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Acute myeloid leukemia (AML) can manifest as de novo AML (dn‐AML) or secondary AML (s‐AML), with s‐AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next‐generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s‐AML, which PPM1D was more frequently associated with therapy‐related AML (t‐AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s‐AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn‐AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s‐AML vs. FLT3, TP53 and U2AF1 in dn‐AML). Age and sex‐related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s‐AML compared to dn‐AML could be due to the older age of s‐AML patients and more poor‐prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers. [ABSTRACT FROM AUTHOR]

Abstract Background Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. Case presentation The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. Conclusions To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.

Background: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. Case presentation: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. Conclusions: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPNs), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal stem cell disorders defined by an excessive production of functionally mature and terminally differentiated myeloid cells. MPNs can transform into secondary acute myeloid leukemia (sAML/blast phase MPN) and are linked to alterations in the redox balance, i.e., elevated concentrations of reactive oxygen species and markers of oxidative stress (OS), and changes in antioxidant systems. We evaluated OS in 117 chronic phase MPNs and 21 sAML cases versus controls by measuring total antioxidant capacity (TAC) and 8-hydroxy-2′-deoxy-guanosine (8-OHdG) concentrations. TAC was higher in MPNs than controls (p = 0.03), particularly in ET (p = 0.04) and PMF (p = 0.01). MPL W515L-positive MPNs had higher TAC than controls (p = 0.002) and triple-negative MPNs (p = 0.01). PMF patients who had treatment expressed lower TAC than therapy-free subjects (p = 0.03). 8-OHdG concentrations were similar between controls and MPNs, controls and sAML, and MPNs and sAML. We noted associations between TAC and MPNs (OR = 1.82; p = 0.05), i.e., ET (OR = 2.36; p = 0.03) and PMF (OR = 2.11; p = 0.03), but not sAML. 8-OHdG concentrations were not associated with MPNs (OR = 1.73; p = 0.62) or sAML (OR = 1.89; p = 0.49). In conclusion, we detected redox imbalances in MPNs based on disease subtype, driver mutations, and treatment history. [ABSTRACT FROM AUTHOR]

Background: AIDS-related NK/T-cell lymphoma is a rare subtype of AIDS-related lymphomas, characterized by a poor prognosis and lack of standardized treatment protocols. To date, there have been no reported cases of AIDS-associated NK/T-cell lymphoma in remission followed by treatment-related acute myeloid leukemia (t-AML), where both the lymphoma and AML achieved remission and long-term survival through chemotherapy alone. Case presentation: We report a case of a patient diagnosed with AIDS-related extra-nodal NK/T-cell lymphoma (ENKTCL). The patient achieved complete remission after receiving six cycles of chemotherapy, local radiotherapy, and combination antiretroviral therapy (cART). Throughout the follow-up period, the patient continued cART treatment, maintaining an HIV-RNA level below the lower limit of detection. However, 70 months later, the patient developed new symptoms and was subsequently diagnosed with acute myeloid leukemia (AML) M4 subtype. Following the completion of 10 cycles of chemotherapy and ongoing cART, the patient achieved complete remission of AML, with an overall survival time exceeding 103 months from the initial ENKTCL diagnosis. Conclusions: This case highlights the effectiveness of chemotherapy combined with cART in the treatment of AIDS-associated NK/T-cell lymphoma and secondary treatment-related leukemia. This approach may serve as a viable option for patients who are not candidates for bone marrow transplantation. Furthermore, this case underscores the importance of long-term follow-up in the management of AIDS-associated malignancies.

