Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as ...cured. This study aimed to identify factors influencing the long-term outcome in these patients.
The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome.
Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11).
In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.
1 Departments of Hematology, Hôpital dInstruction des Armées, Clamart
2 Institut Paoli Calmettes, Marseille
3 Centre Hospitalier Universitaire, Limoges
4 Hôpital Edouard Herriot, Lyon
5 Centre Léon ...Becquerel, Rouen
6 Hôpital Mignot, Versailles
7 Hôpital Avicenne, Assistance Publique, Hôpitaux de Paris (AP-HP), University Paris 13, Bobigny
8 Hôpital Saint-Louis, AP-HP, University Paris 7, Paris, France
Correspondence: Hervè Dombret, Department of Hematology, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France. E-mail: herve.dombret{at}sls.aphp.fr
Background: There is a need for standardization of treatment decisions in older patients with acute myeloid leukemia. The aim of the present study was to analyze the decisional value of poor risk factors in 416 elderly patients treated in the ALFA-9803 trial in order to derive a decisional index.
Design and Methods: Standard multivariate analysis was used to identify risk factors for overall survival. Risk factors were then considered as good decision tools if associated with a frequency >10% and a false positive rate <10% in predicting overall survival as poor as observed after low-dose cytarabine therapy (25% survival or less at 12 months).
Results: Among six independent risk factors (age, performance status, white blood cell count, hematopoietic cell transplantation comorbidity index, infection at baseline, and cytogenetics), cytogenetics was the only potent, independent decision tool. High hematopoietic cell transplantation comorbidity index scores or infections were found too rarely to guide further decisions. The three other factors (age, performance status, and white cell count) needed to be combined to provide a good specificity. The proposed decisional index, therefore, included high-risk cytogenetics and/or the presence of at least two of the following criteria: age 75 years, performance status 2, and white cell count 50 x 10 9 /L. This simple two-class decisional index, which was validated in an independent patient set, enabled us to discriminate 100 patients (24%) who had an estimated overall survival of only 19% at 12 months, with a good 9% false positive rate.
Conclusions: We propose waiting for cytogenetic information before making treatment decisions in elderly patients with acute myeloid leukemia. Those patients with unfavorable cytogenetics, as well as patients with at least two of the following features, age 75 years, performance status 2, and white cell count 50 x 10 9 /L, should not be considered for standard intensive chemotherapy (ClinicalTrials.gov identifier: NCT00363025 ).
Key words: elderly, acute myeloid leukemia, prognosis, risk factors, decision criteria.
Relationships between c-Rel and GCB-DLBCLs remain unclear. We found that strong c-Rel DNA-binding activity was mostly found in GCBs on two independent series of 48 DLBCLs and 66 DLBCLs, the latter ...issued from the GHEDI series. c-Rel DNA-binding activity was associated with increased
mRNA expression. Extending the study to the whole GHEDI and Lenz DLBCL published series of 202 and 233 cases, it was found that the c-Rel gene expression profile (GEP) overlapped partially (12%) but only with the GCB GEP and not with the GEP of ABC-DLBCLs. Cases with both overexpression of
mRNA and c-Rel GEP were defined as those having a c-Rel signature. These cases were GCBs in 88 and 83% of the GHEDI or Lenz's DLBCL series respectively. The c-Rel signature was also associated with various recurrent GCB-DLBCL genetic events, including
gains,
translocation,
,
,
, and
mutations and with the EZB GCB genetic subtype. By CGH array, the c-Rel signature was specifically correlated with 2p15-16.1 amplification that includes XPO1, BCL11A, and USP34 and with the 22q11.22 deletion that covers IGLL5 and PRAME. The total number of gene copy number aberrations, so-called genomic imbalance complexity, was decreased in cases with the c-Rel signature. These cases exhibited a better overall survival. Functionally, overexpression of c-Rel induced its constitutive nuclear localization and protected cells against apoptosis while its repression tended to increase cell death. These results show that, clinically and biologically, c-Rel is the pivotal NF-
B subunit in the GCB-DLBCL subgroup. Functionally, c-Rel overexpression could directly promote DLBCL tumorigenesis without need for further activation signals.
The JAK2V617F mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and ...myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2V617F-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2V617F and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.
PURPOSE First-line treatment for patients with newly diagnosed follicular lymphoma (FL) still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the ...question whether complete remission (CR) translates into better survival. The aim of this study was to assess the long-term follow-up of prospectively treated patients with FL and the potential correlation between response quality to first-line treatment and overall survival (OS). PATIENTS AND METHODS Data from 536 patients with FL with low (n = 193) or high (n = 343) tumor burden enrolled from October 1986 to May 1995 in the French and Belgian GELF86 studies were analyzed. Data from these trials have been previously reported for low-tumor burden and high-tumor burden patients. Results Median follow-up was 14.9 years, and median OS was 9.8 years. Treated patients who achieved a complete response (CR; n = 194; 45%) had a significant longer OS than those only reaching a partial response (PR; n = 168; 39%) throughout treatment (hazard ratio HR, 0.55; 95% CI, 0.42 to 0.72; P < .001) in an univariate time-dependent Cox model. Similar findings were found when response to treatment (CR v PR) was adjusted for potentially confounding factors in a multivariate model (HR, 0.53; 95% CI, 0.38 to 0.73; P < .001). CONCLUSION These data provide a long follow-up of these patients' cohorts and indicate that a better response to first-line treatment translates into an improved survival for patients with FL. Therefore, response-adapted therapy aiming to achieve a CR should be considered as first-line treatment.
Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a ...substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL.
In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75(NTR)/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab.
Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hodgkin's lymphoma (HL) is associated with the presence of EBV in Reed-Sternberg (RS) cells in ∼40% of cases. Here, we studied the presence of human herpesvirus type 6 (HHV-6) variant B in RS cells ...of HL patients and correlated results with clinical parameters. We then examined the implication of HHV-6 DR7B protein in cell deregulation.
HHV-6 DR7B protein was produced in a Semliki Forest virus system. Polyclonal antibodies were then generated and used for immunochemical HHV-6 localization in HL biopsies. Binding between DR7B and p53 was studied using a double-hybrid system. Transactivation of NFκB was observed after transient transfection using reporter gene assays. We looked for Id2 factor expression after stable transfection of the BJAB cell line by reverse transcription-PCR and Western blot analysis.
HHV-6 was more common in nodular sclerosis subtype HL, and DR7B oncoprotein was detected in RS cells for 73.7% of EBV-negative patients. Colocalization of EBV and HHV-6 was observed in RS cells of doubly infected patients. DR7B protein bound to human p53 protein. p105-p50/p65 mRNA expression and activation of the NFκB complex were increased when DR7B was expressed. Stable expression of DR7B exhibited a strong and uniform expression of Id2. A slightly higher percentage of remission was observed in patients with RS cells testing positive for DR7B than in those testing negative.
Collectively, these data provide evidence for the implication of a novel agent, HHV-6, in cases of nodular sclerosis HL.
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