Patterns of mutations in TP53 mutated AML

TP53 mutated acute myeloid leukemia (AML) responds poorly to chemotherapy and has a short overall survival rate with a median of 5–9 months. Poor outcomes in TP53 mutated AML following chemotherapy have been observed and treatment options remain limited, although the presence of TP53 mutations alone should not be a barrier to therapy. Decitabine is emerging as an alternative treatment option for patients with TP53 mutated AML, although the agent has not been associated with deep molecular remissions and requires additional consolidation. The clinical and genomic characteristics of TP53 mutated AML are reviewed in this paper.     

Choosing induction chemotherapy in therapy-related acute myeloid leukemia

Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.     

Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4⁺ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell–mediated suppression of CD4⁺ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

A normal karyotype (NK) is the most common cytogenetic finding in acute myeloid leukemia (AML) cells at presentation (NK-AML), and has long been associated with an intermediate risk for relapse (1). Although most NK-AML patients achieve a complete remission following standard induction chemotherapy (2, 3), the majority of patients experience relapse within 2 y, and fewer than 10% remain in remission beyond 5 y without an allogeneic transplant (4). Refinements introduced with the European LeukemiaNet (ELN) 2017 criteria (presence or absence of mutations in NPM1, FLT3-ITD, ASXL1, RUNX1, TP53, or biallelic CEBPA mutations) have helped to reclassify some NK-AML patients into the favorable- or adverse-risk group categories. However, the mutational heterogeneity of NK-AML, combined with our limited understanding of the biological consequences deriving from the interplay among mutations, still poses a major challenge for risk stratification at presentation, and for postremission treatment decisions (5, 6).The genetic and epigenetic characteristics of NK-AML patients with very long first remissions (LFRs) have not been defined, and it is not clear whether these patients are living free from disease, or whether they harbor “dormant” AML cells that may be held in check by immune surveillance or cell-intrinsic mechanisms. Predictive algorithms for identifying these very long responders at presentation do not yet exist, but clearance of all AML-associated mutations assessed after induction chemotherapy is strongly associated with prolonged relapse-free survival (RFS) and overall survival (OS) (7–12). Persistent ancestral clones have been detected in patients in complete morphologic remission within the first 2 to 3 y after treatment (13, 14), but similar studies of patients with very LFRs have not yet been described.Most published AML studies have justifiably focused on the mechanisms responsible for treatment failure. However, the reasons for chemotherapy successes are underexplored, even though they hold the potential to uncover determinants that are especially important for excellent outcomes that might be identifiable at presentation. To address this, we have studied two well-matched groups of NK-AML patients that were selected retrospectively for dramatically different outcomes after chemotherapy (long vs. standard first remissions, [SFRs]). In this study, we show that the outcomes of AML patients are not only related to their mutational status, but also to an immunosuppressive phenotype of AML cells at presentation (or lack thereof), a finding that was predicted 50 y ago by Freireich and colleagues (15) and extended in this report.     

Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia

Acute myeloid leukaemia (AML) patients with tumour protein p53 (TP53) mutations are often resistant to chemotherapy and have worse clinical outcomes than patients without TP53 mutations. In this study, we compared clinical outcomes of patients with AML with and without TP53 mutations who underwent haploidentical haematopoietic stem cell transplantation (haplo-HSCT). For the TP53-mutation group and TP53 wild-type group, the 2-year cumulative incidence of relapse (CIR) was (39.0% vs. 21.2% respectively, p = 0.088), the 2-year non-relapse mortality (NRM) rate was (3.2% vs. 8.4% respectively, p = 0.370), the 2-year leukaemia-free survival (LFS) was (57.7% vs. 71.3% respectively, p = 0.205), the 2-year overall survival (OS) rate was (69.9% vs. 81.3% respectively, p = 0.317), the 100-day cumulative incidence of Grade II–IV acute graft-versus-host disease (GvHD) was (6.5% vs. 20.7% respectively, p = 0.074), the 2-year cumulative incidence of chronic GvHD was (52.3% vs. 53.1% respectively, p = 0.493) and the 2-year GvHD-free/relapse-free survival (GRFS) was (57.7% vs. 69.6% respectively, p = 0.347). Our data showed that there were no significant differences in 2-year clinical outcomes between the two groups. Multivariable analysis showed TP53 mutations had no significant impact on CIR, NRM, OS, GvHD, LFS or GRFS. Our findings suggest that patients with AML with TP53 mutations may at least partially benefit from haplo-HSCT. Haplo-HSCT might be the recommended treatment for such patients.     

Dose intensity for induction in acute myeloid leukemia: what,when, and for whom?

Intensive chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML) for decades. However, an increase in novel targeted agents, which has been brought about in part by a deeper understanding of the genetic makeup of AML, has led to remission- inducing regimens that do not require traditional cytotoxic agents. Combinations of a hypomethylating agent (HMA) and venetoclax have doubled the chance of remission for patients considered unfit for induction chemotherapy who would have traditionally been offered singleagent HMA. In fact, this regimen may rival the complete remission rate achieved with induction chemotherapy for certain populations such as the very elderly and those with secondary AML, but equivalency has yet to be established. Further advances include the addition of gemtuzumab ozogamicin and FLT3 inhibitors to induction chemotherapy, which improves survival for patients with core-binding factor and FLT3-mutated AML, respectively. Still, much work is needed to improve the outcomes of the highest-risk subgroups: frail patients and those with high-risk cytogenetics and/or TP53 mutations. Promisingly, the landscape of AML therapy is shifting dramatically and no longer is intensity, when feasible, always the best answer for AML.     

Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia

Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap‐mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N‐RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap‐mutations consisted of class I and class II mutations. Although overlap‐mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap‐mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N‐RAS, TP53, MLL‐PTD, and NPM1, suggesting the possibility that these irregular overlap‐mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation.     

Roles of the bone marrow niche in hematopoiesis,leukemogenesis, and chemotherapy resistance in acute myeloid leukemia

ABSTRACT

Objectives: To summarize the effects of the bone marrow niche on hematopoiesis and leukemogenesis and discuss the chemotherapy resistance that can arise from interactions between the niche and leukemia stem cells.

Methods: We review the major roles of the bone marrow niche in cell proliferation, adhesion and drug resistance. The signaling pathways and major molecular participants in the niche are discussed. We also address potential niche-targeting strategies for the treatment of acute myeloid leukemia (AML).

Results: The bone marrow niche supports normal hematopoiesis and affects acute myeloid leukemia (AML) initiation, progression and chemotherapy resistance.

Discussion: AML is a group of heterogeneous malignant diseases characterized by the excessive proliferation of hematopoietic stem and/or progenitor cells. Even with intensive chemotherapy regimens and stem cell transplantation, the overall survival rate for AML is poor. The bone marrow niches of malignant cells are remodeled into a leukemia-permissive environment, and these reformed niches protect AML cells from chemotherapy-induced cell death. Inhibiting the cellular and molecular interactions between the niche and leukemia cells is a promising direction for targeted therapies for AML treatment.

Conclusions: Interactions between leukemia cells and the bone marrow niche influence hematopoiesis, leukemogenesis, and chemotherapy resistance in AML and require ongoing study. Understanding the mechanisms that underlie these interactions will help identify rational niche-targeting therapies to improve treatment outcomes in AML patients.     

Clinical results and issues of acute myeloid leukemia in elderly patients aged 75 years and older

Aim: Clinical outcomes of acute myeloid leukemia (AML) in elderly patients still remain unsatisfactory and the optimal treatment has yet to be clearly established. This report describes the results of a retrospective study of clinical outcomes and prognostic factors of AML in patients aged 75 years and older. In addition, we aimed to elucidate the situation of patients with AML accompanied by dementia, which has been largely ignored in previous studies. Methods: The subjects consisted of 31 patients with untreated AML (including previous myelodysplastic syndrome: AML/MDS). All patients underwent chemotherapy, with 25 undergoing conventional therapy and six undergoing low‐intensity therapy. Results: Complete remission was obtained in 16 of the 31 cases (51.6%), with a 3‐year survival rate of 11.5%. However, in seven cases, Alzheimer's disease (AD) was observed. Although we were able to perform induction therapy in each of these cases, consolidation therapy was difficult in cases of moderate AD. Conclusion: The results of this study suggest that even very elderly patients can benefit from chemotherapy. However, it is thought that the treatment selection for cases which are complicated by moderate to severe dementia should be determined carefully while considering the patient's quality of life. Geriatr Gerontol Int 2011; 11: 290–296 .     