Objective To explore the effect of vemurafenib (VEM) combined with chidamide (CDM) on cellular senescence in secondary acute myeloid leukemia (sAML). Methods sAML cell lines SKM-1 and MOLM-13 were divided into control group (sAML cells), VEM group (sAML cells treated with VEM), CDM group (sAML cells treated with CDM), and COM group (sAML cells treated with VEM combined with CDM)(n=3). CCK-8 assay was used to measure the viability of sAML cells. Immunofluorescence assay was used to verified the cellular senescence of sAML cells. Flow cytometry was used to detect cell cycle and apoptosis of sAML cells. Network pharmacology and RT-qPCR were used to analyze and verify the mechanism of VEM combined with CDM. Results VEM inhibited the proliferation of sAML cells lines in a time- and dose-dependent manner(P < 0.05), the half-maximal inhibitory concentration (IC50) of VEM on SKM-1 and MOLM-13 cells was 24.15±1.18 and 11.30±0.38 μmol/L(P < 0.0001), respectively. VEM (SKM-1: 1/3 IC50-VEM, MOLM-13: 1/2 IC50-VEM) combined with CDM synergistically promoted sAML cellular senescence by upregulating TRF2 and Lamin B1, characterized cycle stagnation in G0/G1 phase(P < 0.05), inhibiting cell proliferation(P < 0.01) and promoting cell apoptosis (P < 0.05). Swiss Target Predict, TargetNe, SEA and PharmMapper discovered the core targets and signaling pathways of VEM collaborating with CDM. RT-qPCR verified that VEM collaborated with CDM to promote senescence of sAML cells through inhibiting PI3K-AKT and MAPK signaling pathways(P < 0.05). Conclusion VEM combined with CDM can induce cellular senescence of sAML cells by downregulating PI3K-AKT and MAPK signaling pathways, inhibiting proliferation and promoting apoptosis of sAML cells. VEM combined with CDM might be a new regime for patients with sAML.

Abstract We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p

Simple Summary: CPX-351 has been approved for the treatment of adults with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML–MRC). The aim of this retrospective study was to evaluate the absolute infectious risk in a real-life setting of 200 AML patients treated with this drug. A total of 249 febrile events were recorded in 336 courses of CPX. The attributable mortality–infection rate in our series was 6%, confirming a good safety profile for CPX-351, with an incidence of infectious complications comparable to that of the pivotal studies. The only factor that was significantly associated with mortality in the multivariate analysis was the lack of response to CPX-351 treatment. In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality–infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01–0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality. [ABSTRACT FROM AUTHOR]

Objective: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder with a high propensity to develop into acute myeloid leukemia (AML). Although abnormal microRNA expression has been implicated in MDS, the exact role of miR-181a-2-3p has not been entirely elucidated. Here, we investigated miR-181a-2-3p levels in bone marrow (BM), and described its utility as a potential indicator for MDS diagnosis and prognosis.Methods: We evaluated miR-181a-2-3p expression in BM samples of 54 newly diagnosed MDS cases, 16 sAML patients and 32 healthy donors and then assessed its association with clinical characteristics and its potential value for MDS diagnosis and prognosis.Results: Compared with healthy controls, miR-181a-2-3p levels were decreased in the total cohort of MDS patients. Additionally, in MDS patients with secondary AML (sAML), miR-181a-2-3p was over-expressed relative to levels in those without this form. The areas under the curve of receiver operating characteristic curves were 0.700 and 0.750 to distinguish MDS patients from controls and sAML from newly diagnosed MDS, respectively. Kaplan–Meier analysis showed a positive correlation between miR-181a-2-3p expression and overall survival (OS). Further, multivariate analysis indicated that miR-181a-2-3p was an independent prognostic index for MDS with respect to OS.Conclusion: Decreased miR-181a-2-3p expression in MDS patients may be considered as one of the underlying markers reflecting MDS progression and prognosis.

We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML. [ABSTRACT FROM AUTHOR]

