[Show abstract][Hide abstract] ABSTRACT: ABSTRACT We retrospectively studied the outcome of 213 consecutive patients who received allo-HSCT for hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors between 2006 and 2011 in our institution. Engraftment was significantly lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the siblings group (99%), (p=0.03). The median OS was 10 months (5-21), 18 months (11-NR) and 60 months (31-NR) respectively with a 2-years probability of 19% (8-44), 43% (31-59) and 63% (54-74) respectively. TRM was significantly higher in the 9/10 HLA group with 1 year cumulative incidence of 45% (35-55), compared to 33% (27-39) in the unrelated 10/10 HLA group and 12% (9-15) in the siblings group (p<0.001). Disease status at transplantation less than first CR/chronic phase was associated with worse OS [HR=3 (1.4-6), p=0.003].
[Show abstract][Hide abstract] ABSTRACT: Although CBF-AML (t(8;21) or inv(16)/t(16;16)) represents a favorable cytogenetic AML subgroup, 30-40% of these patients relapse after standard intensive chemotherapy. The encouraging results of GO in newly diagnosed AML and particularly in CBF-AML incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analysed the outcome of 145 patients with CBF-AML (59 t(8;21), 86 inv(16)/t(16;16)) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median CR1 duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter CR1 duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; p=.05) and OS (65% vs 44%; p=.02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received alloSCT in CR2, GO before transplant significantly improved post-transplant DFS and OS without excess of treatment-related mortality.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Relapse in acute myeloid leukemia (AML) after chemotherapy reflects the persistence of resistant leukemia stem cells (LSCs). These cells have been described in the CD34(+)CD38(-) cell fraction. Leukapheresis products were harvested in 123 patients in morphological complete remission and analyzed by multi-parameter flow cytometry. The CD34(+)CD38(-) cell population showed a prognostic impact on survival. Median event-free survival (EFS) was 8.2 months (3-year EFS: 29%) for those with higher percentage of CD34(+)CD38(-) vs 91.9 months (3-year EFS: 62%) for those with lower percentage for the entire cohort. These differences were confirmed in patients undergoing autologous SCT with median EFS of 7.3 months vs 91.1 months (3-year EFS: 31% vs 70%). Higher proportions of CD34(+)CD38(-) cells were associated with adverse cytogenetics and with earlier relapses. Higher percentages of CD34(+)CD38(-) cells in apheresis products reflect inadequate in vivo purging and reliably distinguish samples enriched in LSCs from those involving mainly normal cells.
[Show abstract][Hide abstract] ABSTRACT: Targeted therapies represent a major breakthrough in the treatment of adult acute lymphoblastic leukaemia (ALL). Because lymphoblastic leukaemia cells express a variety of specific antigens, those ones can serve as targets for monoclonal antibodies (MoAbs). Anti-CD20 (rituximab), anti-CD19 (blinatumomab, SAR3419), anti-CD22 (epratuzumab, inotuzumab ozogamicin), and anti-CD52 (alemtuzumab) have therefore been developed. Possible strategies even include recruitment of CD3 cytotoxic T cells (blinatumomab) or adoptive T-cell therapy by gene transfer of CD19-chimeric antigen receptors (CD19-CARs). Recent data show that antibody-based therapy is a highly promising treatment approach. However, optimal treatment approach still needs to be defined.This article is protected by copyright. All rights reserved.
European Journal Of Haematology 06/2014; · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by Ig/TCR minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as primary endpoint. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with post-induction MRD level ≥ 10(-4) and unfavorable genetic characteristics (i.e. MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL; and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-ALL). These two factors allowed definition of a new risk classification, which is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL, not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and 2005 trials. Both trials were registered at ClinicalTrials.gov (GRAALL-2003, NCT00222027; GRAALL-2005, NCT00327678).
[Show abstract][Hide abstract] ABSTRACT: Compared with younger patients, older adults with acute myeloid leukemia (AML) generally have poorer survival outcomes and less benefit from clinical trials. A recent phase 3 trial demonstrated a trend toward improved overall survival (OS) with decitabine, a hypomethylating agent, compared with treatment choice of either cytarabine or supportive care (7.7 months, 95% CI: 6.2-9.2 vs 5.0 months, 95% CI: 4.3-6.3, respectively) in older adults with newly diagnosed AML. The current analyses investigated prognostic factors for outcomes in this trial and examined OS and responses in prespecified subgroups.