Comparison of invasive fungal diseases between patients with acute myeloid leukemia receiving posaconazole prophylaxis and those not receiving prophylaxis: A single-center,observational, case-control study in South Korea

Posaconazole prophylaxis is effective in decreasing the incidence of invasive fungal diseases (IFDs) in patients with acute myeloid leukemia (AML). However, the use of antifungal prophylaxis varies in real-life practice, and only a small number of studies have compared the incidence of IFDs between those receiving posaconazole prophylaxis and those without prophylaxis. We compared the clinical characteristics and outcomes of IFDs between patients with AML who received posaconazole prophylaxis and those without antifungal prophylaxis.We reviewed the medical records of adult AML patients who underwent induction chemotherapy between June 2016 and October 2019 at Asan Medical Center (Seoul, South Korea), where posaconazole prophylaxis is not administered in patients with gastrointestinal symptoms that may hinder sufficient absorption of oral prophylactic agents, and in patients with abnormal liver functions considering the possible exacerbation of adverse events. Patients who received posaconazole prophylaxis for ≥7 days were included in the prophylaxis group. Clinical characteristics and outcomes including the incidence of IFDs were compared between the 2 groups.Of the 247 patients with AML who underwent induction chemotherapy, 162 (66%) received posaconazole prophylaxis and 85 (34%) did not receive any prophylaxis. The incidence of proven/probable IFD was significantly higher in the no prophylaxis group than in the prophylaxis group (9.4% [8/85] vs 2.5% [4/162], P = .03). Of the 8 cases of IFDs in the no prophylaxis group, 7 were mold infections and 1 was invasive candidiasis. Of the 4 cases of IFDs in the prophylaxis group, 3 were mold infections and 1 was invasive candidiasis. Patients with posaconazole prophylaxis less frequently received therapeutic antifungal therapy (2.5% vs 9.4%, P = .03) and had a longer median, duration from chemotherapy to antifungal therapy compared with the no prophylaxis group (18 vs 11 days, P < .01). The rate of IFD-related mortality was similar between the 2 groups (0.6% vs 0%, P > .99).Patients with AML who received posaconazole prophylaxis had a lower incidence of breakthrough IFDs compared with those who did not receive any prophylaxis. Invasive mold infection was the most common IFD regardless of antifungal prophylaxis.     

Clinical features and outcomes of hypocellular acute myeloid leukemia in adults: A Korean AML registry data

The hypocellular variant of acute myeloid leukemia (AML) is defined as bone marrow cellularity of <20% in a biopsy specimen at presentation. We performed a retrospective analysis of the clinical features and survival outcomes of hypocellular AML in a Korean population. We reviewed the medical records of all patients diagnosed with AML at nine hospitals participating in the Korean AML registry from 2006 to 2012. Overall survival (OS) and event-free survival (EFS) rates were calculated from the time of diagnosis until death or an event, respectively. In total, 2110 patients were enrolled and 102 (4.8%) were identified as having hypocellular AML. Patients with hypocellular AML were older than those with non-hypocellular AML (median age: 59 vs 49 years; P < .001) and presented with leukopenia more frequently (mean white blood cell count: 5810/μL vs 40549/μL; P < .001). There was no difference between patients with and without hypocellular AML in terms of the presence of antecedent hematologic disorders (5.9% vs 5.3%; P = .809). FLT3-ITD and NPM1 mutations were less common in hypocellular than non-hypocellular AML (FLT3-ITD mutations: 1.2% vs 14.3%, P < .001; NPM1 mutations: 0% vs 9.5%, P = .019). No differences were seen between the hypocellular and non-hypocellular AML groups in the complete remission rate (53.9% vs 61.3%, P = .139) or early death rate (defined as any death before 8 weeks; 14.7% vs 13.0%, P = .629). The OS and EFS did not differ between the hypocellular and non-hypocellular AML groups (median OS: 16 vs 23 months, P = .169; median EFS: 6 vs 9 months, P = .215). Hypocellular AML is more frequently observed in older-aged patients and have fewer FLT3-ITD and NPM1 mutation, but the clinical outcomes of hypocellular AML do not differ from those of non-hypocellular AML.     