Background. Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods. The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). Results. The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion. S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of combined application of chidamide (CDM) and mycophenolate mofetil (MMF) on the proliferation of secondary acute myeloid leukemia (sAML) cells. Methods Chronic myeloid leukemia blast-phase cell line K562 and myelodysplastic syndromes (MDS)-transformed leukocyte line SKM-1 were employed in the study. The cells were divided into groups according to different concentrations of intervention drugs: CDM alone groups (0.25, 0.5, 1, 2 and 4 μmol/L), MMF alone groups (0.5, 1, 2, 4 and 8 μmol/L) and combined drug groups (CDM∶MMF=1∶2), respectively. The inhibitory rate of cell proliferation was detected by CCK-8 assay after treatment for 24, 48 and 72 h, respectively. Moreover, the changes of cell cycle and apoptotic rate were determined by flow cytometry after 72 h of intervention under the optimal combined drug concentration, and its mechanism was analyzed by network pharmacology. Results CCK-8 assay showed that the combination index of the combined drug group (1 μmol/L CDM+2 μmol/L MMF) was 0.389 44 in K562 cells and 0.630 98 in SKM-1 cells. When compared with the CDM and MMF monotherapy groups, the combined treatment significantly enhanced the inhibitory effect on the proliferation of both K562 and SKM-1 cells (P < 0.01), and increased the apoptotic rate of K562 cells (P < 0.05). As compared with the MMF alone group, the combination group remarkably arrested the cell cycle at the G0/G1 phase, though which had no statistical difference with CDM alone. Subsequently, a drug-disease target protein-protein interaction (PPI) network including 66 nodes and 222 edges was constructed through network pharmacology, and 9 core targets including CDK1, CDK2, CDK4, CDK6, CDK9, SYK, BTK, KDR, and PIK3CB were screened out according to topology. Enrichment analysis indicated that various biological processes such as protein phosphorylation, cell proliferation, and apoptosis regulation were mainly involved, as well as PI3K-AKT, FOXO and other signaling pathways. Conclusion CDM combined with MMF significantly inhibits the growth of sAML cells.

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder with a high propensity to develop into acute myeloid leukemia (AML). Although abnormal microRNA expression has been implicated in MDS, the exact role of miR-181a-2-3p has not been entirely elucidated. Here, we investigated miR-181a-2-3p levels in bone marrow (BM), and described its utility as a potential indicator for MDS diagnosis and prognosis. We evaluated miR-181a-2-3p expression in BM samples of 54 newly diagnosed MDS cases, 16 sAML patients and 32 healthy donors and then assessed its association with clinical characteristics and its potential value for MDS diagnosis and prognosis. Compared with healthy controls, miR-181a-2-3p levels were decreased in the total cohort of MDS patients. Additionally, in MDS patients with secondary AML (sAML), miR-181a-2-3p was over-expressed relative to levels in those without this form. The areas under the curve of receiver operating characteristic curves were 0.700 and 0.750 to distinguish MDS patients from controls and sAML from newly diagnosed MDS, respectively. Kaplan–Meier analysis showed a positive correlation between miR-181a-2-3p expression and overall survival (OS). Further, multivariate analysis indicated that miR-181a-2-3p was an independent prognostic index for MDS with respect to OS. Decreased miR-181a-2-3p expression in MDS patients may be considered as one of the underlying markers reflecting MDS progression and prognosis. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by the presence of cytopenias, ineffective hematopoiesis and frequent transformation into secondary acute myeloid leukemia (secAML). Recent genomic studies provide unprecedented insight into the molecular landscape of clonal proliferation in MDS. Genetic diversity of both MDS and secAML subclones cannot be defined by a single somatic mutation. Mutations of the founding clone may survive over implemented chemotherapy and allogenic hematopoietic cell transplantation (alloHCT), but new subclonal mutations may also appear. Next generation sequencing (NGS) makes it possible to define the mutational profile of disease subclones during the treatment course and has a potential in pre- and post-alloHCT monitoring. Understanding the molecular pathophysiology of MDS may soon allow for monitoring the course of disease and personalized treatment depending on the mutational landscape. In the present paper we report, for the first time in MDS, ASXL1 c.1945G>T, TET2 c.4044+2dupT and c.4076G>T sequence variants. Moreover, we detected RUNX1 c.509-2A>C and SF3B1 c.1874G>T sequence variants. Furthermore, we verify the clinical utility of NGS and pyrosequencing in MDS and secAML.

