Acute myeloid leukemia: Highlights from the annual meeting of the EHA

<p class="article-intro">Outcomes in Acute Myeloid Leukemia (AML) have improved but remain suboptimal, especially in older patients. To improve outcomes the field is moving towards the addition of targeted agents to cytotoxic chemotherapy. Elucidating specific and unique targets to specifically eliminate AML cells remains a big challenge compared to targeting antigens on the B-cell lineage. Nevertheless, new leukemia specific drugs acting against a specific mutation or epigenetic factors are the focus of current clinical AML trials in addition to personalized treatments involving immune and cellular strategies.</p> <p class="article-content"><div id="keypoints"> <h2>Keypoints</h2> <ul> <li>Nowadays, not only morphologic, immunophenotypic and cytogenetic, but also molecular markers are relevant for the classification and prognosis of patients with AML and especially also for targeted therapy.</li> <li>The number of cytogenetic and molecular aberrations increases with the age of AML patients and a different spectrum of cytogenetic and molecular aberrations is found in older than younger patients with AML.</li> <li>New and highly promising therapeutic options of FLT3 and IDH1/2 inhibitors catapult such predictive markers in the front line of the molecular diagnostic algorithm.</li> </ul> </div> <h2>Essential parameters at diagnosis</h2> <p>Today, cytogenetic and molecular analyses are essential to classify the subtype of leukemia since such aberrations are associated with prognosis and prediction of therapeutic responses and they can be used to monitor residual disease and potential relapses during follow-up. Enormous progress has been made to assess the cytogenetic and molecular heterogeneity of AML.<br /> Cytogenetics and molecular analyses revealed that the mutational profile of older patients differs significantly from the one of younger patients. With increasing age an increased proportion of patients have complex karyotypes and a higher frequency of poor prognostic gene mutations such as ASXL1, RUNX1 and TP53. In addition, mutations in epigenetic modifiers (TET2, ASXL1 and DNMT3A) as well as in the enzymes IDH1 and IDH2 are more frequent. The latter are now attractive targets for the treatment with IDH inhibitors. On the other hand, mutations in signaling genes, such as FLT3, are more frequent in younger patients and led to the development of FLT3 inhibitors.<br /> While cytomorphology and conventional cytogenetics remains the cornerstone at diagnosis of AML, in the era of new therapeutic agents, molecular screening with next generation sequencing (NGS) is now becoming part of standard practice.<br /> Molecular screening for FLT3 and IDH1/2 mutations as well as for mutations in the genes of NPM1, CEBPA, RUNX1, ASXL1, TP53, TET2 and DNMT3A and CBF translocations including RUNX1-RUNX1T1 and CBFb-MYH11 is recommended at diagnosis.^{1, 2} To combine early on targeted inhibitors to standard chemotherapy a fast turnaround time (within 3&ndash;7 days) of results is important.<br /> There are several methods to detect FLT3 mutations, fragment length analysis (FA), next generation sequencing (NGS) approaches and new tools such as karyogene, a method that combines cytogenetic and molecular testing in a single assay.³ Each one of these methods has its advantages and disadvantages in terms of turnaround times, sensitivity and development stage. FA has been first applied in FLT3 mutation testing and is widely used in clinical trials, as it has fast turnaround times (48&ndash;72h), but their limitation is that only a few FLT3-TKD point mutations are detected unless the PCR products are sequenced. NGS allows the analysis of multiple genes simultaneously as well as the detection of rare mutations, but comes at the prize of large amounts of data, sometimes difficult for interpretation and with a longer turnaround time and, in the case of FLT3 ITDs, may not detect large ITDs.<br /> The need of fast detection of FLT3 mutations makes FA more widely used in clinics, however, the great potential of multiple mutations screening with NGS will become part of standard practice in the near future.</p> <h2>How to evaluate responses</h2> <p>Measurable residual disease (MRD) became pivotal in AML. MRD negativity as assessed by multiparametric flow cytometry is highly prognostic in young patients with AML.⁴ Likewise, achieving an MRD negative status after a hypomethylating agent in older AML patients reduces risk of relapse.⁵ MRD positive AML patients have poor outcomes even with allogeneic hematopoietic stem cell transplantation (HSCT). Early post HSCT MRD assessment (on day 30) allows detecting patients with better or worse responses and can guide in the process of decision for further treatment.