The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.     

Expression level and prognostic potential of beta-catenin–interacting protein in acute myeloid leukemia

Inhibitor of beta-catenin and TCF (ICAT) is a key protein in the Wnt-β-catenin signaling pathway. However, its role in acute myeloid leukemia (AML) remains unknown. In this study, we evaluated its expression level as well as its prognostic value in AML patients. A total of 72 patients with AML and 30 control subjects were enrolled in this study during the period of January 2017 and December 2019 at Zhongshan Hospital of SunYat-sen University. ICAT and β-catenin expression levels in peripheral blood were determined via enzyme-linked immunosorbent assays. ICAT levels in AML patients were significantly lower and β-catenin levels were higher than those of the control group. After the first course of standard chemotherapy, the concentration of ICAT in the partial remission group (93.79 ng/mL) was significantly higher than that in the initial diagnosis group (49.38 ng/mL) and the no response group (39.94 ng/mL). AML subtypes had lower ICAT expression levels than controls, and ICAT levels were significantly correlated with body mass index, bone marrow/peripheral blood blast cell proportions, and white blood cell and red blood cell counts at initial diagnosis. Furthermore, low ICAT expression was found to be associated with poor disease-free survival and overall survival in AML. ICAT is closely associated with AML progression and can be used as an indicator to monitor AML treatment efficacy.     

APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells

Background: APR‐246 belongs to a new generation of the compounds that restore normal p53 function in cells with mutated or wild type p53. The purpose of this study was to examine the effects of APR‐246 alone and in combination with other drugs in acute myeloid leukemia (AML) cells. Methods: Primary leukemic cells from patients with AML and AML cell lines were studied with respect to cytotoxic and apoptotic effects and mechanism of action of APR‐246, alone and in combination with Ara‐C, daunorubicin and fludarabine. Results: APR‐246 showed dose‐dependent cytotoxic and apoptotic effects in AML cell lines as well as in primary AML patient cells. Cells from patients with TP53 mutation and complex karyotype were more resistant to conventional drugs while these factors did not significantly affect the sensitivity to APR‐246. APR‐246 increased active caspase‐3, upregulated p53 protein levels, and increased the bax/bcl‐2 ratio independently of TP53 mutational status in patient cells sensitive to APR‐246. AML cells with high p14^ARF expression were significantly more sensitive to APR‐246. APR‐246 induced significant synergistic effects in combination with conventional chemotherapeutic agents. Pre‐incubation with APR‐246 induced more synergistic effects compared to other schedules. In patient cells, pronounced synergism was found when combining APR‐246 with danuorubicin. Conclusion: We conclude that APR‐246 is effective in AML cells irrespectively of TP53 mutational status and that it has promising properties for combination studies in AML.     

Kinetics and apoptotic profile of circulating endothelial cells as prognostic factors for induction treatment failure in newly diagnosed acute myeloid leukemia patients

The circulating endothelial cells (CEC) are proposed to be a noninvasive marker of angiogenesis. Recent data suggest that endothelial cells may enhance the survival and proliferation of leukemic blasts and mediate chemotherapy resistance in acute myeloid leukemia (AML). We analyzed CEC count by the four-color flow cytometry in AML and healthy subjects. We evaluated the kinetics of mature CEC, both resting (rCEC) and activated (aCEC), as well as progenitor (CEPC) and apoptotic CEC (CEC^AnnV+) in AML patients treated with standard chemotherapy and their influence on response to treatment and overall survival. We found significantly higher numbers of aCEC, rCEC, CEPC, and CEC^AnnV+ in AML patients than in healthy controls. The elevated CEPC and absolute blood counts in peripheral blood as well as the low CEC^AnnV+ number were associated with higher probability of induction treatment failure. aCEC, rCEC, CEPC, and CEC^AnnV+ counts determined in complete remission (CR) were significantly lower than those found at diagnosis. In those CR patients, a significant decrease in the CEC count and increase in the number of CEC^AnnV+ were observed already 24h after the first dose of chemotherapy. In refractory AML, the aCEC, rCEC, CEPC, and CEC^AnnV+ counts assessed before and after induction chemotherapy did not differ significantly, and a significant decrease in CEC count and increase in CEC^AnnV+ number were noted only after the last dose of chemotherapy. The number of CEC is significantly higher in AML patients than in healthy subjects and correlates with response to treatment. The evaluation of CEC kinetics and apoptotic profile may be a promising tool to select AML patients with poor response to chemotherapy who may benefit from antiangiogenic therapies.     