Keywords: Secondary acute myeloid leukemia; overall survival; daunorubicin; cytarabine; Haploidentical allogeneic stem cells transplantation EN Secondary acute myeloid leukemia overall survival daunorubicin cytarabine Haploidentical allogeneic stem cells transplantation 1355 1357 3 08/08/23 20230701 NES 230701 Acute myeloid leukemia (AML) is a heterogeneous disease characterized by an excessive proliferation of myeloid precursors in the blood and the bone marrow. However, a few studies have pointed out a greater risk of t-MDS/AML as a late complication of PRRT/peptide receptor chemo radionuclide therapy. Concomitant radiosensitizing chemotherapy with PRRT/PRCRT still plays an important debulking role in NEN patients with high disease burden or biologically aggressive disease, thus t-AML will continue to remain an important issue, particularly in this group of patients. [Extracted from the article]

Simple Summary: Studies addressing the economic costs and burden of secondary acute myeloid leukemia (sAML) are scarce in the literature. We analyzed this topic in a real-life population of sAML patients between 60–75 years receiving intensive chemotherapy induction. In elderly patients with sAML and intensive regimens, it entails an increase in costs and a longer hospital stay. In these specific patients, almost a third of the time is spent hospitalized after the diagnosis of sAML. There are no studies with this type of population and diagnosis, which gives added value to the results obtained. Pharmacoeconomic studies in patients with AML are being carried out due to the need to evaluate the cost-effectiveness of new oral drugs, therapeutic schemes with higher costs than previous treatments. Background: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. Methods: A retrospective review of medical charts identified patients aged 60–75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain. [ABSTRACT FROM AUTHOR]

Background. Secondary malignancies in pediatric cancer survivors is an actual problem in modern oncopediatry. Alkylating agents and topoisomerase II inhibitors used for primary tumors treatment, induce secondary acute myeloid leukemia (sAML), which treatment results are unsatisfactory.Objective. By predicating on literature and own data to evaluate clinical and biologic features and therapeutic potential of pediatric sAML.Materials and methods. Six patients (age 7–16 years) with sAML were enrolled the study from June 1998 to December 2016. Follow up until September 2020. Primary tumors, which therapy could induce sAML were acute lymphoblastic leukemia, Burkitt lymphoma, germ cell tumor, osteosarcoma, nephroblastoma.Results and conclusion. From 6 patients, included in the study, 2 are alive (+58 and +67 months after allogenic stem cell transplantation), that match global data. Fludarabine-containing regimens and allogeneic hematopoietic stem cell transplant could be a method of choice for this unfavorable group of patients.

The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; P = .04). Our data support the use of hypomethylating agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings.

Background: AIDS-related NK/T-cell lymphoma is a rare subtype of AIDS-related lymphomas, characterized by a poor prognosis and lack of standardized treatment protocols. To date, there have been no reported cases of AIDS-associated NK/T-cell lymphoma in remission followed by treatment-related acute myeloid leukemia (t-AML), where both the lymphoma and AML achieved remission and long-term survival through chemotherapy alone., Case Presentation: We report a case of a patient diagnosed with AIDS-related extra-nodal NK/T-cell lymphoma (ENKTCL). The patient achieved complete remission after receiving six cycles of chemotherapy, local radiotherapy, and combination antiretroviral therapy (cART). Throughout the follow-up period, the patient continued cART treatment, maintaining an HIV-RNA level below the lower limit of detection. However, 70 months later, the patient developed new symptoms and was subsequently diagnosed with acute myeloid leukemia (AML) M4 subtype. Following the completion of 10 cycles of chemotherapy and ongoing cART, the patient achieved complete remission of AML, with an overall survival time exceeding 103 months from the initial ENKTCL diagnosis., Conclusions: This case highlights the effectiveness of chemotherapy combined with cART in the treatment of AIDS-associated NK/T-cell lymphoma and secondary treatment-related leukemia. This approach may serve as a viable option for patients who are not candidates for bone marrow transplantation. Furthermore, this case underscores the importance of long-term follow-up in the management of AIDS-associated malignancies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by the presence of cytopenias, ineffective hematopoiesis and frequent transformation into secondary acute myeloid leukemia (secAML). Recent genomic studies provide unprecedented insight into the molecular landscape of clonal proliferation in MDS. Genetic diversity of both MDS and secAML subclones cannot be defined by a single somatic mutation. Mutations of the founding clone may survive over implemented chemotherapy and allogenic hematopoietic cell transplantation (alloHCT), but new subclonal mutations may also appear. Next generation sequencing (NGS) makes it possible to define the mutational profile of disease subclones during the treatment course and has a potential in pre- and post-alloHCT monitoring. Understanding the molecular pathophysiology of MDS may soon allow for monitoring the course of disease and personalized treatment depending on the mutational landscape. In the present paper we report, for the first time in MDS, ASXL1 c.1945G>T, TET2 c.4044+2dupT and c.4076G>T sequence variants. Moreover, we detected RUNX1 c.509-2A>C and SF3B1 c.1874G>T sequence variants. Furthermore, we verify the clinical utility of NGS and pyrosequencing in MDS and secAML. [ABSTRACT FROM AUTHOR]

