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  2. Toward Individualized Therapy in Acute Myeloid Leukemia: A Contemporary Review. - Semantic Scholar
  3. Review ARTICLE
  4. Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety
  5. Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics

This was based on the observations that patients with a genetic defect of adenosine deaminase essential for the conversion of lymphotoxic deoxyadenosine to non-toxic deoxyinosine showed lymphopenia and severe immunodeficiency Recently, it has been tested in combination with anthracycline and cytarabine in fit patients with de novo AML This triplet combination is one of the few enhancement of intensive AML therapy that improves overall survival. We speculate that cost is why cladribine is not used routinely in most of the Western world. Poland has reasonable priced production of cladribine, while most Western European countries have highly priced supplies.

This exemplifies that off-patent drugs not necessarily are cheap but could experience significant cost increases 34 , e. Therefore, it is not likely that agents like cladribine will be included in international guidelines in combination with intensive chemotherapy. It was evident early on that clofarbine was effective against AML However, in the intermediary risk group, a clinical benefit was observed.

This underscores the potential benefit in certain AML subsets and that the search for molecular markers of response should be intensified. Cladribine and clofarabine belong to a large family of nucleoside and nucleobase antimetabolites with great importance in treatment of cancer and infections Many of these molecules inhibit ribonucleotide reductase 39 , likely an important component of the antileukemic effect.

Fludarbine is per orally formulated and registered for combination use in AML 16 , 40 , but both cladribine and clofarabine may well have similar or even better therapeutic effect. Our understanding is that until feasible biomarkers are available, the justified position of cladribine and clofarabine will not be clarified in AML. Actinomycin D dactinomycin, Cosmegen was described in as the first antibiotic demonstrating anticancer effect This is intriguing because of its limited toxicity and the fact that one-third of all AML patients have a NPM1 mutation Mechanistically, actinomycin D has been shown to affect ribosomal biogenesis and thereby altering pre-mRNA splicing of tumor suppressor p53 Finally, the myeloid AML blasts have a high level synthesis of ribosomes and may, therefore, be particular susceptible to actinomycin D Melphalan is an alkylating agent used in a wide dose span, from treatment of unfit multiple myeloma to bone marrow eradication in autologous stem cell transplantation.

Low-dose melphalan has repeatedly been described to benefit selected patients with myelodysplasia and AML. An early report described that 2 mg daily orally administrated melphalan-induced remission in myelodysplasia refractory anemia with excess blasts and in transformation to AML Responses lasted 12—55 weeks, and relapses responded to rechallenge with melphalan. Interestingly, patients with normal karyotype and low bone marrow cellularity were the most frequent responders.

Two cases describing relapses on melphalan demonstrated clonal evolution with appearance of the high-risk loss of 17p including the TP53 gene Both of these patients were resistant to cytarabine, the standard drug used extensively in AML. Based on the knowledge that melphalan induces DNA damage, melphalan is not ideal for treatment of younger patients. Melphalan-induced genomic instability in particularly susceptible patients may be the reason for secondary hematological malignancies, found in a subset of melphalan-treated myeloma patients 53 , Understanding better, the genomic susceptibility to melphalan and other antimetabolites may facilitate safer usage of these agents.

Hydroxyurea is authorized as a drug to decrease the level of white blood cells in AML, but it has never been shown to improve survival compared to best supportive therapy Hydroxyurea is regarded as a safe agent not inducing DNA damage through its extensive use in younger patients with hemoglobinopathies 56 , Interestingly, hydroxyurea provides antileukemic effects in novel combinations. We have preclinically tested hydroxyurea in combination with valproic acid and experienced effects on DNA repair unique for the combination This combination is apparently well tolerated in unfit AML patients 59 , but data from controlled trials are lacking.

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Arsenic trioxide combined with all-trans retinoic acid is close to a standard therapy for patients with t 15;17 M3 AML However, for AML non-APL , arsenic trioxide in combination with low-dose cytarabine or standard induction therapy have not been successful 61 — These clinical observations are disappointing in light of a wide range of preclinical studies that indicate potential combinations with specific mechanisms of action.

