Sylvain Thepot

Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

PURPOSE Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. PATIENTS AND METHODS Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). RESULTS The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. CONCLUSION Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

Acute Myeloid Leukemia With Translocation (8;21) or Inversion (16) in Elderly Patients Treated With Conventional Chemotherapy: A Collaborative Study of the French CBF-AML Intergroup

PURPOSE Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly. PATIENTS AND METHODS Patients with t(8;21) or inv(16) AML who were age 60 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56). RESULTS A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 129 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (10%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS. CONCLUSION Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.

The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation.

Incidence on relapse and nonrelapse mortality (NRM) of chronic graft-versus-host disease (GVHD), per National Institutes of Health (NIH) criteria, is not well defined after reduced-intensity conditioning (RIC) regimens. We analyzed the association of chronic GVHD with the risk of relapse and NRM using Cox models in 177 consecutive patients who underwent transplantation for hematological malignancies after RIC. The cumulative incidence of chronic GVHD at 36 months was 74% when using Seattles criteria compared with 54% with NIH consensus. In Cox model, NRM was significantly higher in patients with late-onset, persistent and recurrent acute GVHD (hazard ratio (HR): 6, 25 and 11; P=0.014, P<0.0001, P<0.0001, respectively). The cumulative incidence of relapse was significantly decreased in patients with chronic GVHD compared with no GVHD group using either Seattles or NIH criteria (HR 0.43 and 0.38; P=0.022 and 0.016, respectively), whereas the presence of late-onset, persistent and recurrent acute GVHD was not associated with a decreased rate of relapse (HR: not significant, 0.70 and 0.71; P=not significant, P=0.73 and P=0.54, respectively). Chronic GVHD per NIH consensus definition is associated with the graft-versus-tumor effect, whereas all forms associated with acute features beyond day 100 are associated with NRM.

Erlotinib antagonizes ABC transporters in acute myeloid leukemia.

Erlotinib was originally developed as an epidermal growth factor receptor (EGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated. Conversely, in preclinical settings, erlotinib has been shown to inhibit the constitutive activation of SRC kinases and mTOR, as well as to synergize with the DNA methyltransferase inhibitor azacytidine (a reference therapeutic for a subset of leukemia patients) by promoting its intracellular accumulation. Here, we show that both erlotinib and gefitinib (another EGFR inhibitor) inhibit transmembrane transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), also in acute myeloid leukemia (AML) cells that do not overexpress these pumps. Thus, inhibition of drug efflux by erlotinib and gefitinib selectively exacerbated (in a synergistic or additive fashion) the cytotoxic response of KG-1 cells to chemotherapeutic agents that are normally extruded by ABC transporters (e.g., doxorubicin and etoposide). Erlotinib limited drug export via ABC transporters by multiple mechanisms, including the downregulation of surface-exposed pumps and the modulation of their ATPase activity. The effects of erlotinib on drug efflux and its chemosensitization profile persisted in patient-derived CD34+ cells, suggesting that erlotinib might be particularly efficient in antagonizing leukemic (stem cell) subpopulations, irrespective of whether they exhibit or not increased drug efflux via ABC transporters.

Azacitidine frontline therapy for unfit acute myeloid leukemia patients: Clinical use and outcome prediction ☆

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.

Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure

Between 30% and 40% of myelodysplastic syndrome (MDS) patients progress to acute myeloid leukaemia (AML). The prognosis of these secondary AML (sAML) cases is poor with frequent resistance to conventional chemotherapy and an overall survival of <1 year (Nimer, 2008). Epigenetic deregulation has recently been demonstrated as one of the driving phenomena during disease progression (Jiang et al, 2009). Demethylating agents lead to significant clinical benefit for both MDS and AML patients (Fenaux et al, 2009) and represent an attractive option for AML arising after MDS. Nevertheless, a majority of patients fail to respond to azacitidine (AZA) and most responders progress within 2 years (Fenaux et al, 2010). There is no standard of care for salvage therapy after AZA failure and investigational agents have been extensively studied. We recently showed that the outcome of high risk MDS after AZA failure was poor (Prebet et al, 2011), with a median overall survival (OS) of 5·6 months but, to date, the outcome of sAML after AZA failure has not been described, representing a potential limitation for the design and interpretation of clinical studies. We therefore analysed the outcome of 74 patients with sAML after AZA treatment failure, collected from two Johns Hopkins University trials (J9950 and J0443, n = 14) (Gore et al, 2006; Fandy et al, 2009) and the French AZA compassionate programme (n = 60) (Itzykson et al, 2011). Inclusion criteria were: (i) diagnosis of AML arising from MDS according to the French-American-British classification; (ii) 30% or more bone marrow blasts before AZA onset; (iii) having received at least one cycle of AZA. Details of the methodology and AZA regimens have been previously described (Prebet et al, 2011). A minimum of four cycles was planned for each patient. Cytogenetic risk was assessed according to the European Leukaemia Net classification. Response had been assessed with the International Working Group 2003 criteria (Cheson et al, 2003) and haematological improvements (HI) were also classified as response. Survival was calculated from the date of AZA failure. Disease status at the end of AZA was categorized as primary failure in the absence of any response to AZA (including HI), secondary failure if disease progressed after a first response (loss of HI or bone marrow progression) or AZA intolerance (if AZA was stopped because of adverse events regardless of clinical response). Statistical methods were as previously described (Prebet et al, 2011) and statistical analysis was performed using the R.2.3.0. software (R Development Core Team, Vienna, Austria). Patient characteristics are presented in Table I. Overall, patients had advanced disease, with 70% of the cases having a prior duration of MDS of more than 1 year and high-risk cytogenetics in 27% of the patients (including 14 complex cytogenetics). Fifty-two percent of the patients had received prior therapy before AZA: chemotherapy in 37 patients (low dose cytarabine n = 7, AML-like induction chemotherapy n = 30), and immunomodulatory drugs (n = 2). Thirty-two patients had received another drug in addition to AZA [histone deacetylase (HDAC)] inhibitors (n = 25, valproic acid, phenylbutyrate or entinostat) and chemotherapy (n = 7, anthracyclines and hydroxycarbamide given for cytoreduction on cycle 1). The median number of cycles of AZA was 4; 11 patients (15%) achieved a significant response (including six complete responses) and 12 patients (16%) achieved an HI without significant marrow response. At last follow-up, 66 patients had died, and eight remained alive. Median OS was 3·4 months with a 1-year survival probability of 8% [95% confidence interval (2·3–12·1%), Fig 1A]. There was no impact of age, cytogenetic stratification, bone marrow blast count or AZA treatment-related variables (schedule or duration of exposure). There was a trend for a better OS for patients that were not treated with intensive chemotherapy prior to AZA (median OS 4 months vs. 2·8 months, P = 0·12). Only complex cytogenetics (n = 14) were associated with significantly poorer outcome (median OS 1·9 months vs. 3·9 months for non complex cytogenetics (P = 0·05)). Survival of the present sAML patients following AZA failure was significantly shorter than that of higher risk MDS (median OS = 7·5 months, P = 0·001), but similar to that of refractory anaemia with excess blasts in transformation (i.e. bone marrow blast count between 20% and 29% median OS: 4·1 months, P = NS) we previously reported (Prebet et al, 2011). Information regarding treatment given after AZA failure was available in 39 patients (Fig 1B). Most of the patients were treated with best supportive care (BSC, n = 20) or palliative chemotherapy (n = 6, hydroxycarbamide, 6-mercaptopurine or low dose melphalan). Median survival was 2 months and was not influenced by the need for palliative chemotherapy (data not shown). Thirteen patients (33%) were treated with ‘active’ therapies: none of four patients treated with intensive AML-like chemotherapy responded or could bridge to transplantation (i.e. bone marrow blast count between 20% and 29% median OS 7·7 months). This is in line with a recent report regarding intensive chemotherapy for sAML (Bello et al, 2011), which showed that treatment with hypomethylating agents prior to induction chemotherapy was associated with a poorer outcome. Six patients were treated with other epigenetic agents (decitabine (n = 4) or HDAC inhibitors (n = 2)) but none responded (median survival 11 months). Finally, three patients were treated with allogeneic SCT. None of them received salvage regimens before transplantation. Two of them died of progressive disease after 10 and 11 months, respectively, and one patient was still alive after 14 months. There was a trend for improved survival in the group who received ‘active’ treatments as compared to palliative care (10 months vs. 2 months respectively, P = 0·08, Fig 1B). These results may possibly reflect patient selection bias but also stress the need for clinical trials in that subgroup of patients. Fig 1 (A) Kaplan Meier estimates of the overall survival after azacitidine (AZA) failure for secondary acute myeloid leukaemia. (B) Survival analysis according to the salvage treatment regimen. The curves represent the survival estimates for the cohort of patients. ... Table I Characteristics of the secondary AML patients who failed AZA treatment. This report is the first to specifically address the issue of the outcome of sAML after primary or secondary AZA failure. The median OS of 3·6 months was even poorer than the survival of higher risk MDS in this situation, with a 1-year survival of only 8%. This even worse prognosis also indicates the need for closer monitoring of sAML during AZA treatment. Conventional treatment, such as BSC or cytotoxic drugs, appeared of little benefit for such patients. Besides cytogenetics, no significant pretreatment variable was associated with OS, possibly due to the limited number of patients and/or the dismal outcome in all sub-groups. Our study gives the expected baseline for patients treated with conventional care and will be useful for the design of future clinical trials.

Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine.

Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine

Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia

The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agent, notably azacitidine, constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine, and to a lesser degree azacitidine, induced the activation of checkpoint kinases Chk-1 and Chk-2 and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephoasphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro-apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the reactivation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts.

Outcome of patients with low-risk myelodysplasia after azacitidine treatment failure

Erythropoiesis stimulating agent (ESA) treatment failure is associated with poor prognosis for patients with IPSS[1][1] low and intermediate-1 (‘lower risk’) myelodysplastic syndromes (MDS)[2][2] and, to date, there is no standard treatment option. In this subgroup of patients, disease modifying

Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure

Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0-28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC<13G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1-27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2-5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting.