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1.
Cytometry B Clin Cytom ; 102(2): 123-133, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34964255

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) with KMT2A (MLL) rearrangement is known for monocytic or myelomonocytic differentiation, but the full immunophenotypic spectrum and dynamic changes of the immunophenotype in this genetically defined disease have not been systematically studied. METHODS: We reviewed the immunophenotype, karyotype, and mutations at the time of initial diagnosis and relapse of adults with AML with KMT2A rearrangement in our institution between 2007 and 2020. RESULTS: We identified 102 patients: 44 men and 58 women with a median age of 52 years (range, 18-87). Forty-three patients were considered to be therapy-related. Twenty-four out of 64 patients relapsed from complete remission after induction therapy, 34 had persistent/progressive disease, and 58 patients died with a median overall survival of 17 months. We detected five immunophenotypes: immature monocytic (38%); myelomonocytic (22%); myeloblastic (22%); mature monocytic (10%); and acute promyelocytic (APL)-like (8%). By chromosomal breakpoints, we presumed 11 different partners; t(9;11) (p22;q23)/MLLT3-KMT2A was the most common rearrangement (n = 56, 55%), followed by t(6;11) (q27;q23)/AFDN-KMT2A (n = 13,13%). Patients with t(6;11) (q27;q23)/AFDN-KMT2A preferentially showed a myeloblastic phenotype (p = 0.026). Mutations were detected in 39/64 (61%) cases, and RAS pathway (NRAS/KRAS/PTPN11) was involved in 26/64 (41%) cases. None of the APL-like cases had mutations detected. At the time of disease relapse, 10/24 (42%) showed major immunophenotypic change, and 7/10 cases gained additional cytogenetic and/or molecular alterations. CONCLUSION: The immunophenotype of AML with KMT2A rearrangement is more diverse than previously recognized, with a substantial subset showing no evidence of monocytic differentiation. Major immunophenotype change is common at the time of relapse.


Assuntos
Rearranjo Gênico , Leucemia Mieloide Aguda , Aberrações Cromossômicas , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Recidiva , Translocação Genética
2.
Br J Haematol ; 195(3): 378-387, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34340254

RESUMO

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos/efeitos adversos , Antimetabólitos/farmacologia , Artralgia/induzido quimicamente , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Constipação Intestinal/induzido quimicamente , Metilação de DNA/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Risco
3.
Cancer ; 127(20): 3761-3771, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34171128

RESUMO

BACKGROUND: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML. METHODS: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m2 on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles. RESULTS: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy. CONCLUSIONS: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML. LAY SUMMARY: This report describes the results of a phase 1b/2 study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Azacitidina/efeitos adversos , Antígeno B7-H1 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Adulto Jovem
4.
Blood Cancer Discov ; 2(2): 125-134, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33681815

RESUMO

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
6.
Clin Infect Dis ; 72(10): 1755-1763, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32236406

RESUMO

BACKGROUND: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. METHODS: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. RESULTS: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. CONCLUSIONS: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. CLINICAL TRIALS REGISTRATION: NCT03019939.


Assuntos
Leucemia Mieloide Aguda , Micoses , Síndromes Mielodisplásicas , Adulto , Idoso , Antifúngicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Nitrilas , Estudos Prospectivos , Piridinas , Triazóis/uso terapêutico
8.
Am J Hematol ; 96(3): 282-291, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264443

RESUMO

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m2 /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Terapia Combinada , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/cirurgia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pontuação de Propensão , Recidiva , Indução de Remissão , Estudos Retrospectivos , Risco , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
9.
J Hematol Oncol ; 13(1): 132, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032648

RESUMO

BACKGROUND: Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45-55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. METHODS: We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. RESULTS: In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. CONCLUSION: CRc rates drop progressively with sequential exposure to FLT3i's in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
10.
Lancet Haematol ; 7(10): e724-e736, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32896301