Purpose of Review: Despite recent advances in the treatment of de novo acute myeloid leukemia (AML), AML arising from antecedent chronic myelomonocytic leukemia (CMML) continues to have dismal outcomes. While the unique biological drivers of CMML and subsequent leukemic transformation (LT) have been revealed with advances in molecular characterization, this has not yet translated to the bedside. Here, we review these biologic drivers, outcomes with current therapies, and rationale avenues of future investigation specifically in blast phase CMML (CMML-BP). Recent Findings: CMML-BP outcomes are studied as an aggregate with more common categories of AML with myelodysplasia-related changes (AML-MRCs) or the even broader category of secondary AML (sAML), which illustrates the crux of the problem. While a modest survival advantage with allogeneic hematopoietic stem cell transplant exists, the difficulty is bridging patients to transplant and managing patients that require an allograft-sparing approach. Limited data suggest that short-lived remissions can be obtained employing CPX-351 or venetoclax-based lower intensity combination therapy. Promising future strategies include repurposing cladribine, exploiting the supportive role of dendritic cell subsets with anti-CD123 therapies, MCL-1 inhibition, dual MEK/PLK1 inhibition, FLT3 inhibition in RAS-mutated and CBL-mutated subsets, and immune therapies targeting novel immune checkpoint molecules such as the leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune-modulatory transmembrane protein restrictively expressed on monocytic cells. Summary: The successful management of an entity as unique as CMML-BP will require a cooperative, concerted effort to design and conduct clinical trials dedicated to this rare form of sAML. [ABSTRACT FROM AUTHOR]

Despite continuous attempts to improve therapy, the outcomes of acute myeloid leukemia remain almost unchanged over last decades. Drugs made with a more complete understanding of the biology of acute myeloid leukemia do not equal the hopes for better prognosis. The best results are achieved only with high-dose chemotherapy, which is only possible for a limited number of patients. High phenotypic and genotypic heterogeneity of acute myeloid leukemia defines the relevance to develop personalized approaches to therapy, including those based on determination of individual drug sensitivity of blast cells.This article presents the results of developing an ex-vivo model of acute myeloid leukemia, as well as testing of two in vitro sensitivity assessment methods: evaluation of the genotoxicity of drugs in the micronucleus test and vitality and sensitivity to chemotherapy in sorted blast cells. Prospects of individualized therapy of acute myeloid leukemia were determined based on introduction into clinical practice and continuing the research.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038. [ABSTRACT FROM AUTHOR]

Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival. [ABSTRACT FROM AUTHOR]

