Abstract:
BACKGROUND:Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma. METHODS:In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m2, subcutaneously) on days 1, 4, 8, 11; lenalidomide (25 mg, orally) on days 1-14; dexamethasone (20 mg, orally) on days 1, 2, 4, 5, 8, 9, 11, and 12; and escalating doses of panobinostat (10-20 mg, orally) on days 1, 3, 5, 8, 10, and 12. The dose level exceeded the maximum tolerated dose if at any given dose more than one of three patients, or two of six patients, had a dose-limiting toxic event. In the dose-expansion cohort, patients were given the maximum tolerated dose of the drug combination as determined from the dose-escalation cohort. Patients could proceed with upfront ASCT after two to four cycles of initial therapy or store their stem cells and proceed with a delayed ASCT approach. Patients with delayed ASCT could continue therapy for up to eight cycles, followed by maintenance with lenalidomide, dexamethasone, and panobinostat at their last tolerated dose for up to 2 years. The primary objective was to determine the maximum tolerated dose of VRd with panobinostat. Safety was assessed in all patients who completed at least one cycle of therapy. This trial is registered with ClinicalTrials.gov, number NCT01440582, and is no longer recruiting participants. FINDINGS:Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg orally on days 1-14; dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12; and panobinostat 10 mg orally on days 1, 3, 5, 8, 10 and 12) was established as the maximum tolerated dose. INTERPRETATION:The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results. FUNDING:Novartis and MD Anderson Cancer Center Support Grant.
journal_name
Lancet Haematoljournal_title
The Lancet. Haematologyauthors
Manasanch EE,Shah JJ,Lee HC,Weber DM,Thomas SK,Amini B,Feng L,Berkova Z,Hildebrandt M,Orlowski RZdoi
10.1016/S2352-3026(18)30174-1subject
Has Abstractpub_date
2018-12-01 00:00:00pages
e628-e640issue
12issn
2352-3026pii
S2352-3026(18)30174-1journal_volume
5pub_type
杂志文章abstract:BACKGROUND:High-dose melphalan is of little benefit as a regimen for patients with relapsed or refractory myeloma undergoing an autologous stem-cell transplant (ASCT). The poor performance of single-agent melphalan in this setting prompted us to study a new high-dose combination of infused gemcitabine, busulfan, and me...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(17)30080-7
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND:Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (<100 mSv) radiation is less certain, although this is the dose range most relevant to the general populatio...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(18)30092-9
更新日期:2018-08-01 00:00:00
abstract:BACKGROUND:Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thrombo...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(18)30063-2
更新日期:2018-07-01 00:00:00
abstract:BACKGROUND:Mechanisms of red blood cell delivery and their contribution to the incidence of venous thromboembolism are not well understood in the clinical setting. We assessed whether red blood cell transfusion through peripherally inserted central catheters (PICCs) affects the risk of venous thromboembolism compared w...
journal_title:The Lancet. Haematology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/S2352-3026(16)30132-6
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND:Anaemia and iron deficiency are common after post-bariatric abdominoplasty, which can involve removal of large areas of skin with associated blood loss. Because the oral absorbability of iron is reduced after bariatric surgery (through reduced intake, reduction of gastric acid secretion for conjugation of ir...
