Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study.

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.

[Clonal haematopoiesis: A concise review]. / L'hématopoïèse clonale : un concept émergent à la croisée des spécialités.

Clonal hematopoiesis of undetermined significance or CHIP describes the identification, in individuals without hematologic disease, of one or more somatic mutations in hematopoietic cells. These mutations, detected by high-throughput genes sequencing (Next-Generation Sequencing or NGS), affect genes first identified in acute myeloid leukemia or myelodysplastic syndrome, such as DNMT3A, TET2 and ASXL1. CHIP is associated with an increased risk of malignant hemopathy, both myeloid and lymphoid, evaluated from 0.5 to 1% per year. CHIP is also associated with an increased risk of overall mortality and cardiovascular diseases. CHIP detection using NGS is currently limited to basic science field, but recent studies suggest that it may be of clinical interest.

Use of 5-azacitidine for therapy-related myeloid neoplasms in patients with concomitant active neoplastic disease.

BACKGROUND: Patients diagnosed with therapy-related myeloid neoplasms (TRMN) with concomitant active neoplastic disorder (CAND) are usually proposed for best supportive care (BSC). We evaluated the feasibility of using 5-azacytidine (AZA) in this setting. METHODS: All patients referred to Gustave Roussy between 2010 and 2015 for TRMN diagnosis (less than 30% blast) and eligible for AZA treatment were included. Patients with CAND proposed for BSC were also described. Patient's outcomes were analyzed based on the presence or not of a CAND. RESULTS: Fifty-two patients with TRMN were analyzed, including 19 patients with CAND (14 eligible for AZA) and 33 without CAND eligible for AZA. The 5 patients with CAND ineligible for AZA had a worst performance status (p=0.016) at diagnosis and a shorter overall survival (OS) (0.62 months). Baseline characteristics of patients eligible for AZA were similar in the 2 groups except a trend for best performance status in patients with CAND (p=0.06). Overall response rate (71.4% vs 60.3%), transfusion independence (50.0% vs 45.5%) and OS (12.7 months vs 10.8 months) were similar between patients with and without CAND respectively (p=ns). CONCLUSION: Here we report the feasibility and efficacy of AZA for selected patients with TRMN and a CAND.

SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-ß signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia.

PURPOSE: The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. PATIENTS AND METHODS: We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500ng/mL were considered as under dosed. RESULTS: Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003). CONCLUSION: This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML.

Discontinuation of empirical antibiotic therapy in neutropenic acute myeloid leukaemia patients with fever of unknown origin: is it ethical?

Based on recommendations of the ECIL-4, we prospectively evaluated discontinuation of empirical antibiotic therapy in high-risk neutropenic acute myeloid leukaemia patients with fever of unknown origin. Seven patients (median neutropenia duration 30 days) were included. Four of them remained afebrile but quickly recovered from neutropenia. The other three had rapid recurrent fever. Two of these three patients had bacteraemia with susceptible strains and one of them was transferred to the ICU for septic shock. Median duration of sparing of antibiotics for the seven patients was 3 days (2-4). Because of these limited results the study was stopped.

Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia.

The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro-apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects.

Allogeneic stem-cell transplantation with fludarabine and 2-Gy TBI-based conditioning regimen for chronic hematological malignancy: a study of 25 consecutive patients and a literature review.

We analyzed the outcome of 25 consecutive patients with chronic hematological malignancy who underwent allogeneic stem-cell transplantation conditioned with fludarabine (30 mg/m2/day, thrice) and total body irradiation (2 Gy). All patients received peripheral blood stem cells from an HLA-identical sibling donor. With a median follow-up of 769 days (range, 244 - 1231), the estimated 2-year overall survival (OS), event-free survival (EFS), transplantation-related mortality and relapse rates were 53%, 45%, 27%, and 39%, respectively. All patients had initial engraftment. Acute Grade II - IV graft-versus-host disease (GVHD) was recorded in 14 patients (56%), including 7 (28%) with Grade III - IV GVHD. Sixteen of the 23 patients (70%) who survived more than 100 days developed chronic GVHD. OS and EFS were adversely influenced by acute Grade III - IV GVHD (p < 0.001 and p = 0.033, respectively), but chronic GVHD seemed to favorably influence these two parameters (p = 0.03 and p < 0.001, respectively). Patients with full-donor chimerism at day 30 had lower relapse rates, as did those who received high-dose allogeneic CD8+ lymphocytes with their graft (p = 0.026). Collectively, these results provide a framework for refining nonmyeloablative conditioning, to improve outcome with an acceptable risk of GVHD.

A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy.

CC-chemokine receptor 7 (CCR7), a chemokine receptor required for transmigration into lymphoid organs, is only expressed by naive and central memory T cells. T cells with a capacity of homing into lymphoid organs can initiate acute graft-versus-host disease (GVHD) in mice and respond vigorously in vitro to alloantigens in humans, but their impact on clinical outcomes is unknown. We evaluated prospectively the distribution of naive, central memory and CCR7neg memory T-cell subsets in 39 bone marrow and 23 granulocyte colony-stimulating factor-mobilized peripheral blood stem cell allografts and investigated their impact on patient outcomes. Ranges of the relative proportions of CCR7+ cells within CD4+ and CD8+ T-cell populations were broad, but did not differ between the two sources of allografts. By multivariate analysis, high percentage of donor-derived CD4+CCR7+ T cells (>73.5%) significantly correlated with incidence, earliness of onset and severity of acute GVHD, conferring the highest adjusted hazard ratio (HR=3.9; 95% confidence interval 1.4-10.8; P=0.008) without interfering in other clinical events, especially chronic GVHD and relapse. Determination of the percentage of CD4+CCR7+ T cells in the graft provides a predictive indicator of acute GVHD. Partial depletion of this subset may reduce the risk of acute GVHD while preserving immunotherapeutic effects.

[Thalidomide: mechanisms of action and new insights in hematology]. / Thalidomide: mécanismes d'action et indications en hématologie.

Purpose. - Thalidomide, a major teratogen drug, was rehabilitated mainly in malignant hemopathy. Current knowledge and key points. - Thalidomide-mechanisms of action are well known, multiple, they combine immunomodulatory, antiangiogenic properties, and the modulation of cytokines, particularly tumour necrosis factor-alpha. Multiple trials are ongoing, however, the main indication remain multiple myeloma with a response rate of 30% in relapsed patients. Future prospects and projects. - New structural analogues of the thalidomide which priviligiate some of the thalidomide-specific mechanisms of action, the selected cytokine inhibitory drugs (SelCIDS) and the immunomodulatory drugs (IMiDs) family are under evaluation. The IMiDs, which mechanism is based on stimulation of T lymphopoiesis rather than inhibition of tumour necrosis factor-alpha, are under clinical trials in multiple myeloma with interesting results.