⁶<br /> The European Leukemia Net (ELN) recommendations for MRD² propose that morphology based complete remission (CR) should be refined with assessment of MRD by multiparametric flow cytometry (which is informative in ~90 % of AML patients). Molecular MRD assessment for mutant NPM1, RUNX1-RUNX1T1, CBFb- MYH11, PML-RARA is recommended at informative clinical time points, such as after induction, after consolidation and at the end of treatment as well as every 3 months for 24 months in peripheral blood and in bone marrow. For allogeneic HSCT, MRD by multiparametric flow cytometry should be assessed before and after transplantation. All trials should require MRD assessment by multiparametric flow cytometry and, nowadays also molecularly, at all time points of evaluation. So far, there are no defined time points for follow- ups beyond 2 years after CR; patients with high risk of relapse should be monitored more closely.</p> <h2>Targeted therapy in AML</h2> <p><strong>First-line treatment</strong></p> <p><em>Patients with FLT3 mutations</em><br /> FLT3-ITD and FLT3-TKD mutations both lead to activation of FLT3 tyrosine kinase, making these gene mutations a potential therapeutic target. There are some differences in the mechanisms of activation of the FLT3 receptor. FLT3-ITD mutations occur in the juxtamembrane region, which exerts a negative regulatory function over the kinase receptor, while FLT3-TKD are point mutations in the activation loop of the kinase domain, resulting in a less aberrant signaling. These differences in activation mechanisms may account for their biological and clinical differences. FLT3 mutations are of the most frequent somatic mutations in AML. FLT3-ITD occur in approximately 23 % ⁷ while FLT3-TKD mutations in 7 % of newly diagnosed patients with AML.<br /> While the prognostic value of FLT3- TKD mutations remains controversial, FLT3-ITD mutations are associated with poor prognosis due to highest rates of relapse. It is also important to notice that these driver mutations are predictive for chemoresistance and relapse, but so far they have been poor MRD markers. The reason for this is that there is great patient- to-patient heterogeneity in terms of FLT3-ITD length, insertion site and allelic ratio (mutant to wild-type FLT3-ITD), and FLT3 ITDs may be unstable during the course of the disease. However, with the development of new PCR and NGS-based methods, FLT3 mutations will also become a suitable MRD marker in the near future.<br /> The FLT3-ITD ratio is a context-dependent prognostic marker that conveys an intermediate or poor prognosis in the absence or presence of other markers.² It is also a predictive factor with respect to allogeneic-HCT in first CR.⁸ In a retrospective study, patients with high FLT3- ITD mutant to wild-type allelic ratio (&ge;0,51) benefited most from allogeneic HSCT with respect to relapse-free survival (RFS) and overall survival (OS), while patients with low allelic ratio did not improve in RFS and OS.<br /> FLT3-ITD mutations are often associated with a normal karyotype (approximately 2/3 of patients with FLT3 mutations have a normal karyotype), a higher white blood cell count and a higher percentage of bone marrow blasts. Furthermore, they are associated with translocations such as t(15;17), t(6;9) and NPM1 and DNMT3A mutations.<br /> Finally, new diagnostic tools will allow gaining more knowledge about complex molecular and cytogenetic interactions and with new targeted treatments being available, an important progress in classification, risk stratification and precision medicine for patients with AML will be expected in the near future.</p> <p><em>Clinical trials with FLT3 inhibitors</em><br />FLT3 tyrosine kinase inhibitors are distinguished into two categories; first generation of non-selective inhibitors and second generation containing more specific and potent inhibitors. They can also be subdivided into type I inhibitors that are active in both ITD and TKD mutations (for example midostaurin) and type II that are only active in ITD positive cells (for example sorafenib) (table 1).<br /> There are numerous ongoing studies with FLT3 inhibitors. Here, we just summarize some of them:<br /> The RATIFY study that led to the approval of midostaurin in 2017 is a large multicentric, double blind, phase III trial, in which cooperative trial groups, pharmaceutical industry and governmental agencies collaborated. Patients under 60 years of age were randomized to receive standard 7+3 chemotherapy combined with either placebo or midostaurin as induction, consolidation and maintenance treatment. For ITD as well as for TKD FLT3 mutated AML patients there was a significantly longer OS (75 months vs. 25 months; p=0,0009) in the midostaurin arm. Based on the RATIFY trial the 2017 ELN recommendations on AML propose the use of midostaurin with intensive induction and consolidation therapy for FLT3 mutated patients with AML.⁹<br /> Results from a phase Ib study in patients with FLT3 mutated AML using crenolanib¹⁰ (CR rate of 88 % after 1^st induction with 7+3 + crenolanib) and a phase I study using gilteritinib¹¹ (90,5 % of CR in patients with FLT3-ITD mutation after 7+3 induction + HiDAC consolidation + gilteritinib, at the end of consolidation), demonstrate high response rates and tolerable toxicities. In a phase II study crenolanib was also combined with standard chemotherapy in newly diagnosed FLT3 mutated AML,¹² demonstrating low relapse rates after consolidation (only 3/21 patients, none of whom received &gt;1 week of crenolanib maintenance), suggesting that long-term outcomes may improve with addition of this FLT3 inhibitor. Based on these promising results we expect second-generation FLT3 targeted agents to become available in the near future, creating additional options for patients with FLT3 mutated AML besides midostaurin.