journal_title:The Lancet. Haematology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2018-07-01 00:00:00
abstract:BACKGROUND:Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemop...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(15)00289-6
更新日期:2016-03-01 00:00:00
abstract:BACKGROUND:Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving ...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,随机对照试验
doi:10.1016/S2352-3026(18)30221-7
更新日期:2019-03-01 00:00:00
abstract:BACKGROUND:In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(19)30113-9
更新日期:2019-09-01 00:00:00
abstract:BACKGROUND:Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative condi...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(16)30149-1
更新日期:2016-11-01 00:00:00
abstract:BACKGROUND:Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,随机对照试验
doi:10.1016/S2352-3026(17)30078-9
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abstract:BACKGROUND:Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgk...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(14)00039-8
更新日期:2015-02-01 00:00:00
abstract:BACKGROUND:Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS:We did a retrospective co...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(14)00037-4
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND:Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS:We did a single-arm, phase 2 trial at MD...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(15)00127-1
更新日期:2015-09-01 00:00:00
abstract:BACKGROUND:Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared wit...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,随机对照试验
doi:10.1016/S2352-3026(17)30120-5
更新日期:2017-08-01 00:00:00
abstract:BACKGROUND:In patients with pulmonary embolism, right ventricular dysfunction is associated with early mortality. The Hokusai-VTE study used N-terminal pro-brain natriuretic peptide (NT-proBNP) and right to left ventricular diameter ratio on CT as indicators of right ventricular dysfunction and reported that recurrent ...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/S2352-3026(16)30080-1
更新日期:2016-09-01 00:00:00
abstract:BACKGROUND:Sintilimab (Innovent Biologics, Suzhou, China), a highly selective, fully humanised, monoclonal antibody, blocks the interaction between PD-1 and its ligands. We aimed to assess the activity and safety profile of sintilimab in Chinese patients with relapsed or refractory classical Hodgkin lymphoma. METHODS:...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(18)30192-3
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety ...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(16)30050-3
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pub_type: 临床试验,杂志文章
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更新日期:2017-04-01 00:00:00
abstract:BACKGROUND:Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond sy...
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pub_type: 杂志文章
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更新日期:2017-05-01 00:00:00
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journal_title:The Lancet. Haematology
pub_type: 杂志文章,随机对照试验
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更新日期:2017-06-01 00:00:00
abstract:BACKGROUND:The ability of the pulmonary embolism rule-out criteria (PERC) to exclude pulmonary embolism without further testing remains debated outside the USA, especially in the population with suspected pulmonary embolism who have a high prevalence of the condition. Our main objective was to prospectively assess the ...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(17)30210-7
更新日期:2017-12-01 00:00:00
abstract::Machine learning is a branch of computer science and statistics that generates predictive or descriptive models by learning from training data rather than by being rigidly programmed. It has attracted substantial attention for its many applications in medicine, both as a catalyst for research and as a means of improvi...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,评审
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更新日期:2020-07-01 00:00:00
abstract:BACKGROUND:Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究
doi:10.1016/S2352-3026(16)30165-X
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND:Among the syndromes characterised by thrombotic microangiopathy, thrombotic thrombocytopenic purpura is distinguished by a severe deficiency in the ADAMTS13 enzyme. Patients with this disorder need urgent treatment with plasma exchange. Because ADAMTS13 activity testing typically requires prolonged turnaroun...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(17)30026-1
更新日期:2017-04-01 00:00:00
abstract:BACKGROUND:Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in t...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/S2352-3026(20)30358-6
更新日期:2021-01-01 00:00:00
abstract:BACKGROUND:The introduction of donors other than HLA-matched siblings has been a pivotal change in stem cell transplantation. We aimed to assess the evolution of outcomes within donor groups over time and explore whether donor-recipient HLA disparity might be advantageous in patients with aggressive disease. METHODS:I...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
doi:10.1016/S2352-3026(19)30158-9
更新日期:2019-11-01 00:00:00
abstract:BACKGROUND:Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METH...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2020-01-01 00:00:00
abstract:BACKGROUND:Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcom...
journal_title:The Lancet. Haematology
pub_type: 杂志文章
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更新日期:2016-10-01 00:00:00
abstract:BACKGROUND:The INO-VATE study demonstrated efficacy and safety of inotuzumab ozogamicin versus standard care in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Here, we report the frequency of, and potential risk factors for, hepatotoxicity in patients in this trial and after treatment and subs...
journal_title:The Lancet. Haematology
pub_type: 杂志文章,随机对照试验
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更新日期:2017-08-01 00:00:00