A multivariate Cox proportional hazards model was used to investigate effects of demographic and baseline characteristics, including age, sex, cytogenetic risk, AML type, ECOG Performance Status, geographic region, bone marrow blasts, platelets, and white blood cells on OS, based on mature data. Similar analyses were conducted with a logistic regression model to predict response rates. Prespecified subgroup analyses were performed for OS and response rates, also using mature data. ClinicalTrials.gov identifier is NCT00260832.
Patient characteristics that appeared to negatively influence OS included more advanced age (hazard ratio [HR] 1.560 for >=75 vs <70 years; p = 0.0010), poorer performance status at baseline (HR 0.771 for 0 or 1 vs 2; p = 0.0321), poor cytogenetics (HR 0.699 for intermediate vs poor; p = 0.0010), higher bone marrow blast counts (HR 1.355 for >50% vs <=50%; p = 0.0045), low baseline platelet counts (HR 0.775 for each additional 100 x 109/L; p = 0.0015), and high white blood cell counts (HR 1.256 for each additional 25 x 109/L; p = 0.0151). Regarding geographic regions, patients from Western Europe had the longest median OS. Response rates favored decitabine for all subgroups investigated, including patients >=75 years (odds ratio 5.94, p = 0.0006).
Response to decitabine in AML is associated with known prognostic factors related to both patient demographics and disease characteristics.Trial registration: ClinicalTrials.gov identifier NCT00260832.
BMC Cancer 02/2014; 14(1):69. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.Bone Marrow Transplantation advance online publication, 3 February 2014; doi:10.1038/bmt.2013.235.
Bone marrow transplantation 02/2014; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patient: Male, 52 Final Diagnosis: L-asparaginase associated steatohepatitis and pulmonary Pneumocystis Symptoms: Cholestasis • hepatomegaly Medication: Corticosteroids • atovaquone • antioxidant therapy Clinical Procedure: Liver biopsy Specialty: Hematology • Infectious Disease • Hepatology.
Challenging differential diagnosis.
L-asparaginase (L-aspa) is an important component of chemotherapy in acute lymphoblastic leukemia (ALL). Main adverse effects of L-aspa include allergic reactions, pancreatitis, thrombosis, and liver disturbances. L-aspa-associated steatohepatitis may be a life-threatening disorder but has very rarely been reported in the literature.
ALL was diagnosed in a 52-year-old man with a history of cardiovascular disease and obesity. Chemotherapy combining daunorubicin, vincristine, cyclophosphamide, and L-aspa was initiated. At the time of neutrophil recovery, the patient developed hepatomegaly in the context of fever and cough. On day 25, after 6 injections of L-aspa, liver function tests showed elevated alkaline phosphatase and transaminases levels. Although pulmonary Pneumocystis was concomitantly diagnosed, biological hepatic disturbances were attributed to L-aspa-associated toxicity. A liver biopsy revealed severe diffuse micro- and macrovesicular steatosis affecting more than 50% of hepatocytes. Other causes of liver dysfunction were eliminated. L-aspa and other hepatotoxic treatments were stopped, and treatment with antioxidant therapy, atovaquone, and corticosteroids was initiated. The clinical outcome was rapidly favorable.
This case illustrates the necessity of carefully monitoring liver function test results in patients receiving L-aspa. In case of major increase of hepatic enzymes, a hepatic biopsy should rapidly be performed to exclude differential diagnosis in patients with prolonged neutropenia. L-aspa should be stopped and further administration definitively avoided. In the present case, the early administration of systemic corticosteroids as treatment of the concomitant Pneumocystis with hypoxemia could have participated to the favorable clinical evolution.
The American journal of case reports. 01/2014; 15:13-7.
[Show abstract][Hide abstract] ABSTRACT: Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.
Neoplasia (New York, N.Y.) 01/2014; 16(1):21-30. · 5.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). A hundred fourty nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient named program. AML diagnosis was de novo, post-MDS, post-MPN and therapy-related AML in 51, 55,13 and 30 patients, respectively. Median age was 74 years, median WBC was 3.2 10(9) /l and 58% of the patients had ≥ 30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of 5 cycles (range 1-31). Response rate (including CR/CRi/PR) was 27.5% after a median of 3 cycles (initial response), and 33 % at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two-year OS was 51% in responders and 10% in non-responders (P<.0001). Adverse cytogenetics, WBC >15.10(9) /l and ECOG-PS ≥2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high-risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies.