RESUMO

BACKGROUND: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups. METHODS: This single centre, phase 2 trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). The study enrolled older patients (aged >60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML (progressed after myelodysplastic syndrome or chronic myelomonocytic leukaemia); and relapsed or refractory AML. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, white blood cell count less than 10 × 109 per L, and adequate end-organ function. Patients with favourable-risk cytogenetics (eg, t[15;17] or core-binding factor AML) or who had received previous BCL2-inhibitor therapy were excluded. Patients received decitabine 20 mg/m2 intravenously for 10 days with oral venetoclax 400 mg daily for induction, followed by decitabine for 5 days with daily venetoclax for consolidation. The primary endpoint was overall response rate. The secondary endpoints analysed within this report include safety, overall survival, and duration of response, in keeping with recommendations of European LeukemiaNet 2017 guidelines. All patients who received at least one dose of treatment were eligible for safety and response assessments. The trial was registered on ClinicalTrials.gov (NCT03404193) and continues to accrue patients. FINDINGS: Between Jan 19, 2018, and Dec 16, 2019, we enrolled 168 patients; 70 (42%) had newly diagnosed AML, 15 (9%) had untreated secondary AML, 28 (17%) had treated secondary AML, and 55 (33%) had relapsed or refractory AML. The median age was 71 years (IQR 65-76) and 30% of patients had ECOG performance status of 2 or higher. The median follow-up for all patients was 16 months (95% CI 12-18; actual follow-up 6·5 months; IQR 3·4-12·4). The overall response rate was 74% (125 of 168 patients; 95% CI 67-80) and in disease subgroups were: 89% in newly diagnosed AML (62 of 70 patients; 79-94), 80% in untreated secondary AML (12 of 15 patients; 55-93), 61% in treated secondary AML (17 of 28 patients; 42-76), and 62% in relapsed or refractory AML (34 of 55 patients; 49-74). The most common treatment-emergent adverse events included infections with grades 3 or 4 neutropenia (n=79, 47%) and febrile neutropenia (n=49, 29%). 139 (83%) of 168 patients had serious adverse events, most frequently neutropenic fever (n=63, 38%), followed by pneumonia (n=17, 10%) and sepsis (n=16, 10%). The 30-day mortality for all patients was 3·6% (n=6, 95% CI 1·7-7·8). The median overall survival was 18·1 months (95% CI 10·0-not reached) in newly diagnosed AML, 7·8 months (2·9-10·7) in untreated secondary AML, 6·0 months (3·4-13·7) in treated secondary AML, and 7·8 months (5·4-13·3) relapsed or refractory AML. The median duration of response was not reached (95% CI 9·0-not reached) in newly diagnosed AML, 5·1 months (95% CI 0·9-not reached) in untreated secondary AML, not reached (95% CI 2·5-not reached) in previously treated secondary AML, and 16·8 months (95% CI 6·6-not reached) in relapsed or refractory AML. INTERPRETATION: Venetoclax with 10-day decitabine has a manageable safety profile and showed high activity in newly diagnosed AML and molecularly defined subsets of relapsed or refractory AML. Future larger and randomised studies are needed to clarify activity in high-risk subsets. FUNDING: US National Institutes of Health and National Cancer Institute.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
12.
Ann Hematol ; 98(7): 1611-1616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093708

RESUMO

Recent evidence suggests that renal dysfunction may be a direct consequence of primary myelofibrosis (PMF). We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib, and compared them to 105 patients, receiving frontline treatment with a non-ruxolitinib-based therapy, matched by age, sex, DIPSS plus, and estimated glomerular filtration rate (eGFR). Use of ruxolitinib associated with a significantly higher rate of renal improvement (RI) > 10% (73% vs 50%, p = 0.01) confirmed on multivariate analysis (MVA) [odds ratio 3, 95% confidence interval (CI) 1.6-5.5, p < 0.001]. After a median follow-up of 41 months (range, 1-159 months), median failure-free survival (FFS) was 14 months (range, 1-117 months). Achievement of a RI > 10% maintained its independent association with prolonged FFS on MVA (hazard ratio 1.4, 95% CI 1.1-2, p = 0.02). Ruxolitinib can significantly improve renal function in patients with PMF, significantly impacting failure-free survival.


Assuntos
Bases de Dados Factuais , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim , Mielofibrose Primária , Pirazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Mielofibrose Primária/mortalidade , Mielofibrose Primária/fisiopatologia , Pirimidinas , Estudos Retrospectivos , Taxa de Sobrevida
14.
Int J Hematol ; 109(5): 545-552, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830579

