Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Simple Summary AML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients. Abstract Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients

Target Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common form of acute leukemia in elderly patients. Over the past four decades the basic therapeutic armamentarium was the standard cytotoxic treatment. The new insights in understanding the pathogenesis of AML was the momentum that revolutionized the treatment landscape in AML. The last five years unprecedented growth has been seen in the number of target therapy drugs for the treatment of AML. These new drugs did not just have a clinical benefit as single agents but also have improved AML patient outcomes if combined with conventional cytotoxic therapy. Here, we review recent advances in target-based therapy for patients with AML focusing on their mechanism of action and the results from already published clinical trials

Refining AML treatment: the role of genetics in response and resistance evaluation to new agents

The number of treatment options for acute myeloid leukemia (AML) has greatly increased since 2017. This development is paralleled by the broad implantation of genetic profiling as an integral part of clinical studies, enabling us to characterize mutation–response, mutation–non-response, or mutation–relapse patterns. The aim of this review is to provide a concise overview of the current state of knowledge with respect to newly approved AML treatment options and the association of response, relapse and resistance with genetic alterations. Specifically, we will highlight current genetic data regarding FLT3 inhibitors, IDH inhibitors, hypomethylating agents (HMA), the BCL-2 inhibitor venetoclax (VEN), the anti-CD33 antibody conjugate gemtuzumab ozogamicin (GO) and the liposomal dual drug CPX-351

Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma

Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody-drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3-ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A-directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A-rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2, RAS, MEK, Bruton's tyrosine kinase, JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance

Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

Myelodysplastic syndromes (MDS) are a group of diseases in which bone marrow stem cells acquire genetic alterations and can initiate leukemia, blocking the production of mature blood cells. It is of crucial importance to identify those genetic abnormalities because some of them can be the targeted. To date only very few drugs are approved for patients manifesting this group of disorders and there is an urgent need to develop new effective therapies. This review gives an overview of the genetic of MDS and the therapeutic options available and in clinical experimentation.Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine

Harnessing the potential of epigenetic therapies for childhood acute myeloid leukemia

There is a desperate need for new and effective therapeutic approaches for AML in both children and adults. Epigenetic aberrations are common in adult AML, and many novel epigenetic compounds are in clinical development that may improve patient outcomes. Mutations in epigenetic regulators occur less frequently in AML in children compared to adults. However, investigating the potential benefits of epigenetic therapy in paediatric AML is an important issue that will be discussed in this review

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML

Cellular vulnerabilities of glioblastoma

Glioblastoma (GB) is the most fatal and frequent malignant brain tumor, and it is driven by multiple oncogenic pathways. Despite intensive screening of genomic, transcriptomic, metabolic, and post-translational landscape of GB, targeted therapies have provided no improvements for the survival of GB patients. This incurability of GB is due to its infiltrative growth, intratumoral heterogeneity and intrinsic resistance towards treatment modalities which are driven by its subpopulations, such as glioblastoma stem cells (GSCs). Therefore, it is crucial to try to understand the mechanisms of GBs cellular resistance and potential vulnerabilities of GSCs. In this thesis we demonstrate alternative targets for GB therapy. Protein phosphatase 2A (PP2A) is inhibited in GB by non-genetic mechanisms, therefore, its therapeutic reactivation is possible. We described that small molecule reactivators of PP2A (SMAPs) efficiently cross the blood-brain barrier (BBB) and exhibit robust cytotoxicity towards heterogenous GB cell lines. Furthermore, we present specific kinases which inhibition induce synthetic lethality under PP2A reactivation. Collectively, these studies present SMAPs as a novel therapy for GB and propose an alternatives for multikinase inhibitors. In GB, nanoparticles have been researched for their potential to circumvent insufficient drug properties. However, opposed to traditional utilization of nanoparticles, we discovered an alternative use of them in GB. We demonstrated that mesoporous silica nanoparticles (MSNs) functionalized with polyethylenimine (PEI) induce cell death specifically in GSCs. The PEI-MSNs accumulated in the lysosomes of GSCs and caused lysosomal membrane permeabilization potentially through proton sponge effect. Furthermore, we determined that PEI-MSNs efficiently cross the BBB in mice. In summary, this thesis presents a novel therapy concepts for GB.Glioblastooman solutason haavoittuvuudet Glioblastooma (GB) on yleisin ja pahanlaatuisin aivosyöpä, jossa useat onkogeeniset signalointipolut ovat yliaktiivisia. Huolimatta genomiikan, transkriptomiikan, metabolomiikan ja translaation jälkeisten muutosten intensiivisestä seulonnasta GB:ssa, kohdennetut hoidot eivät ole tuottaneen lisäelinaikaa GB-potilaille. GB:n hoidon vaikeus johtuu sen infiltratiivisesta kasvusta, kasvaimen sisäisestä heterogeenisyydestä ja synnynnäisestä resistenssistä hoitoja vastaan. Syynä näihin on usein glioblastooman kantasolut. Tästä syystä, on erittäin tärkeää pyrkiä ymmärtämään GB:n solutason resistanssimekanismeja ja glioblastooman kantasolujen potentiaalisia heikkouksia. Tässä väitöskirjassa esitämme uusia kohteita GB:n hoitoon. GB:ssa proteiinifosfataasi 2A (PP2A) on estetty muilla tavoin kuin geneettisillä mekanismeilla. Tästä syystä sen terapeuttinen uudelleenaktivointi on mahdollista. Osoitimme tutkimuksissamme, että pienimolekyyliset PP2A aktivaattorit (SMAP) läpäisevät veri-aivoesteen ja ovat sytotoksisia GB:n heterogeenisiä solulinjoja kohtaan. Tämän lisäksi selvitimme, minkä kinaasien hiljentäminen altistaa GBsoluja entisestään PP2A:n aktivaatiolle. Yhteenvetona tutkimus esittää SMAP lääkkeet uutena terapiamuotona GB:n hoitoon ja ehdottaa vaihtoehtoja multikinaasiestäjille. Nanopartikkelitutkimus GB:aan liittyen on pääasiassa pyrkinyt parantamaan lääkkeiden ominaisuuksia. Me löysimme kuitenkin vaihtoehtoisen tavan käyttää nanopartikkeleita GB:ssa. Osoitimme, että mesohuokoiset piioksidi-nanopartikkelit, jotka on pinnoitettu polyetyyliemiinillä, aiheuttavat solukuoleman glioblastooman kantasoluissa. Kyseiset nanopartikkelit kerääntyivät glioblastooman kantasolujen lysosomeihin ja aiheuttivat sen membraanin tuhoutumisen ”proton sponge” efektin avulla. Kokonaisuudessaan väitöskirja esittää uusia heikkouksia glioblastooman kantasoluissa

Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN)

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy

Modeling normal and malignant hematopoiesis in vitro. To screen for extrinsic regulators and differentiation therapy.

The incredible thing with blood stem cells, also known as hematopoietic stem cells (HSC), is that they can restore normal hematopoiesis in patients that need a new blood system. Since a prerequisite for successful transplantation is immune compatibility, it requires large donor registries to find a suitable match for a recipient. Unfortunately, there is still a shortage of immune-compatible donors in these registries. Thus one potential approach to improve the quantity and quality of these registries is to expand HSC in umbilical cord blood units. However, robust in vitro expansion of human HSC is not possible yet. Thus, in vitro expansion of HSC is a high-value objective in hematological research.A common reason patients need a new blood system is blood cancer. An added benefit of transferring someone’s else blood system to a cancer patient is that the donor’s immune cells can help eradicate the cancer cells. Because the transfer of a new blood system is not without risks, as the donor’s immune cells also target normal tissues, physicians will only transplant when the cancer treatment is not potent enough to eradicate the cancer cells. Even though the cancer therapies of some AML subtypes are effective today, the prognosis of most cancer types would improve with new therapies. Thus, developing new therapies is another high-value objective in hematological research.Here we addressed both of these objectives by using a mesenchymal stroma-based co-culture model for culturing primary acute myeloid leukemia (AML) cells and HSC to identify differentiation therapy of AML (papers I and II), improve culture conditions of HSC (paper III), and for investigating synthetic lethality in AML (paper IV). Thus, the common thread of the four papers included in this thesis is the use of OP9M2 cells to model normal and malignant hematopoiesis.In paper I, we identified a natural product that induces differentiation in AML through activation of the PKC pathway. Moreover, we show that AML with FLT3-ITD or FLT3 mutations are resistant to differentiation, highlighting the importance of neutralizing the effect of mutated FLT3 in differentiation therapy. This study illustrates how small molecule screening and genetic profiling are powerful tools for developing personalized treatments.Paper II is a small molecule screening protocol based on the OP9M2 co-culture model of primary AML cells. With a flow-cytometry readout, the protocol is highly adjustable to different study objectives, including screening for novel therapeutic agents, drug repurposing, drug synergism, patient selection, mechanism of action analysis, and drug resistance. Methods such as these will continue to be crucial for developing new therapies to improve outcomes for many patient groups.In Paper III, we identified potential regulators of HSC, which we screened by shRNA knockdown in the OP9M2 model. However, it did not identify any candidates, likely due to a sub-optimal screening methodology. Still, the list of potential regulators could be helpful for similar studies. Improving in vitro culture conditions remains a high-value objective as cellular therapies will continue to be essential for treating hematological diseases.Paper IV shows that STAG1 and STAG2 have a synthetic lethal interaction in primary AML cells. Thus, targeting STAG1 or STAG2 in STAG1- or STAG2-null AML is potentially a new precision medicine for molecular targeted therapy. This study shows how an in-depth understanding of disease heterogeneity and subtype-specific weaknesses is critical for developing precision medicine