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML.Myeloproliferative neoplasms (MPNs) are hematopoietic disorders characterized by clonal proliferation of mature myeloid elements which manifest clinically as an excess of RBC [polycythemia vera (PV)], platelets [essential thrombocytosis (ET)], or WBC [primary myelofibrosis (PMF)] (1). Mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF (2–6), underscoring the importance of activated JAK–STAT signaling to the pathogenesis of chronic-phase MPN. Despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). Leukemic transformation occurs in 1%, 4%, and 20% of patients over a 10-y period in ET, PV, and PMF, respectively (7). MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo (8). Advanced age (>60 y) and exposure to chemotherapy increase the risk of leukemic transformation; however, the mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. Importantly, the use of standard AML therapies, including induction chemotherapy, has not been shown to improve outcome for patients with post-MPN AML (8, 9). These data indicate a need for new models and improved therapeutic approaches to improve outcomes for patients who have transformed from MPN to AML and to identify genetic lesions associated with leukemic transformation.Genetic studies of paired samples before and after leukemic transformation have suggested there are at least two distinct routes for leukemic transformation. Some patients who present with a JAK2/MPL-positive MPN progress to JAK2/MPL-positive AML that is associated with the acquisition of additional genetic alterations (10–13). A second, more complex route to AML from MPN has been described in which a JAK2/MPL-positive MPN is followed by JAK2/MPL-negative AML (14, 15). Clonality studies using X-chromosome inactivation in informative females demonstrated that JAK2/MPL-positive MPN and JAK2/MPL-negative AML are clonally related, consistent with transformation of an antecedent, preJAK2/MPL-mutant clone which can progress to AML. As such, there is a need to elucidate better the mutations that govern the two divergent pathways that lead to leukemic transformation.Recent candidate gene studies have begun to improve our understanding of the somatic mutations that contribute to transformation from MPN to AML. These data suggest that post-MPN AML has a somatic mutational spectrum that is distinct from that observed in de novo AML. JAK2V617F mutations are relatively rare in de novo AML (16), and AML patients with JAK2V617F mutations almost always have a history of an antecedent MPN (17). The most common mutations observed in de novo AML, including nucleophosmin (NPM1), DNMT3A, and FMS-like tyrosine kinase-3 (FLT3), are largely absent from post-MPN AML (10). SNP array analysis of post-MPN AML patients has identified recurrent gains and losses involving chromosomes 8, 12, 17, and 21, which contain MYC, ETV6, tumor protein 53 (TP53), and RUNX1, respectively (18, 19). Candidate gene studies have identified specific, recurrent point mutations that are more common in post-MPN AML than in de novo AML, including mutations in tet methylcytosine dioxygenase 2 (TET2), serine/arginine-rich splicing factor 2 (SRSF2), TP53, and isocitrate dehydrogenase 1/2 (IDH1/2) (10–13). These genetic data suggest post-MPN AML is molecularly distinct from de novo AML.In this study we used high-throughput sequence analysis to characterize the somatic mutational spectrum of post-MPN AML and used these genetic data to develop a genetically accurate murine model of leukemic transformation. We demonstrate that loss of Tp53 in combination with expression of JAK2V617F results in the development of post-MPN AML. This leukemia is transplantable and is enriched for blasts expressing markers consistent with hematopoietic stem and progenitor cell populations, particularly megakaryocyte/erythroid progenitors (MEPs). In vitro and in vivo studies reveal therapeutic liabilities that can be used to inform the development of novel therapies for patients with in post-MPN AML. These data collectively reveal novel insights into the pathogenesis of leukemic transformation and demonstrate new potential therapeutic strategies for this disease.     