A novel KMT2A-USO1 fusion gene-induced de novo secondary acute myeloid leukaemia in a patient initially diagnosed with acute promyelocytic leukaemia Keywords: secondary acute myeloid leukemia; acute promyelocytic leukemia; KMT2A-USO1; clonal evolution; pre-leukemic event EN secondary acute myeloid leukemia acute promyelocytic leukemia KMT2A-USO1 clonal evolution pre-leukemic event e32 e36 5 12/21/20 20210101 NES 210101 The question whether secondary acute myeloid leukaemia (sAML) originates from a newly acquired or pre-existing clone has not been resolved for decades. Most cases of sAML are generally considered as therapy-related leukaemia,1 especially those with chromosomal translocations at 11q23 that involve the I KMT2A i gene (also known as I MLL i ).2,3 Here, we describe a 62-year-old male who was initially diagnosed with acute promyelocytic leukaemia (APL) carrying t(15;17)(q24;q21)/ I PML-RAR i . We found that KMT2A-USO1 also harboured the common characteristics of KMT2A fusions in significantly upregulating HOXA cluster genes ( I HOXA9 i and I HOXA10 i ) and the HOX coregulator gene I PBX3 i (Fig 1F). [Extracted from the article]

Secondary acute myeloid leukemia (sAML) is a high-risk AML evolving from heterogenous prior hematological disorders. Compared to de novo AML, sAML has even worse responses to current therapy and thus is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed. Recent research has identified that CLL1 is highly expressed on AML leukemia stem cells and blasts cells but not on normal hematopoietic stem cells. In this case report, we treated a secondary AML patient with anti -CLL1 CAR-T therapy and achieved morphological, immunophenotypic and molecular complete remission for over 10 months. Although only one successful case is presented here, the anti-CLL1 CAR T-cells should be considered as another treatment option for secondary AML in the future.

Secondary acute myeloid leukemia (sAML) is a high-risk AML evolving from heterogenous prior hematological disorders. Compared to de novo AML, sAML has even worse responses to current therapy and thus is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed. Recent research has identified that CLL1 is highly expressed on AML leukemia stem cells and blasts cells but not on normal hematopoietic stem cells. In this case report, we treated a secondary AML patient with anti -CLL1 CAR-T therapy and achieved morphological, immunophenotypic and molecular complete remission for over 10 months. Although only one successful case is presented here, the anti-CLL1 CAR T-cells should be considered as another treatment option for secondary AML in the future. [ABSTRACT FROM AUTHOR]

Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and prognostication of the disease. Treatment has typically consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "7 + 3" regimen. Attempts have been made to improve on this regimen with modest improvements in response rates but no change in overalll survival, until the recent introduction of mutation-specific agents. However, the re-vamping of the delivery of both daunorubicin and cytarabine in a liposomal encapsulation, known as CPX-351, did show improvements of overall survival compared to traditional 7 + 3 in newly diagnosed secondary and therapy-related AML in patients aged 60–75. This led to the Food and Drug Administration (FDA) approval of the agent for both of these subtypes of AML in August of 2017. Herein we will review the rationale and preclinical development of CPX-351 and discuss the pivotal studies that led to its FDA approval. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a disease of the elderly population and survival remains poor after failure of hypomethylating agents (HMA). The BCL‐2 inhibitor venetoclax demonstrated activity as monotherapy and in combination with chemotherapy or HMA in AML. In this case series, patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA were treated with venetoclax within a named patient program at our tertiary cancer center in Salzburg, Austria. Between April 2017 and September 2018, seven patients with sAML received venetoclax therapy. Two out of seven patients achieved a complete remission upon venetoclax initiation with a PFS of 505 days and 352 days and another patient achieved complete peripheral blood blast clearing within nine days after start of venetoclax. Among the venetoclax responders, primary refractory disease to prior HMA therapy was documented, 2 patients harbored IDH1/IDH2 mutations and one patient had an antecedent myeloproliferative neoplasm. High BCL‐2 and/or BIM expression in myeloblasts was found in venetoclax responders and response was significantly associated with overall survival (responders: 364 days versus non‐responders: 24 days, P = 0.018). Venetoclax monotherapy is safe and is able to induce durable responses in elderly patients with secondary AML after treatment failure with HMA. [ABSTRACT FROM AUTHOR]

Abstract Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS , KRAS , PTPN11 , FLT3), mutations in genes more commonly observed in AML (NPM1 , WT1 , IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation. [ABSTRACT FROM AUTHOR]