American Journal of Hematology 12/2013; · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Busulfan (Bu) represents a backbone as conditioning prior to hematopoietic stem cell transplantation (HSCT). The intravenous (IV) form of Busulfan allows 100% bioavaibility and a limited inter- and intra-patient (pt) variability compared to the oral form. In Europe, IV Bu (Busilvex® fixed dose of 0.8 mg/kg x 16 doses) in combination with Cyclophosphamide (60 mg/kg/d x 2 ) is indicated prior to conventional HSCT in adults when the combination is the best available option. IV BuCy2 allows a precise delivery with 80% of adult pts within the defined therapeutic window [900 μmol/L x min-100 μmol/L x min] without dose-adjustments. Despite major advances in the risk-stratification and management of acute myelogenous leukaemia (AML) based on cytogenetics and molecular biology, the relapse rate remains high. Several published experiences suggested that Bu exposure may have an impact on the clinical outcomes after allogeneic HSCT.
Study objective:The study was implemented to explore the use of a narrow range and high values of Bu exposure [4400 µmol/Lx min to 6000 µmol/Lx min] with a PK-guided dose adjustments and once-daily administration x 4 days.
Methods:The study was a prospective non-randomized multicentric phase II. The eligible pts were required to have AML in first complete (CR1, cytological remission) and to be eligible allogeneic HSCT following a myeloablative regimen. On the first day of the conditioning regimen IV Bu was administered as a single dose of 3.2 mg/kg; further daily dose of IV Bu were determined based on the previous Bu AUC exposure. The graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor, IV methotrexate post-transplant. The addition of antithymoglobulin (ATG) for unrelated donors was decided by each center based on their institutional guidelines. Pts could either receive related or unrelated bone marrow or peripheral blood stem cells. Nine centres with laboratory facilities for the pharmacokinetics analysis entered the study.
Patient and transplant characteristics: Thirty AML pts in CR1 (21 males, 70%) were treated between may 2010 and may 2012, 87% of pts had de novoAML. Twenty pts (67%) had matched sibling donor, the remaining pts received allograft from an unrelated donor. The median age of the cohort was 43.5 years [19.3-55.5]. The performance status score was comprised between 90 and 100. The majority of the cohort (83%) had an intermediate or unfavorable cytogenetic risk-factors. In 3 cases (10%) the karyotyping analyses could not be performed; 1 pt (3%) did not have cytogenetic test performed.
Results: Thirty pts were treated and analyzed. The expected cumulative AUC over 4 days [17600 µmol/Lxmin -24000 µmol/Lxmin ] was reached in 90% of pts. The mean dose of IV Bu administered was 3.51 mg/kg/day. The mean total cumulative dose of IV Bu over 4 days was 13.25 mg/kg [8-21.3]. All pts engrafted. For the entire cohort, the neutrophil engraftment [absolute neutrophil count (ANC) > 0.5 x 10 9/L] occured at a median time of 17.5 d (11-35). Overall, 3 episodes (10%) of sinusoidal obstruction syndrome (S.O.S) occured (one mild, two severe, all resolved) in two patients. One pt developed 2 severe episodes of S.O.S and received defibrotide. Overall, 12 pts out of 30 (40%) developed acute GVHD between day 0 and day +100 after transplant (4 pts had grade III, 6 pts had grade II and 2 pts developed grade III, no patient developed grade IV). The median follow-up was 12 months [95% CI (11.9-12.2)] After day +100, 4 pts died of non-relapse causes ; one death from pulmonary fibrosis was related to the conditioning regimen. The cumulative incidence of TRM was 13.3% [95% CI (11.1%-15.6%)]. Five pts relapsed at a median time of 3.3 months [2-5.6] and 4 pts died of relapse. The cumulative incidence of one-year survival was 73.3% [95% CI (53.7%-85.7%)].
Conclusion: The AUC intensification with once-daily IV BuCy2 is effective and yields an acceptable one year TRM for pts with high-risk AML in CR1. However, longer follow-up is needed in order to assess the impact of AUC intensification on the relapse rate and survivals.
55th ASH Annual Meeting Exposition, New Orlean, LA; 12/2013
[Show abstract][Hide abstract] ABSTRACT: Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.
The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.
At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.
HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
Journal of Clinical Oncology 12/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to overcome the shortcomings of cytarabine. Resistance to cytarabine has been associated with decreased expression of the human equilibrative nucleoside transporter 1 (hENT1) and unlike cytarabine, elacytarabine has been shown to be independent of hENT1 to enter blasts. This single arm, open label phase II study tested the hypotheses that hENT1 blast expression level can be used as a predictive marker for cytarabine response and that the efficacy of elacytarabine is independent of hENT1 expression. A total of 51 patients with acute myeloid leukaemia (AML) that did not attain blast clearance after the first cytarabine-based induction course were given elacytarabine-idarubicin as the second induction course. The hENT1 expression level was analyzed prior to cytarabine treatment and/or after cytarabine failure prior to treatment with elacytarabine. The overall response rate (ORR) to elacytarabine-idarubicin was 41% and the safety profile was manageable, indicating that this combination is an active treatment for patients where an initial cytarabine based induction course has failed. There is a slight indication that hENT1 expression influences response to cytarabine, but not enough to support it as a biomarker for guiding treatment and we conclude that activity of elacytarabine is not affected by the hENT1 expression level.
[Show abstract][Hide abstract] ABSTRACT: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Journal of Clinical Oncology 10/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate quantitatively and qualitatively the different CD34(+) cell subsets after priming by chemotherapy granulocyte colony-stimulating factor (± G-CSF) in patients with acute myeloid leukemia.
Peripheral blood and bone marrow samples were harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4 (CXCR4) (CD184), VLA-4 (CD49d/CD29) and CD47.
Chemotherapy ± G-CSF mobilized immature cells (CD34(+)CD38(-) population), while the more mature cells (CD34(+)CD38(low) and CD34(+)CD38(+) populations) decreased progressively after treatment. Circulating CD34(+) cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34(+) cell mobilization was correlated with a gradual increase in CXCR4 and CD47 expression, suggesting a role in cell protection and the capacity of homing back to the marrow.
Chemotherapy ± G-CSF mobilizes into the circulation CD34(+) bone marrow cells, of which, the immature CD34(+)CD38(-) cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients' outcomes.
World journal of stem cells. 10/2013; 5(4):196-204.
[Show abstract][Hide abstract] ABSTRACT: This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML).
Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS).
The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality.
As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.
Journal of Clinical Oncology 10/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a multicenter, randomized, open-label phase III study, patients ≥ 65 years with newly diagnosed AML received decitabine 20 mg/m(2) once daily for 5 days every 4 weeks (n = 242) or treatment choice (supportive care or cytarabine 20 mg/m(2) once daily for 10 days every 4 weeks; n = 243). Decitabine use demonstrated greater response rates (P = .001) and OS data favored decitabine.
In a post hoc sensitivity analysis of mature data of patients in the intent-to-treat population (N = 485), OS at 3, 6, 12, 18, and 24 months after randomization was estimated for each arm using Kaplan-Meier methods. Age, cytogenetic risk, and Eastern Cooperative Oncology Group performance status were used as stratification factors in the Cox regression model to estimate the hazard ratio.
A survival advantage was seen with decitabine at each cutoff time point; hazard ratios for OS for decitabine vs. treatment choice were 0.83, 0.71, 0.83, 0.80, and 0.79 at 3, 6, 12, 18, and 24 months, respectively. A trend toward improved OS with decitabine was observed at fixed time points over 2 years.
Decitabine should be considered as a treatment option for older patients with AML and poor prognostic risk factors.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT The absolute lymphocyte count (ALC) at presentation has been associated to survival in various malignancies. However its prognostic value in acute myeloid leukemia (AML) has not been established. In a series of 1702 newly diagnosed AML patients, we evaluated the prognostic value of ALC at diagnosis with regards to induction chemotherapy response, disease-free survival (DFS) and overall survival (OS). Low initial ALC (< 1 x 10(9)/l) appeared as a poor prognostic factor for DFS (P = 0.01) and OS (P = 0.02), while higher ALC (> 4.5 x 10(9)/l ) showed a lower response rate after one (P = 0.004) or two induction chemotherapy courses (P = 0.01). However, ALC did not appear as an independent predictor of outcome in a multivariate analysis model also including age, cytogenetics, and WBC count. Examination of lymphocyte subsets is warranted to specify the relationship between ALC at diagnosis and clinical outcome in AML.
[Show abstract][Hide abstract] ABSTRACT: To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low-dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post-relapse survival was 6.8 months (0%, 17%, 42.5%, 53%, 80% and 3.2, 5.6, 8.9, 9, 19.8 months in BSC, LDAC, GO, ICT, and ICT+GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post-relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post-relapse survival, at least in patients with CR1 duration ≥ 12 months (P= 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT+GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥ 12 months appeared to benefit from intensive salvage and results observed with GO-containing salvage suggest that GO combination studies should be actively pursued in this setting.
American Journal of Hematology 06/2013; · 4.00 Impact Factor