The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival ...(EFS) in adults with
acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with
AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m
on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m
/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided
=0.006, corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin
control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at
).
Summary Background The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were ...contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. Methods In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50–70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m2 on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. Findings 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20–2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8–27·1) in the control group versus 40·8% (32·8–50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43–0·78; p=0·0003), OS 41·9% (33·1–53·1) versus 53·2% (44·6–63·5), respectively (0·69, 0·49–0·98; p=0·0368), and RFS 22·7% (14·5–35·7) versus 50·3% (41·0–61·6), respectively (0·52, 0·36–0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 16% vs 4 3%; p<0·0001), without an increase in the risk of death from toxicity. Interpretation The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. Funding Wyeth (Pfizer).
In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability ...to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.
Patients diagnosed with acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 (FLT3) mutations have a very poor prognosis, despite use of allogeneic hematopoietic stem cell transplantation ...(allo-HSCT) and salvage treatments.
We previously reported the safety and efficacy of sorafenib, an FLT3 inhibitor, as a maintenance agent after allo-HSCT in patients diagnosed with AML with FLT3 mutations. We provide an update on the 27 patients with FLT3-mutated AML in our original report, who received sorafenib as a single maintenance agent.
Since our previous report, others have confirmed our reported significant overall survival and progression-free survival in patients who received sorafenib before and/or after allo-HSCT. In this update on the 27 patients with FLT3-mutated AML in our original report, we show persistence of the previously reported impressive long-term disease control.
Our results, with longer follow-up than in our previous report, together with those of others, further support the use of sorafenib as a maintenance agent after allo-HSCT.
Patients with acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 (FLT3) mutations have a very poor prognosis, despite use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and salvage treatments. We previously reported the safety and efficacy of sorafenib, as a maintenance agent after allo-HSCT in 27 patients with FLT3-mutated AML. We provide an update on the patients in our original report, who received sorafenib as a single maintenance agent, and show persistence of the previously reported impressive long-term disease control. Our results continue to support the use of sorafenib as a maintenance agent after allo-HSCT.
The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo ...acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50-70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 received GO as follow-up therapy) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.
Chemotherapy resistance is the main cause of treatment failure in acute myeloid leukemia (AML) and has been related to ATP-binding cassette (ABC) transporter activity. However, the links between ABC ...activity, immunophenotype, and molecular AML parameters have been poorly evaluated. Moreover, the prognostic value of ABC activity, when compared to new molecular markers, is unknown. Here we investigated the links between ABC activity, as evaluated by JC-1 +/- cyclosporine A assay, and immunophenotypic, cytogenetic, molecular, and targeted next-generation sequencing features in 361 AML patients. High ABC activity was found in 164 patients and was significantly associated with less proliferating disease, an immature immunophenotype (expression of CD34, HLA-DR, CD117, CD13), and gene mutations defining AML as belonging to secondary-type ontogenic groups. Low ABC activity was associated with more mature myeloid differentiation (CD34-, cyMPO+, CD15+, CD33+) or monocytic commitment (CD64+, CD4+weak, CD14+), with NPM1 mutations, KMT2A rearrangements, and core-binding factor gene fusions, hallmarks of the de novo-type AML ontogeny. ABC activity was one of the major factors we identified using a random forest model for early prediction of AML ontogeny. In the 230 patients evaluated at diagnosis and intensively treated, high ABC activity was a predictive factor for primary resistance, and in multivariate analysis including full molecular data, an independent factor for event-free survival (P=0.0370). JC-1 +/- cyclosporine A assay could be used at diagnosis to predict AML ontogeny and to complete prognosis evaluation in addition to new molecular markers.
The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation ...of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent
hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases.
The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a ...new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17
and P15
models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.
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