The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) in multiple myeloma (MM) survivors using the Surveillance Epidemiology and End Results (SEER) Research Plus 9 database. To identify 64,753 cases of MM which included 136 cases with sAML; these patients were juxtaposed with patients with de novo AML from the same database. Younger MM patients who received chemotherapy (ChT) had a higher sAML risk. The novel agent era saw a decreased sAML incidence (0.15% vs. 0.26%) and shorter latency period (median: 56 vs. 66 months, P =0.031). Compared to de novo AML, sAML patients were older (median age 69 vs. 68 years, P =0.027), less likely to receive ChT (51.9% vs. 67.4%, P <0.001), and had inferior overall survival (OS) (median OS: 2 vs. 5 months, P <0.001). Multivariate Cox regression revealed that younger diagnosis age, diagnosis after 2003, and ChT were associated with prolonged OS in sAML patients. Clinicians should be aware of the sAML risk in younger, intensively-treated MM patients. Given the poor sAML prognosis compared to de novo AML, clinical trials of novel therapies based on age, geriatric assessment, and cytogenetic features are warranted., Competing Interests: None., (AJCR Copyright © 2023.)

Background: The phase III trial that led to the approval of CPX-351 for treating secondary acute myeloid leukemia (sAML) in 2017 did not study the effect of specific mutations on outcomes., Methods: This retrospective study was done to evaluate the effect of next-generation sequencing (NGS) results at the time of best response and before allogeneic stem cell transplant (alloSCT) in patients treated with CPX-351 as frontline therapy for sAML between 2017 and 2021., Results: The most common mutations seen were DNMT3A (n = 17, 29.8%), SRSF2 (n = 13, 22.8%), RUNX1 (n = 13, 22.8%), TET2 (n = 9, 15.8%), ASXL1 (n = 9, 15.8%), and BCOR (n = 9, 15.8%). Median OS (mOS) for the entire cohort was 47 months. Though 64.7% patients cleared the DNMT3A mutation, only 44.4% and 22.2% of patients cleared the TET2 and ASXL1 mutations, respectively. The mOS for patients who cleared their mutations vs. for those who did not was not significantly longer (46 vs. 30 months; P = .991). The relapse-free survival (RFS) for patients who cleared mutations was numerically longer compared to those who had persistent mutations; however, this did not reach statistical significance (44 months vs. 26 months; P = .786)., Conclusion: This is the first study reporting NGS at best response and before alloSCT and its effect on OS and RFS. We found that OS and RFS were numerically longer among patients who cleared mutations; however, this did not reach statistical significance. In addition, alloSCT led to improved RFS irrespective of mutational clearance., Competing Interests: Disclosures AGJ, SB, DL, LEA, KT: No conflicts of interest to declare. OC: Research Funding: Syntrix Pharmaceuticals. EP: Research Funding: Bristol Myers Squibb, Syntrix Pharmaceuticals, Kura, Incyte; Honoraria: Taiho, Stemline, Blueprint. AK: Research Support: Protagonist, Blueprint Medicines Corporation, GSK - Sierra Oncology, Prelude Pharmaceuticals, Bristol Myers Squibb, Morphosys; Consultancy: Imago Biosciences, Incyte, Blueprint Medicines Corporation, Novartis, Abbvie, GSK - Sierra Oncology, Bristol Myers Squibb, Pharmaessentia, CTI Biopharma; Honoraria: Imago Biosciences, Incyte, Blueprint Medicines Corporation, Novartis, Abbvie, GSK - Sierra Oncology, Bristol Myers Squibb, Pharmaessentia, CTI Biopharma; Speakers Bureau: Imago Biosciences, Incyte, Blueprint Medicines Corporation, Novartis, Abbvie, GSK - Sierra Oncology, Bristol Myers Squibb, Pharmaessentia, CTI Biopharma. RK: Consultancy: Servier, AbbVie, Geron, Acceleron Pharma, Taiho Oncology, Novartis, Jazz Pharmaceuticals, Bristol Myers Squibb; Honoraria: Servier, AbbVie, CTI