Overlapping features of therapy-related and de novo NPM1-mutated AML.

NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of "therapy-related" NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.

Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment.

Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.

Performance of Mucorales spp. qPCR in bronchoalveolar lavage fluid for the diagnosis of pulmonary mucormycosis.

To estimate the diagnostic performance of Mucorales polymerase chain reaction (PCR) in Bronchoalveolar lavage fluid (BALF) in routine practice. This was a single-center retrospective study including all consecutive patients >18 years who underwent Mucorales PCR assay in BALF between January 2021 and May 2022. Index testing was prospectively performed using the MycoGENIE Aspergillus spp.-Mucorales spp. PCR. The reference was the diagnosis of pulmonary mucormycosis by the Adjudication Committee. Mucorales PCR in BALF was performed for 938 patients and was positive for 21 of 938 (2.2%). Eleven pulmonary mucormycosis (including one disseminated) were diagnosed. Among them, one (9.1%) was classified as proven mucormycosis, three (27.3%) as probable, and seven (63.6%) as possible according to the EORTC/MSGERC 2019 criteria. The main host factor was hematological malignancy (10 of 11, 90.9%). Mucorales PCR was positive in serum for eight patients (72.7%). Three patients had positive PCR in BALF, but negative in serum. The mean cycle threshold value was significantly lower in mucormycosis than false-positive cases. Sensitivity was 72.7% (95% confidence interval [CI], 43.4-90.3%), and specificity was 98.6% (95% CI, 97.6-99.2%). The positive and negative predictive values were 38.1% (95% CI, 20.8-59.1%) and 99.7% (95% CI, 99.1-99.9%), respectively. Mucorales PCR in BALF showed good diagnostic performance for mucormycosis, particularly in combination with serum PCR. A positive result should be interpreted with caution, given the possibility of carriage in the airway. However, its high negative predictive value and specificity suggest the utility of Mucorales PCR in BALF in the diagnosis of pulmonary mucormycosis.

A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.

VANDA regimen followed by blinatumomab leads to favourable outcome in patients with Philadelphia chromosome-negative B-precursor acute lymphoblastic leukaemia in first relapse.

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia (R/R BCP-ALL) have very poor outcome. Blinatumomab as single agent has shown activity in R/R BCP-ALL. We aimed to assess the activity of blinatumomab in concomitant association with intensive chemotherapy. Seventeen patients with R/R BCP-ALL were treated with combination of blinatumomab and VANDA (etoposide, cytarabine, mitoxantrone, dexamethasone and asparaginase) regimen. Complete remission (CR) was achieved in 14/17 patient (82%) and 11/17 (65%) were transplanted. One-year leukaemia-free survival was 58.8% for the whole cohort and 90.9% for transplanted patients. These preliminary data suggest that the VANDA-blinatumomab salvage regimen leads to a very high rate of CR and HSCT in suitable patients.

Conventional chemotherapy for acute myeloid leukemia in older adults: Impact on nutritional, cognitive, and functional status.

OBJECTIVES: The impact of conventional treatment for acute myeloid leukemia (AML) on the nutritional, cognitive, and functional status of elderly patients is seldom studied. This assessment was performed in the context of the LAMSA 2007 trial. METHODS: The trial enrolled 424 patients with de novo AML. Among them, 316 benefited from geriatric assessment (GA) including nutritional, cognitive, and functional status and were scored according to Eastern Cooperative Oncology Group (ECOG) and sorror for the prediction of treatment toxicity, morbidity, and mortality. Patients were investigated at diagnosis for three times during follow-up. RESULTS: This study showed that AML and its treatment have no impact on cognitive (P = .554) nor functional status (P = .842 for Activity of Daily Living and P = .087 for Instrumental Activities of Daily Living). The nutritional status improved over time (P = .041). None of these three parameters at baseline, associated or not with ECOG and sorror scores, impacted survivals or toxicities. CONCLUSIONS: The cognitive, functional, and nutritional status had no impact in this cohort of fit elderly AML patients without unfavorable cytogenetics. The GA tools used provided no additional information compared with ECOG and sorror scores, to predict toxicity, morbidity, or mortality due to intensive chemotherapy.

Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial.

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m2 of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms.

BACKGROUND: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients. METHODS: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34+ cells with lentiviral vectors encoding the pri-miR-10a precursor. RESULTS: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. CONCLUSIONS: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.

Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT.

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

BACKGROUND: Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. METHODS: From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. RESULTS: Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). CONCLUSIONS: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study.

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution.

CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.

A tyrosine kinase network composed of the TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib-resistance of chronic myeloid leukaemia (CML) cells. Here, we show that the E3-ubiquitin ligase CBL down-regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL in K562 cells increases AXL and LYN protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL in nilotinib-resistant K562 cells (K562-rn) dramatically reduces AXL and LYN expression and resensitizes K562-rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34(+) cells. Mechanistically, the E3-ligase CBL counteracts AXL/SYK signalling, promoting LYN transcription by controlling AXL protein stability. Surprisingly, the role of AXL in resistance was independent of its ligand GAS6 binding and its TK activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML cells.

Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

Prognostic value of postinduction medullary myeloid recovery by flow cytometry in acute myeloid leukemia.

Risk stratification and treatment response evaluation are key features in acute myeloid leukemia (AML) management. Immunophenotypic and molecular approaches all rely on the detection of persisting leukemic cells by measurable residual disease techniques. A new approach is proposed here by assessing medullary myeloid maturation by flow cytometry through a myeloid progenitor ratio (MPR). The normal MPR range was defined using reference normal bone marrows (n = 48). MPR was considered balanced if between 1 and 4 and unbalanced if < 1 or > 4. MPR was retrospectively assessed at baseline and post-induction for 206 newly diagnosed AML patients eligible for intensive treatment from two different French centers. All AML baseline MPR were unbalanced and thus significantly different from normal MPR (p < 0.0001). Patients with an unbalanced MPR after induction had worse 3-year overall survival (OS) (44.4% vs. 80.2%, HR, 2.96; 95% CI, 1.81-4.84, p < 0.0001) and 3-year relapse free survival (RFS) (38.7% vs. 64.4%, HR, 2.11; 95% CI, 1.39-3.18, p < 0.001). In multivariate analysis, postinduction unbalanced MPR was significantly associated with shorter OS and RFS regardless of the European LeukemiaNet 2010 risk stratification or NPM1/FLT3-ITD status. A balanced postinduction MPR conversely conferred favorable outcomes and reflects medullary myeloid recovery.

Molecular relapse after first-line intensive therapy in patients with CBF or NPM1-mutated acute myeloid leukemia - a FILO study.

Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved first complete remission (CR) to detect morphologic relapse and drive preemptive therapy. How to best manage these patients is unknown. We retrospectively analyzed 303 patients with CBF and NPM1-mutated AML, aged 18-60 years, without allogeneic hematopoietic cell transplantation (HCT) in first CR, with molecular monitoring after first-line intensive therapy. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse (53 received preemptive therapy and 42 progressed to morphologic relapse at salvage therapy), and 55 (18%) had upfront morphologic relapse. Patients who received preemptive therapy had higher OS than those who received salvage therapy after having progressed from molecular to morphologic relapse and those with upfront morphologic relapse (three-year OS: 78% vs. 51% vs. 51%, respectively, P = 0.01). Preemptive therapy included upfront allogeneic HCT (n = 19), intensive chemotherapy (n = 21), and non-intensive therapy (n = 13; three-year OS: 92% vs. 79% vs. 58%, respectively, P = 0.09). Although not definitive due to the non-randomized allocation of patients to different treatment strategies at relapse, our study suggests that molecular monitoring should be considered during follow-up to start preemptive therapy before overt morphologic relapse.

Dismal outcome of refractory or relapsing patients with myelodysplasia-related acute myeloid leukemia partially alleviated by intensive chemotherapy.

BACKGROUND: Acute myeloid leukemia (AML) with myelodysplasia-related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate- or adverse-risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. METHODS: A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63-year-old) with what was called at the time AML-MRC has been explored, and data are reported here. RESULTS: Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1-5.6) with a mean 1-year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. CONCLUSIONS: These data, reporting about an ill-explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.

Artificial intelligence-based prediction models for acute myeloid leukemia using real-life data: A DATAML registry study.

We designed artificial intelligence-based prediction models (AIPM) using 52 diagnostic variables from 3687 patients included in the DATAML registry treated with intensive chemotherapy (IC, N = 3030) or azacitidine (AZA, N = 657) for an acute myeloid leukemia (AML). A neural network called multilayer perceptron (MLP) achieved a prediction accuracy for overall survival (OS) of 68.5% and 62.1% in the IC and AZA cohorts, respectively. The Boruta algorithm could select the most important variables for prediction without decreasing accuracy. Thirteen features were retained with this algorithm in the IC cohort: age, cytogenetic risk, white blood cells count, LDH, platelet count, albumin, MPO expression, mean corpuscular volume, CD117 expression, NPM1 mutation, AML status (de novo or secondary), multilineage dysplasia and ASXL1 mutation; and 7 variables in the AZA cohort: blood blasts, serum ferritin, CD56, LDH, hemoglobin, CD13 and disseminated intravascular coagulation (DIC). We believe that AIPM could help hematologists to deal with the huge amount of data available at diagnosis, enabling them to have an OS estimation and guide their treatment choice. Our registry-based AIPM could offer a large real-life dataset with original and exhaustive features and select a low number of diagnostic features with an equivalent accuracy of prediction, more appropriate to routine practice.