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We evaluated prognostic factors in 83 intensively treated adult patients with NPM1 mutated AML. Targeted next-generation sequencing revealed high frequency of co-mutations in epigenetic modifiers or proliferation pathways. NPM1 minimal residual disease (MRD), assessed in bone marrow by specific polymerase chain reaction after one chemotherapy course, was >0.01% in 50 patients considered poor responders (PR). On multivariate analysis, including all variables with a p value <.1 on univariate analysis, age >60, performance status (PS) ≥1, presence of FLT3 mutations, DNMT3A-R882, and PR status, were independently associated with lower leukemia-free survival. Age >60, a previous hematological disease and PR status were independent negative predictive factors for overall survival. In our study, early NPM1 MRD was confirmed as an important prognostic factor. All FLT3 and DNMT3A-R882 mutations have also an independent prognostic value. We support the rational for in-depth investigations for a better approach in patients who achieving a first complete remission. [ABSTRACT FROM AUTHOR]

Patients received a median of one line of treatment (range, 1-4) prior to IDHi therapy and three patients had already received a first allo-SCT. No patients received IDHi as maintenance therapy after allo-SCT; four patients received a prophylactic treatment with azacitidine. There were no treatment-related deaths (one patient, treated with ivosidenib, developed a differentiation syndrome which evolved favourably after appropriate treatment and three patients developed a grade III-IV infection during IDHi treatment). Five patients had sequential conditioning (chemotherapy with broad antitumour activity followed by reduced-intensity conditioning regimen) and two patients had reduced-intensity conditioning.12 All patients had a haploidentical donor. [Extracted from the article]

Background: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes. [ABSTRACT FROM AUTHOR]

The benefit associated with chemotherapy in older patients with acute myeloid leukemia (AML) is debated. The prognostic impact of molecular mutations in these patients is unknown. We identified 79 patients with AML aged 75 years or over. Forty-two received chemotherapy and 37 supportive care only. In intensively treated patients, overall survival was longer (p< 0.001). Achieving complete remission was associated with longer survival (p< 0.001). NPM1 mutations tended to be associated with a higher complete remission rate (p = 0.12). In multivariate analysis, FLT3-ITD was associated with poorer survival (p = 0.049). Patients harboring FLT3-ITD and no NPM1 mutation had a poorer prognosis than others (p = 0.02). Intensive treatments can benefit a portion of elderly patients. FLT3-ITD and NPM1 mutational status might be useful for prognosis stratification. [ABSTRACT FROM AUTHOR]

Background: Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the Pgp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts. Methods: The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test. Results: Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp. Conclusion: These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients. [ABSTRACT FROM AUTHOR]

This retrospective study assessed the prognostic factors associated with early and long-term outcome in consecutive patients with acute myeloid leukaemia (AML) admitted to the intensive care unit (ICU) over a 9-year period. A total of 83 patients were studied (age 48 ± 16 years), among whom 60% were neutropenic on admission. For 68%, admission occurred within the first month following diagnosis of AML. The main reason for ICU admission was an acute respiratory disease in 82% of cases. Mechanical ventilation (MV) was required in 57% of patients. In-ICU mortality was 34%. Among patients discharged alive from ICU, 49% died within a year after discharge. Factors significantly associated with in-ICU death in multivariate analysis were simplified acute physiology score II and need for invasive MV (IMV). Age, performance status, AML3 subtype and complete remission were significantly associated with 1-year survival. Patients with acute respiratory failure initially supported with non-invasive MV had significantly better ICU outcome than patients initially supported with IMV. In conclusion, ICU admission is justified for selected patients with AML. The ICU mortality rate is highly predictable by the acute illness severity score. A 1-year survival is predicted by haematological prognostic factors. [ABSTRACT FROM AUTHOR]