BioPharma, Innovent, PharmaEssentia, Takeda, Jazz Pharmaceuticals, Bristol Myers Squibb; Speakers Bureau: Servier, AbbVie, Jazz Pharmaceuticals; Advisory board: CTI BioPharma, Taiho Oncology, PharmaEssentia, Takeda, Novartis, Bristol Myers Squibb; Speakers Bureau: Bristol Myers Squibb; Research Funding: Bristol Myers Squibb. DAS: Advisory Board: Intellia, Aprea, Syndax, Bristol Myers Squibb, Nemucore, Agios, AbbVie, Kite, Shattuck Labs, Novartis; Consultancy: Takeda, Novartis, Magenta; Speakers Bureau: Bristol Myers Squibb, Incyte; Research funding: Aprea, Syntrix Pharmaceuticals; Patents & Royalties: Lixte. JEL: Consultancy: Dedham Group, Jasper Therapeutics, Astellas, Dava, Oncology, Novartis, Agios/Servio, Boxer Capital, Jazz, BerGenBio, Millenium Pharma/Takeda, ElevateBio Management, Daiichi Sankyo, AbbVie, Servier; Research Funding: Syntrix Pharmaceuticals, Celgene/ Bristol Myers Squibb. KS: Consultancy: Pfizer, Mablytics, berGenBio, Curis, Novartis, Gilead Sciences, Inc, AROG, Astellas, Bristol Myers Squibb; Advisory board: Pfizer, berGenBio, Curis, Novartis, Gilead Sciences, Inc, AROG, Astellas, Bristol Myers Squibb; Research funding: Pfizer, Syntrix Pharmaceuticals, Incyte; Honoraria: Mablytics, berGenBio, Curis, Novartis, Gilead Sciences, Inc, AROG, Astellas, Bristol Myers Squibb., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25–35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest promising outcomes with FLAG. We conducted a single-center, retrospective cohort study assessing outcomes in treatment-naïve patients with sAML treated with fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG, n = 40) compared with 7 + 3 (n = 66). Median patient age was 63 years (range: 27–82) in the FLAG group and 60 years (range: 21–76) in the 7 + 3 group ( P   =  0.968). Patients treated with FLAG achieved higher overall response rates (CR + CRi + MLFS) compared to 7 + 3 (70% vs. 48%, P   =  0.043). FLAG was well tolerated, with only one induction death (30-day mortality rate, 3% vs. 8%, P  = 0.405) and no cases of cerebellar toxicity. Duration of neutropenia was significantly shorter with FLAG (median 16 vs. 23 days, P <  0.001). Half of the FLAG-treated patients proceeded to consolidative therapy compared with only 27% of those who received 7 + 3 ( P  = 0.022). Overall survival was comparable between groups (8.5 mos, FLAG vs . 9.1 mos, 7 + 3; P   =  0.798). Thus, FLAG may represent a low-cost treatment strategy in sAML that produces higher response rates and promising survival outcomes with minimal treatment-related toxicity. Further studies are required to prospectively compare FLAG to the newly FDA-approved CPX-351 in sAML. [ABSTRACT FROM AUTHOR]

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The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation. [ABSTRACT FROM AUTHOR]

Approximately 5–10% of patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprising of essential thrombocythemia, polycythemia vera and primary myelofibrosis) experience transformation to acute myeloid leukemia (AML, ≥20% blasts). Treatment options for post-MPN AML patients are limited, as conventional approaches like standard chemotherapy, fail to offer long-term benefit. Median survival for secondary AML is ∼2.4 months. Post-MPN AML therefore represents an area of urgent clinical need. At present, allogeneic stem cell transplant (ASCT) following induction therapy is the best therapeutic option. Patients ineligible for ASCT are treated with hypomethylating agents. New agents under investigation include histone deacetylase inhibitors, JAKinhibitors and agents targeting the BRD4 protein. Combined treatment strategies involving these novel agents are being tested. In this review we present the current evidence regarding treatment options for post-MPN AML patients. [ABSTRACT FROM AUTHOR]