<br /> Furthermore, we report data published in the American Journal of Hematology¹³ from a recent promising study in which quizartinib, a selective, 2^nd generation FLT3 inhibitor, was tested. The addition of quizartinib to standard 7+3 induction chemotherapy in newly diagnosed FLT3 mutated patients with AML, followed by consolidation and maintenance with the addition of this selective inhibitor, led to high composite complete remission (CRc: includes complete remission [CR], complete remission with incomplete hematological recovery [CRi] and complete remission with incomplete platelet counts [CRp]) of 74 % .</p> <p><em>Non-intensive treatment</em><br />Median age of AML at diagnosis is 69 years. A population-based study published in 2012 reported that 39 % of older patients with newly diagnosed AML in the United States are not offered any treatment.¹⁴ Comorbidity index (HCT-CI) score identifies patients who are not eligible for intensive treatment. Physical and cognitive factors but also disease related factors can define patients suitable for intensive treatment. Based on results from randomized studies, hypomethylating agents (HMA) such as decitabine and azacytidine are now the standard of care for patients who are ineligible for intensified treatment options. CR when achieved after HMA is associated with prolonged OS.</p> <p><em>BCL-2 inhibitor: venetoclax</em><br />BCL-2 inhibitor, venetoclax (VEN), is one of the most promising treatment options. BCL-2 overexpression allows cancer cells to evade apoptosis by sequestering proapoptotic proteins. Venetoclax binds BCL-2 releasing proapoptotic proteins that induce apoptosis. It has been shown that venetoclax is not effective enough when given as monotherapy, it needs the addition of a cytotoxic drug or a HMA to be effective.<br /> Venetoclax in combination with lowdose cytarabine (LDAC) in newly diagnosed AML, including secondary AML or AML with high risk cytogenetics, showed high overall response rates (CR + Cri at 62 % ), even in very high risk profile patients.¹⁵ It also demonstrated a shorter median time to response (1 month) comparing to HMA as monotherapy (4 months).¹⁶ Based on these results, a phase III randomized study of Venetoclax co-administered with LDAC versus LDAC alone in treatment na&iuml;ve patients with AML who are ineligible for intensive chemotherapy is currently under way.</p> <p><em>Histone deacetylase inhibitors (HDACi)</em><br />HDAC inhibitors cause accumulation of acetylated histone and hence chromatin remodeling and ultimately apoptosis of tumor cells. A phase III study with pracinostat added to HMA showed high CR of 42 % and also higher OS of 19,4 months with low 30-day mortality (2 % ).¹⁷ In contrast, a study with vorinostat, another HDAC inhibitor, combined with HMA showed no improval in OS.¹⁸</p> <p><strong>Refractory/relapsed setting</strong><br />It is important to mention the results of the Quantum-R study comparing quizartinib as monotherapy versus salvage chemotherapy in FLT3-ITD mutated relapsed/ refractory (r/r) AML. For this purpose, patients were randomized in a 2:1 ratio in order to receive quizartinib at a dose of 60 mg p.o. versus other salvage treatment with OS as a primary end point. The OS and event-free survival (EFS) was improved at 52 weeks (OS: 27 % in quizartinib arm versus 20 % in standard salvage arm) and quizartinib seemed safe and well tolerated (table 2).¹⁹<br /> Finally, another phase I/II trial for r/r, older (&gt;60 years) patients previously untreated or treated with HMA with FLT3- ITD mutated AML compared the addition of quizartinib to either LDAC or an HMA. The very first results show significantly prolonged OS in the quizartinib arm (14 vs. 7 months) and in contrast to the expected CR rates of 30 % with azacytidine alone, there are response rates of 70 % with quizartinib. This combination seems very promising as a non-intensive treatment approach in r/r disease.²⁰</p> <p><em>Isocitrate dehydrogenase inhibitors (IDH)</em><br />IDH enzyme mutations are present in 20 % of patients with newly diagnosed AML. IDH1 mutations are less frequent than IDH2 mutations in AML (7&ndash;14 % versus 8&ndash;19 % ) and their frequency increases with age. They rarely co-occur in the same patient.<br /> Here we report some important ongoing studies with these agents:<br /> The AG-221-C-001 study²¹ is an open label, single arm, multicenter clinical trial of enasidenib in IDH2 mutated r/r AML patients. Median overall survival in patients with more than 2 previous treatments was 8 months. Notably, median survival in patients with r/r AML who were treated with 1 or more salvage treatments is extremely poor (3,3 months according to a large randomized phase III study)²² therefore IDH inhibitors seem to be a better treatment option for this group of patients. The FDA has now approved enasidenib as monotherapy in r/r AML with IDH2 mutation.