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1.
Blood ; 136(13): 1499-1506, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32603426

RESUMO

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.


Assuntos
Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Sirolimo/uso terapêutico , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos
2.
Blood ; 133(26): 2765-2775, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-30862645

RESUMO

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
3.
Haematologica ; 106(6): 1599-1607, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32499241

RESUMO

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Condicionamento Pré-Transplante , Doadores não Relacionados
4.
Br J Haematol ; 188(3): 404-412, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468521

RESUMO

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.


Assuntos
Benzimidazóis/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
5.
Blood ; 131(13): 1415-1424, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29348128

RESUMO

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.


Assuntos
Azacitidina/administração & dosagem , Ciclopentanos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Pirimidinas/administração & dosagem , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Ciclopentanos/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pirimidinas/efeitos adversos , Fatores de Risco , Enzimas de Conjugação de Ubiquitina/metabolismo
6.
Am J Hematol ; 94(12): 1325-1334, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31490009

RESUMO

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Terapia de Alvo Molecular , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Esquema de Medicação , Toxidermias/etiologia , Resistencia a Medicamentos Antineoplásicos , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/enzimologia , Linfoma não Hodgkin/enzimologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Intervalo Livre de Progressão , Purinas/administração & dosagem , Purinas/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Terapia de Salvação , Trombocitopenia/induzido quimicamente
7.
Blood ; 124(2): 287-95, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24797298

RESUMO

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/mortalidade , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Comorbidade , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Adulto Jovem
8.
Cancer ; 121(20): 3709-16, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26207349

RESUMO

BACKGROUND: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL). METHODS: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%). RESULTS: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03). CONCLUSIONS: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Tratamento Farmacológico/métodos , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Irradiação Corporal Total/métodos
9.
Br J Haematol ; 170(4): 574-83, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25945807

RESUMO

The haematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed in a single centre as a weighted scoring system to predict risks of non-relapse mortality (NRM) following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT-CI in multi-centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen-matched grafts from five different US institutions were analysed. Among all patients, HCT-CI scores of 0 vs. 1-2 vs. ≥3 were associated with 2-year NRM rates of 14%, 23% and 39% (P < 0·0001), respectively, and 2-year overall survival (OS) rates of 74%, 61% and 39%, respectively (P < 0·0001). Using regression models, increasing HCT-CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT-CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C-statistic estimates for the prognostic power of the HCT-CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT-CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Modelos Biológicos , Adolescente , Adulto , Fatores Etários , Idoso , Aloenxertos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
10.
Br J Haematol ; 168(6): 796-805, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25403830

RESUMO

This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2)  d 1, 8, 15; B: 72 mg/m(2)  d 1, 8; C: 72 mg/m(2) or 90 mg/m(2)  d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2)  d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/administração & dosagem , Tiazóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Naftiridinas/efeitos adversos , Naftiridinas/sangue , Naftiridinas/uso terapêutico , Prognóstico , Análise de Sobrevida , Tiazóis/efeitos adversos , Tiazóis/sangue , Tiazóis/uso terapêutico , Resultado do Tratamento
11.
Haematologica ; 100(2): 231-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25381131

RESUMO

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Estudos de Coortes , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Naftiridinas/administração & dosagem , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Tiazóis/administração & dosagem , Adulto Jovem
12.
Haematologica ; 99(10): 1624-31, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25085357

RESUMO

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Doadores não Relacionados , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Rejeição de Enxerto , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Leucemia/diagnóstico , Leucemia/mortalidade , Leucemia/terapia , Linfoma/diagnóstico , Linfoma/mortalidade , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análogos & derivados , Recidiva , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Quimeras de Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
13.
Blood Adv ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39347584

RESUMO

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating outpatient monitoring safety and efficacy following liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. Primary end point was incidence of grade ≥3 cytokine release syndrome (CRS), neurological events (NE), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient-monitored, 70%; inpatient-monitored, 30%). Median (range) follow-up was 10.6 months (1.0‒24.5). In outpatients and inpatients, respectively, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%. Among outpatients, 25% were never hospitalized after infusion and 32% were hospitalized ≤72 hours after the day of infusion; median (range) time to hospitalization was 5.0 days (2‒310). Median (range) initial hospitalization duration after liso-cel was 6.0 days (1‒28) for outpatients and 15.0 days (3‒31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and median duration of response was 14.75 months (95% confidence interval, 5.0‒not reached). OUTREACH is the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support feasibility of liso-cel administration at community sites with outpatient monitoring. ClinicalTrials.gov: #NCT03744676.