RESUMO

Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) have near-normal life expectancies. With this comes the possibility of developing second cancers; we aimed to evaluate the incidence of second malignancies in patients with CML using Surveillance, Epidemiology, and End Results Program data. We identified 13,276 patients with CML newly diagnosed in 2001-2014. Patients who had prior history of cancer, a concurrent diagnosis of other malignancies in the same diagnostic year, or a second leukemia after CML diagnosis were excluded. Second malignancies were observed in 597 patients (4%) with a median follow-up of 69 months. The 5- and 10-year cumulative incidences of death for all patients were 30.5% and 41.8%. The 5- and 10-year cumulative incidences of second malignancies were 4.4% and 7.2%, respectively. The overall standardized incidence ratio (SIR) was 1.204. Increased SIRs compared to the general population were observed for the male genital system, 1.593; digestive system, 1.291; skin, 1.588; and urinary system, 1.366. Overall excess absolute risk was 1.714 per 1000 person-years at risk. Our results suggest that relative incidence of overall second malignancies in CML is slightly higher than that of the general population, with minimal increase in the excess absolute risk.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Segunda Neoplasia Primária , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Estudos Retrospectivos , Fatores de Risco
15.
Cancer Discov ; 9(3): 370-383, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30409776

RESUMO

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Terapia de Salvação , Resultado do Tratamento , Adulto Jovem
16.
Mod Pathol ; 32(1): 48-58, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30181564

RESUMO

Mature B-cell neoplasms and immature or precursor B-cell neoplasms need to be distinguished because these patients usually require different therapeutic approaches. B-cell neoplasms that express TdT without unequivocal other features of immaturity may therefore present a diagnostic challenge. We describe 13 patients with TdT-positive aggressive B-cell lymphoma. The clinicopathologic features of these patients were highly heterogeneous, but for the purpose of this study we grouped these cases as follows: (1) de novo high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) with TdT expression. In this group we included two cases of de novo composite lymphoma in which there were components of diffuse large B-cell lymphoma and TdT-positive blastic B-cell lymphoma; (2) TdT-positive aggressive B-cell lymphoma arising in patients who previously had follicular lymphoma; (3) initial relapse of TdT-negative aggressive B-cell lymphoma in patients who previously had follicular lymphoma, followed by relapses in which the neoplasm acquired TdT expression; and (4) mature B-cell lymphomas that acquired TdT expression at relapse. This group included one case of EBV-positive diffuse large B-cell lymphoma and one case of pleomorphic variant mantle cell lymphoma. All patients in this study had an aggressive clinical course and a dismal outcome despite appropriate therapy. Rather than "squeezing" these cases into current World Health Organization classification categories, we suggest the use of a descriptive term such as high-grade B-cell lymphoma with TdT expression. In these tumors, the cytogenetic findings and poor prognosis of this patient subgroup suggest that these neoplasms need to be distinguished from B-lymphoblastic leukemia/lymphoma. Segregation of these neoplasms also may foster additional research on these neoplasms.


Assuntos
DNA Nucleotidilexotransferase/biossíntese , Linfoma de Células B/classificação , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Cancer ; 124(12): 2534-2540, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29645075

RESUMO

BACKGROUND: The prognosis is poor for patients who have relapsed-refractory acute myelogenous leukemia (AML). Most published reports analyzed results from therapies in first-salvage AML or in studies that were conducted before 2000. Several novel agents and strategies are being tested for potential approval as treatment for patients with relapsed-refractory AML in second salvage. Therefore, it is important to establish the historic results of anti-AML therapies in this setting in the modern era. The objective of the current study was to analyze the results from second salvage therapies in patients with AML since 2000 with regard to response and survival. METHODS: In total, 673 patients who received second salvage therapies for AML since 2000 were analyzed. Their median age was 60 years (range, 18-89 years). Salvage therapy consisted of cytarabine-based regimens in 267 patients, noncytarabine combinations in 37, hypomethylating agent-based regimens in 136, and phase 1 and 2 single agents in 233. RESULTS: Eighty-six of the 673 patients (13%) achieved a complete response (CR) or a CR with low platelet count (CRp). The median duration of CR-CRp was 7.2 months. The median survival was 4.4 months (95% confidence interval, 4.0-4.8 months), and the 1-year survival rate was 16% (95% confidence interval, 14%-19%). Multivariate analysis identified the following as independent adverse factors for achievement of CR-CRp: platelets < 50 × 109 /L (P < .001), complex karyotype with ≥3 chromosomal abnormalities (P = .02), regimens that did not include cytarabine or hypomethylating agents (P = .014), and no prior CR lasting ≥12 months with frontline or salvage 1 therapies (P < .001). The independent adverse factors associated with worse survival were age ≥60 years (P = .01), platelets < 50 × 109 /L (P = .02), peripheral blasts ≥ 20% (P = .03), albumin ≤ 3 g/dL (P = .04), and complex karyotype (P = .003). The authors also applied and validated, in the current population, the 2 multivariate-derived prognostic models for CR and survival developed in their previous study of 594 patients who received treatment for second salvage AML from the previous 2 decades. CONCLUSIONS: This large-scale analysis establishes the modern historic results of second salvage therapy in AML and validates the prognostic models associated with outcome. These data could be used to analyze the differential benefits of current or future investigational strategies under evaluation in this setting and for the purpose of potential approval of new agents in the United States and the world. Cancer 2018;124:2534-40. © 2018 American Cancer Society.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Indução de Remissão/métodos , Terapia de Salvação/métodos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ensaios Clínicos como Assunto , Citarabina/farmacologia , Citarabina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Retratamento/métodos , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Clin Lymphoma Myeloma Leuk ; 18(1): e19-e25, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29107583