<br /> Importantly, late responders (patients who still responded after day 90 during continued treatment with enasidenib) had significant OS benefit compared with patients with no late response,²³ suggesting that, as with HMA-based therapy, it may be prudent for patients to receive multiple enasidenib treatment cycles (at least 6 cycles).<br /> Older patients (&ge; 60 years) with IDH2 mutated AML, who were previously untreated, were included in the AG- 221-C-001 study. These 39 of the 345 study patients with a median age of 77 years²⁴ had a median OS of 11,3 months as compared to results from a large observational study including patients aged &gt;65 years who had an unadjusted median OS of only ~5 months even when treated with either HSCT or intensive therapy or HMA therapy.²⁵<br /> Based on such encouraging responses, enasidenib is now being studied in a larger cohort of previously untreated patients with IDH2 mutations.²⁶<br /> It is important to mention that, among the adverse effects of IDH inhibitors the most important is a differentiation syndrome, potentially a lethal entity, which occurs in approximately 12 % of r/r AML patients treated with enasidenib.²⁷ Early recognition and treatment with corticosteroids can reduce morbidity and mortality.<br /> A phase I study with ivosidenib as monotherapy for patients with r/r AML with IDH1 mutation²⁸ showed CR rates of 21 % with median duration of CR of 10,1 months and an OS rate of 50,1 % at 18 months. These results are very important in this setting of patients compared to the very poor outcomes of patients with r/r AML after prior salvage treatments.<br /> Combinations of these agents with HMA in untreated, newly diagnosed IDH mutated AML patients are being tested in ongoing trials.²⁹</p> <h2>Novel approaches in AML</h2> <p>Immunotherapy strategies are well known in AML, with allogeneic stem cell transplantation being so far the most successful treatment, based on the power of donor&rsquo;s T cells against leukemic cells.<br /> Novel strategies in immunotherapy can be divided in two groups, according to the target antigen: checkpoint inhibitors and therapeutic vaccines are driven against intracellular antigens, while monoclonal antibodies and CAR-T cells are targeting membrane proteins.<br /> Immune checkpoint inhibitors as monotherapy have demonstrated insufficient efficacy, most likely due to the low number of somatic mutations when compared to solid tumors. HMA exert immunomodulatory effects and combination of HMA with immune checkpoint inhibitors leads to promising results in ongoing trials: 1st salvage treatment in patients with r/r AML with azacytidine + nivolumab: benefit in median OS of 10,6 vs. 4,1 months based on historical data.³⁰ Dendritic cell vaccine strategies seem to be safe and can induce anti-leukemic responses in patients with AML.<br /> CD33 and CD123 are the most commonly targeted antigens in ongoing trials for patients with AML. Several of these trials utilizing drug conjugates have been terminated early due to relevant toxicity of these agents. Gemtuzumab-ozogamicin is so far the only monoclonal antibody approved for the treatment of CD33 positive AML in combination with chemotherapy or as a single agent, as well as in patients with r/r AML.<br /> Bispecific T cell recruiting antibodies create immune synapses between leukemic cells and T cells, inducing expansion and proliferation of T cells. Results from a phase I trial with the first bivalent, bispecific CD33/CD3 T cell engager³¹ demonstrate some anti-leukemic efficacy with good tolerability. These agents could be an option in patients with r/r AML who already have received salvage treatment.<br /> Finally, immunotherapy with CAR-T cells is now also entering the field of AML. Most of the trials including CAR-T cells are performed in China and the US; trials in Europe are still lacking behind. The first phase I clinical trial with CAR-T cells targeting two antigens, CLL1-CD33 simultaneously, has proved to be safe and well tolerated in patients with aggressive r/r AML who achieved CR.³² It is though important to keep in mind that currently &ndash; but this might change in the future &ndash; CAR-T cells seem more toxic than antibody- based strategies, with cytokine release syndrome being one of the most common and harmful toxicity of this treatment.</p> <p><img src="/custom/img/files/files_datafiles_data_Zeitungen_2018_Leading Opinions_Onko_1805_Weblinks_lo_onko_1805_s36_tab1+2.jpg" alt="" width="1422" height="2744" /></p></p> <p class="article-footer"> <a class="literatur" data-toggle="collapse" href="#collapseLiteratur" aria-expanded="false" aria-controls="collapseLiteratur" >Literatur</a> <div class="collapse" id="collapseLiteratur"> <p><strong>1</strong> ASH-CAP Guidelines for the Diagnosis of Acute Leukemia 2018 (cited 2018 Aug 30); available from: http://www. hematology.org/Thehematologist/Mini-Review/7120.aspx <strong>2</strong> D&ouml;hner H et al.: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 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