We investigated whether etoposide might be a suitable alternative to anthracyclins for the treatment of elderly patients with acute myeloid leukemia (AML) in whom anthracyclins are contraindicated. In total, 88 patients over 60 years old were treated in our department between 1988 and 2000 for de novo or secondary AML. Of these 88 patients, 21 had severe cardiac disease and received a combination of etoposide and cytosine arabinoside (group A). They were compared with 23 patients who received daunorubicin plus cytosine arabinoside (group B) and 44 patients who received mitoxantrone, cytosine arabinoside and etoposide (group C). In group A, the complete remission (CR) rate was 33% (7/21), median disease-free survival (DFS) was 365 days and median overall survival (OS) was 214 days. These results were not statistically different from those for the anthracyclin-based regimens (CR 43%, DFS 210 days, OS 150 days for group B and CR 47%, DFS 216, OS 295 days for group C). Moreover, there was no significant difference in the number of treatment-related toxic events and deaths in the 3 treatment groups. Etoposide combined with a standard dose of cytosine arabinoside is relatively safe and effective in elderly patients with AML and offers an alternative approach to patients with cardiac contraindications to anthracyclin treatment. [ABSTRACT FROM AUTHOR]

Summary. Following the recommendations of the European Group for the Immunological Characterization of Leukaemias (EGIL) in 1995, few reports have been published comparing enzyme cytochemistry (EC) and flow cytometry (FC) for the detection of myeloperoxydase (MPO) in acute myeloid leukaemia (AML). The EGIL guidelines defined MPO positivity in FC, by the presence of this enzyme in 10% or more of the blast cells. We studied 136 adult patients with the systematic use of both EC and FC, using a 3% threshold for positivity for EC, and 10% and 3% consecutively for FC. FC was less sensitive than EC using the currently recommended threshold of 10%, but a 3% cut-off showed more sensitivity and was superior to EC. The joint use of both techniques identified 14 discordant patients (positive in FC/negative in EC or vice versa), all of whom displayed at least one poor-prognosis biological factor, which correlated with a mediocre clinical result. In conclusion, we recommend that the cut-off for a positive MPO value should be lowered to 3%, and suggest that the concomitant use of FC and EC is a fast clinically relevant prognostic tool. [ABSTRACT FROM AUTHOR]

Out of 75 consecutive elderly AML patients who did not receive anti-leukemic treatment (52pts) or failed to respond to differentiating agent (23pts), 6 patients had survivals of 13.2 to 98 months with treatment restricted to supportive care. This cut-point is far longer than the median survival of the 235 elderly patients (3.5mo.), either untreated (med. survival: 1mo.) or treated (with treatment ranging from conventional induction to palliative chemotherapy) (4mo.), admitted to our department within the same period of time. These cases of smoldering AML (4 women, 2 men) were all of AML2 FAB subtype (4 de novo, 2 post MDS) and presented with a significantly better performance status, lower WBC and circulating blast counts, higher platelet counts and with lower bone marrow infiltration than AML cases with more rapid progression. Cytogenetical analysis when available (3pts) showed normal karyotypes and clonogenic assay performed in 3 of these patients showed a lack of (2pts) or reduced in vitro leukemic cell growth (1pt). The identification of specific characteristics of smoldering leukemia in the elderly might be an important development in the understanding of the physiopathology of acute leukemia and a tool for helping decision-making when selecting the time and intensity of cytotoxic treatment in these older patients. [ABSTRACT FROM AUTHOR]

Body Mass Index (BMI) prognosis in acute myeloid leukaemia (AML) is unknown. Capping chemotherapy dose at 2 m 2 of body surface area (BSA) is used without any rationale. We assessed whether both of them could be correlated with outcome in 233 AML patients. Thirty three percent were overweight, 10% obese and BSA over 2 m 2 was observed in 15%. BMI and BSA > 2 m 2 were not associated with OS ( p = 0.16; p = 0.39), nor with DFS ( p = 0.18; p = 0.42), nor with CR. OS-associated factors were age ( p < 0.001), cytogenetic ( p = 0.002), FLT3-ITD ( p = 0.01). BMI and chemotherapy dose capping are not pejorative factors on intensively treated AML patients. [ABSTRACT FROM AUTHOR]

The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML. [ABSTRACT FROM AUTHOR]