RESUMO

PURPOSE: To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse. MATERIAL AND METHODS: We conducted a retrospective analysis of 92 patients with CBF-AML in first relapse who presented to our institution from 1990-2014. Clinical and demographic parameters were included in univariate and multivariate Cox proportional hazards regression model to predict overall survival. RESULTS: Among the 92 relapsed patients, 60 (65%) patients had inv (16) and 32 (35%) had t (8;21). The median survival for patients with inv(16) cytogenetic group was 15.6 months (range 10.32 to 20.88 months) while for the t(8;21) group was 9 months (range 3.68 to 14.32) (P = .004). Univariate Cox model analysis showed that increased age, high white blood cell count, t (8;21) cytogenetic group, and high bone marrow blast percentage were associated with poor overall outcome, while stem cell transplant intervention was associated with better survival. Additional cytogenetic aberrations at relapse were not associated with survival outcomes (P = .4). Multivariate Cox model analysis showed that t(8;21) cytogenetic group has more hazard of death after adjusting, age, marrow blast percentage, blood cell count, and stem cell transplant(hazard ratio 1.802; P = .02). CONCLUSION: Among patients with relapsed CBF-AML, median survival was less than a year and half and the outcome was worse in patients with t (8;21). Despite the relatively better outcomes, dedicated clinical trials are needed to improve the outcome in all patients with relapsed CBF-AML.


Assuntos
Leucemia Mieloide Aguda/terapia , Indução de Remissão/métodos , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
20.
Am J Hematol ; 92(12): 1295-1302, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28850699

RESUMO

Newer treatment modalities are being investigated to improve upon historical outcomes with standard immunosuppressive therapy (IST) in aplastic anemia (AA). We analyzed outcomes of adult patients with AA treated with various combinatorial anti-thymoglobulin-based IST regimens in frontline and relapsed/refractory (R/R) settings. Pretreatment and on-treatment clinical characteristics were analyzed for relationships to response and outcome. Among 126 patients reviewed, 95 were treatment-naïve (TN) and 63, R/R (including 32 from the TN cohort); median ages were 49 and 50 years, respectively. Overall survival (OS) was superior in IST responders (P < .001). Partial response to IST was associated with shorter relapse-free survival (RFS), as compared with complete response (P = .03). By multivariate analysis, baseline platelet and lymphocyte count predicted for IST response at 3 and 6 months, respectively. While additional growth factor interventions led to faster count recovery, there were no statistically significant differences in RFS or OS across the various frontline IST regimens (i.e., with/without G-CSF or eltrombopag). While marrow cellularity did not correlate with peripheral-blood counts at 3 months, cytomorphological assessment revealed dyspoietic changes in all nonresponders with hypercellular-marrow indices. Covert dysplasia, identified through early bone marrow assessment, has implications on future therapy choices after IST failure. Salvage IST response depended upon prior response to ATG: prior responders (46%) vs. primary refractory (0%) (P < .01). In the R/R setting, there was no survival difference between IST and allogeneic stem cell transplant groups, with a trend toward superior OS in the former. Transplant benefits in the R/R setting may be underrealized due to transplant-related mortality.


Assuntos
Anemia Aplástica/tratamento farmacológico , Imunossupressores/uso terapêutico , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/mortalidade , Soro Antilinfocitário/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Testes Hematológicos , Humanos , Imunossupressores/farmacologia , Imunossupressores/normas , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Taxa de Sobrevida , Resultado do Tratamento
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