8 for patients with NETs and neuroendocrine carcinomas (NECs), respectively (p < 0.001). The OS were not reached and 5.9 months for patients with NETs and NECs, respectively (p = 0.001). Patients with NECs were divided into two groups, according to their Ki-67 index. In patients with a tumor Ki-67 index of 21-55%, PFS was 4.1 months, and OS was not reached; in those with a tumor Ki-67 index of >55%, they were 1.5 and 1.8 months, respectively (p < 0.001 and p = 0.013). CONCLUSION: NETs, and grade 3 NECs, with Ki-67 indices of 20-55% had good responses to DTIC-based chemotherapy, with acceptable side effects. Ki-67 index could predict prognosis for grade 3 NEC patients, and guide further chemotherapy choices.