47 research outputs found
Influence of cytogenetic abnormalities on outcome after allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission
AbstractCytogenetic abnormalities detected at diagnosis are recognized as important in predicting response to chemotherapy in acute myeloid leukemia (AML). However, there is controversy concerning the prognostic significance of karyotype for outcome after allogeneic bone marrow transplantation (allo-BMT) performed in first complete remission (CR1). This single-institution report describes allo-BMT for AML in CR1 and the effect of diagnostic cytogenetic findings on the results of that treatment. Between August 1981 and December 1999, 93 patients underwent related donor (n = 82) or unrelated donor (n = 11) BMT. Conditioning and GVHD prophylaxis were achieved predominantly with busulfan and cyclophosphamide and with cyclosporine and methotrexate, respectively. Seventy-nine (85%) of 93 patients had successful marrow karyotyping at diagnosis, and the patients were categorized into 3 prognostic groups based on the British Medical Research Council AML 10 trial classification: 15 patients(19%) were classified as having favorable risk [inv(16), t(8;2 1), t(15;17)]; 55 (70%) as having intermediate risk [no abnormality, +8, +21, +22, del(7q), del(9q), 11q23 rearrangement, and other numerical or structural abnormalities]; and 9 (11%) as having adverse risk [-5, del(5q), -7, 3q rearrangements, > or = 5 abnormalities, t(6;9), t(9;22)]. The median follow-up was 93 months (range, 16-241 months). The overall survival (OS) rate, event-free survival (EFS) rate, relapse rate, and treatment-related mortality (TRM) were not statistically different between the groups. The 5-year actuarial EFS rates for favorable, intermediate, and adverse risk groups were 58% (95% confidence interval [CI], 29%-79%), 58% (95% CI, 43%-70%), and 67% (95% CI 28%-88%), respectively. Reclassification of patients into cytogenetic prognostic subgroups according to Southwest Oncology Group criteria did not change these results. In univariate analysis, the only variable found to have a prognostic influence on OS (P = .04) and TRM (P = .03) was the type of donor (unrelated donor was linked to a worse prognosis), which was confirmed in multivariate analysis. Our study suggests that presentation karyotype has less prognostic significance for outcome following allo-BMT than for outcome following conventional chemotherapy. In particular, AML patients with poor prognostic cytogenetic changes in CR1 who are unlikely to be cured with chemotherapy alone may benefit from allo-BMT.Biol Blood Marrow Transplant 2002;8(8):435-43
Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML
CPX-351 is a liposomal formulation of cytarabine: daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2: 1 to first-line CPX-351 or 713 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission 1 incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P \u3c .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count \u3e= 1000: 36 vs 32; platelets \u3e100 000:37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892
Early Stem Cell Transplantation for Refractory Acute Leukemia after Salvage Therapy with High-Dose Etoposide and Cyclophosphamide
AbstractPrimary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m2 followed by cyclophosphamide (Cy) 6.0-7.2 g/m2 intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients (P = .04), and only male sex was predictive of a favorable outcome (P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients
Quality of Life and Socioeconomic Indicators Associated with Survival of Myeloid Leukemias in Canada
Understanding how patientâreported quality of life (QoL) and socioeconomic status (SES) relate to survival of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may improve prognostic information sharing. This study explores associations among QoL, SES, and survival through administration of the EuroâQoL 5âDimension, 3âlevel and Functional Assessment of Cancer TherapyâLeukemia and financial impact questionnaires to 138 adult participants with newly diagnosed AML or MDS in a longitudinal, panâCanadian study. Cox regression and lasso variable selection models were used to explore associations among QoL, SES, and established predictors of survival. Secondary outcomes were changes in QoL, performance of the QoL instruments, and lost income. We found that higher QoL and SES were positively associated with survival. The Lasso model selected the visual analog scale of the EQâ5Dâ3L as the most important predictor among all other variables (P = .03; 92% selection). Patients with AML report improved QoL after treatment, despite higher mean outâofâpocket expenditures compared with MDS (up to 239 for MDS; P = .05), greater loss of productivityârelated income (reaching id="mce_marker"786/month for AML vs $709 for MDS; P < .05), and greater caregiver effects (65% vs 35% caregiver productivity losses for AML vs MDS; P < .05). Our results suggest that including patientâreported QoL and socioeconomic indicators can improve the accuracy of survival models
Economic impact of genomic diagnostics for intermediateârisk acute myeloid leukaemia
Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decisionâmaking for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the costâeffectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediateârisk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the longâterm (10âyear) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of firstâremission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of 49Â 493 per qualityâadjusted lifeâyear gained. Costâeffectiveness was dependent on quality of life during the longâterm (5â10) years of survival, relapse rates following firstâremission chemotherapy and the upfront cost of transplantation. Nonârelapse mortality rates, shortâterm quality of life and the cost of genomic sequencing had only minor impacts. Further research on postâremission outcomes can lead to improvements in the costâeffectiveness of curative treatments for AML
Fotografia B221
The
front-line treatment for adult acute myeloid leukemia (AML)
is anthracycline-based combination chemotherapy. However, treatment
outcomes remain suboptimal with relapses frequently observed. Among
the mechanisms of treatment failure is multidrug resistance (MDR)
mediated by the ABCB1, ABCC1, and ABCG2 drug-efflux transporters.
Although genetic and phenotypic heterogeneity between leukemic blast
cells is a well-recognized phenomenon, there remains minimal data
on differences in MDR activity at the individual cell level. Specifically,
functional assays that can distinguish the variability in MDR activity
between individual leukemic blasts are lacking. Here, we outline a
new dielectrophoretic (DEP) chip-based assay. This assay permits measurement
of drug accumulation in single cells, termed same-single-cell analysis
in the accumulation mode (<i>SASCA-A</i>). Initially, the
assay was optimized in pretherapy samples from 20 adults with AML
whose leukemic blasts had MDR activity against the anthracyline daunorubicin
(DNR) tested using multiple MDR inhibitors. Parameters tested were
initial drug accumulation, time to achieve signal saturation, fold-increase
of DNR accumulation with MDR inhibition, ease of cell trapping, and
ease of maintaining the trapped cells stationary. This enabled categorization
into leukemic blast cells with MDR activity (MDR<sup>+</sup>) and
leukemic blast cells without MDR activity (MDR<sup>âve</sup>). Leukemic blasts could also be distinguished from benign white
blood cells (notably these also lacked MDR activity). MDR<sup>âve</sup> blasts were observed to be enriched in samples taken from patients
who went on to enter complete remission (CR), whereas MDR<sup>+</sup> blasts were frequently observed in patients who failed to achieve
CR following front-line chemotherapy. However, pronounced variability
in functional MDR activity between leukemic blasts was observed, with
MDR<sup>+</sup> cells not infrequently seen in some patients that
went on to achieve CR. Next, we tested MDR activity in two paired
AML patient samples. Pretherapy samples taken from patients that achieved
CR to front-line chemotherapy were compared with samples taken at
time of subsequent relapse. MDR<sup>+</sup> cells were frequently
observed in leukemic blast cells in both pretherapy and relapsed samples,
consistent with MDR as a mechanism of relapse in these patients. We
demonstrate the ability of a new DEP microfluidic chip-based assay
to identify heterogeneity in MDR activity in leukemic blasts. The
test provides a platform for future studies to characterize the mechanistic
basis for heterogeneity in MDR activity at the individual cell level