283 research outputs found
Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia
Background: A single-arm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific T-cell\u2013engaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosome\u2013positive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC). Methods: The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 second-generation tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosome\u2013negative ALL. Results: In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61-3.89) or 1.70 (95% credible interval [CrI], 0.94-2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57-1.14) or 0.77 (95% CrI, 0.61-0.96) with Bayesian data augmentation. Conclusions: These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL
Bleeding related to disturbed fibrinolysis
The components and reactions of the fibrinolysis system are well understood. The pathway has fewer reactants and interactions than coagulation, but the generation of a complete quantitative model is complicated by the need to work at the solidâliquid interface of fibrin. Diagnostic tools to detect disease states due to malfunctions in the fibrinolysis pathway are also not so well developed as is the case with coagulation. However, there are clearly a number of inherited or acquired pathologies where hyperfibrinolysis is a serious, potentially lifeâthreatening problem and a number of antifibrinolytc drugs are available to treat hyperfibrinolysis. These topics will be covered in the following review
Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia
Peripheral blood minimal/measurable residual disease assessed in flow cytometry in acute myeloblastic leukemia
Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status
Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged >= 55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (>= 0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline.Peer reviewe
Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow.
Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr-/- cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34+ cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation
Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia
BACKGROUND
Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive
T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL)
blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL
on the basis of single-group trials that showed efficacy and manageable toxic effects.
METHODS
In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated
B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standardof-
care chemotherapy. The primary end point was overall survival.
RESULTS
Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients)
or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was
significantly longer in the blinatumomab group than in the chemotherapy group. The
median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the
chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71;
95% confidence interval [CI], 0.55 to 0.93; P = 0.01). Remission rates within 12 weeks after
treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy
group, both with respect to complete remission with full hematologic recovery
(34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete
hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted
in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31%
vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full,
partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001),
as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the
patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse
events of grade 3 or higher were reported in 87% of the patients in the blinatumomab
group and in 92% of the patients in the chemotherapy group.
CONCLUSIONS
Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy
among adult patients with relapsed or refractory B-cell precursor ALL. (Funded
by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.
Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia
Background
A singleâarm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific Tâcellâengaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosomeâpositive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC).
Methods
The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 secondâgeneration tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosomeânegative ALL.
Results
In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61â3.89) or 1.70 (95% credible interval [CrI], 0.94â2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57â1.14) or 0.77 (95% CrI, 0.61â0.96) with Bayesian data augmentation.
Conclusions
These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL
Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data
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