14.
Clin Hematol Int ; 6(4): 43-52, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39417014

RESUMO

The treatment setting influences acute myeloid leukemia (AML) outcomes. Most cancer patients receive care in the community, yet few studies have evaluated the effectiveness of clinical programs outside of academic or National Cancer Institute (NCI)-designated cancer centers. This was a multi-level, case-controlled study of real-world outcomes for initial AML treatment in a community-based network for 1,391 patients with AML between 2011 and 2018. We benchmarked survival within our network against the Surveillance, Epidemiology, and End Results (SEER) database. Coarsened exact matching was performed against 17,186 chemotherapy-treated patients in the SEER database. Cox proportional and accelerated failure time multivariable modeling were performed to identify patient, disease, therapy and center characteristics associated with the risk of AML mortality. Within the network, 799 patients were treated at six specialized blood cancer centers and 592 at 63 other hospitals. Patients receiving high-intensity induction at specialized centers had improved median survivals of 31 months versus 18 months [P<0.001] at non-specialized centers. Median survivals were 13 for non-specialized centers versus 10 months for SEER [P<0.001], and 18 for the entire network versus 10 months for SEER [P<0.001]. Multivariable modeling showed significant impacts from age (HR = 1.025), high-intensity induction therapy (HR= .695), diagnosis year (HR= .937), neighborhood income (HR = .997; P<0.01), higher acuity (HR = 1.002) and Charlson comorbidity score (HR = 1.117). AML treatment may be effectively delivered in the community hospital setting, with specialized centers producing better outcomes for higher intensity treatments.

15.
Blood Adv ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39418599

RESUMO

We analyzed access barriers to anti-CD19+ chimeric antigen receptor T-cells (CART) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. 357 intended recipients of FDA-approved anti-CD19+ CART were identified in the study period (2018 to 2022). Results showed that the median age at referral was 61 years, referral year was 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses were diffuse large B-cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were Axi-cel (62%), Tisa-cel (16%), Brexu-cel (13%) and Liso-cel (9%). 182 patients were infused with CART. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022. [P <0.0001] 124 patients (41%) did not receive CART mostly for disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared to those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018-2020 to 34% by 2021-2022 [P=0.001]. In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes while overall time to infusion exceeded four months. Time to infusion as well as the proportion receiving CART improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary.

16.
Cancer Res Commun ; 2(8): 795-805, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36923307

RESUMO

Purpose: NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883). Experimental Design: Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule. Results: The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease. Conclusions/Discussion: Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily. Significance: BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis.


Assuntos
Antineoplásicos , Linfoma , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Linfoma/tratamento farmacológico , NF-kappa B/metabolismo , Comprimidos
17.
Clin Lymphoma Myeloma Leuk ; 22(1): 52-59, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34454850

RESUMO

BACKGROUND: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene. METHODS: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS. RESULTS: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%). CONCLUSIONS: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.


Assuntos
DNA/metabolismo , Linfoma Difuso de Grandes Células B/terapia , Oligonucleotídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Oligonucleotídeos/farmacologia , Recidiva , Resultado do Tratamento
18.
Haematologica ; 96(8): 1113-20, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21508120

RESUMO

BACKGROUND: Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia. DESIGN AND METHODS: Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplantation from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation. Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. Eighteen of these patients received post-grafting imatinib. RESULTS: With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%, respectively. The cumulative incidence of chronic graft-versus-host disease was 44%. Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall survival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remission and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first remission who received post-grafting imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of minimal residual disease at transplantation, the overall survival was 73%. CONCLUSIONS: For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-myeloablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term survival.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Fatores Etários , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Benzamidas , Criança , Progressão da Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Piperazinas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Recidiva , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
19.
JAMA ; 306(17): 1874-83, 2011 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22045765

RESUMO

CONTEXT: A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. OBJECTIVE: To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. DESIGN, SETTING, AND PARTICIPANTS: From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m(2), before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. MAIN OUTCOME MEASURES: Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. RESULTS: Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall). CONCLUSION: Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Irradiação Corporal Total , Fatores Etários , Idoso , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doses de Radiação , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem
20.
Clin Cancer Res ; 27(8): 2190-2199, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33451977

RESUMO

PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.


Assuntos
Antígeno CD47/antagonistas & inibidores , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoglobulina G/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoglobulina G/administração & dosagem , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Resultado do Tratamento , Adulto Jovem
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