Acute myeloid leukemia in the elderly: conventional and novel treatment approaches

Acute Myeloid Leukemia (AML) is a disorder affecting primarily elderly individuals and poses significant treatment challenges. Much has been learned about the underlying immunologic, cytogenetic and molecular features of AML in recent years, and many features have been identified that portend a poor prognosis for elderly patients with newly diagnosed AML. Despite this, treatment outcomes for elderly patients remain poor for both newly diagnosed and relapsed disease. While conventional treatment approaches may be appropriate for some elderly patients, the vast majority do not tolerate intensive chemotherapy well, thus alternative strategies have been investigated. Here we review both conventional and novel treatment approaches for elderly patients with AML, including agents in early clinical trials. Treatment options have been divided into several discussions, including conventional treatments, agents complementary to conventional treatments, alternatives to conventional induction therapies, post-induction treatment, and relapsed disease. Current and developing research focuses upon identifying subgroups of patients that benefit more from specific chemotherapeutic agents. Treating elderly patients with AML requires an organized, multidisciplinary approach, taking into account individual patient characteristics, preferences, and comorbidities when formulating treatment plans.     

TP53 mutation in patients with high‐risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation

Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse‐risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three‐year probabilities of overall survival (OS) and event‐free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53‐mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.     

TP53 and therapy-related myeloid neoplasms

Therapy-related myeloid neoplasms (t-MNs) are the most serious late complications in patients treated with traditional cytotoxic chemotherapy and/or radiation. T-MNs are aggressive and chemorefractory hematologic malignancies, with a median survival of less than 6 months. TP53 mutations are highly enriched in t-MN patients, though the mechanism for this selective enrichment has only come to light over the past several years. In this review, we discuss the history and function of p53, and the role of TP53 mutations in the origin and progression of t-MNs. Emerging data has begun to elucidate who may be at highest risk of developing t-MNs, which ideally will enable us to develop preventative strategies for this devastating disease. As t-MNs may not be avoidable, novel therapies are urgently needed for this patient group and are underway as exemplified by recent investigation in restoring wild-type p53 function as well as directly targeting TP53 mutant variants. With better prevention and treatment, outcomes will hopefully begin to improve in the near future.     

Two Cases of Secondary Acute Myeloid Leukemia Accompanying Adult T-Cell Leukemia/Lymphoma

We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.     

Research on the clinical effect and in vitro study of HLA-mismatched hematopoietic stem cell infusion for acute myeloid leukemia

Abstract

Purpose

The treatment for acute myeloid leukemia (AML) remains an important clinical problem. Recently, hematopoietic stem cell therapy provides promising outcomes. In this study we examined the clinical effect of HLA-mismatched hematopoietic stem cell infusion combined with chemotherapy as a postremission therapy to improve the survival and reduce the graft-versus-host disease (GVHD).

Method

Thirty patients who achieved complete remission were divided into two groups and received different therapeutic regimes. Patients in combined therapy group received stem cell infusion with the chemotherapy. The patients' clinical indexes were monitored in both groups to evaluate therapy responses. Furthermore, the collected cells used in the therapy were also tested for their tumoricidal activity toward U937 cell lines.

Results

The combined therapy exhibited an improved effect than conventional chemotherapy. There were no delays in hematopoietic recovery and GVHD after the intense treatment. This method prolonged the 2.5-year disease-free survival as well as overall survival, and increased the therapeutic effect for patients in good/intermediate prognosis. Moreover, the donor microchimerism was detected in four female patients who had male donors. The experimental study revealed that HLA-mismatched hematopoietic stem cell could induce U937 cells death and the tumoricidal activity enhanced proportionally with the increase in effector-target ratio.

Conclusion

HLA-mismatched hematopoietic stem cell infusion combined with chemotherapy improved the clinical outcomes and prevented severe GVHD. This comprehensive treatment can be used as a potential postremission therapy for AML.