The delineation of chemotherapeutics and many non-chemotherapeutics could be artificial. If doses are increased, most therapeutic molecules will induce cytotoxicity. However, we will discuss agents that are regarded non-toxic when used at approved doses. Lessons learned from all-trans retinoic acid in APL AML M3 , as well as new molecules with strong pro-differentiating effects, indicate just how cells are brought out of their proliferative state matters for therapy response. Furthermore, several agents appear to show low toxicity by themselves, but alter the threshold for undergoing cell death when exposed to additional antileukemic therapy.

A general concept of non-chemotherapy agents, including all-trans retinoic acid in APL, seems to be that monotherapy usage is not feasible. Glucocorticoids in AML, so far, play no therapeutic antileukemic role, and its use is actually discouraged due to an immunosuppressive effect. However, two reports suggest that glucucorticoids may be beneficial in AML subsets. Patients resistant to cytarabine and with wild-type FLT3 may respond to glucocorticoids A biomarker for glucocorticoid use may be implemented quickly in routine therapy of AML, particularly since glucocorticoids are already routinely used in the treatment of ALL.

Per oral antidiabetics are proposed to have a role in AML therapy, particularly based on awareness of metabolism as an important mechanism in AML cells. The oral hypoglycemic metformin activates the adenosine monophosphate-activated protein kinase pathway dependent on the tumor suppressor LKB1. Particularly, FLT3-ITD mutated AML cases may be susceptible for metformin and maybe with enhanced efficiency when combined with the kinase inhibitor sorafenib or the experimental drug 6-benzoylthioinosine 70 , Experiments in animal model xenografts of colon cancer and prostate cancer have demonstrated tumor suppressive effects of metformin 72 , Further, registry studies of diabetic patients on metformin have indicated reduced risk of pancreatic cancer Statins tested as monotherapy in clinical trials have not shown convincing results.

Statins may exemplify the limited potential of monotherapy of a repurposed drug in an aggressive blood cancer like AML. Current understanding of the dosing of statins is not complete 75 , 76 and likely needs careful modeling for optimal effects of statins in AML. Two reports suggest that pravastatin may be beneficial in combination with idarubicin and cytarabin in relapsed AML, while de novo AML did not benefit from this combination 75 , These clinical trials combining statins with other agents have demonstrated encouraging results.

Interestingly, experimental evidence indicates immunomodulatory properties, including increased tumor infiltration of effector CD8 T-cells and M2-like tumor-associated macrophages These and novel combinations need to be further developed.

The benzimidazole family of antihelmintic drugs have been evaluated for antileukemic effects. The benzimidazoles are suggested to inhibit amino peptidase activity and glutamate catabolism, reduce glucose uptake, increase intracellular calcium levels, and inhibit microtubule formation [for references, see Ref. The antileukemic activity of mebendazole was discovered in an in vitro drug screen of AML cells with genetic alterations in Mixed Lineage Leukemia More in-depth characterization of the antileukemic effect of flubendazole demonstrates altered microtubule function and mitotic catastrophe with a binding site on tubulin that differed from Vinca alkaloids tubulin inhibitors The synergism of flubendazole with Vinca alkaloid vinblastine in the cell line OCI-AML2 and in a leukemia xenograft animal model may reflect the different tubulin-binding sites of flubendazole and vinblastine.

To this date, no clinical trials in AML have been initiated using these antihelmintic agents. Thalidomide was developed as a sedative and antiemetic in the late s, and its use by pregnant women resulted in a catastrophic occurrence of birth defects and stillborn.

Toward Individualized Therapy in Acute Myeloid Leukemia: A Contemporary Review. - Semantic Scholar

Recently, the combination of thalidomide and azacitidine was demonstrated tolerable in a phase II clinical trial in patients with clinically advanced MDS, chronic myelomonocytic leukemia, and low-blast count AML But it took more than 60 years before a more complete understanding of the molecular mechanism emerged 7. Explaining both the teratogenicity and its antitumor response, the inhibitory action on the E3 ubiquitin ligase cereblon was discovered.

Several more efficient thalidomide analogs were already in development based on the clinical effect. One such analog, lenalidomide, has shown to be particular effective in myelodysplasia lacking one copy of the 5q chromosome. Among several genes affected, 5q deletion results in haploinsufficency of casein kinase 1, and lenalidomide targeting of cereblon results in devastating low level of casein kinase 1 and subsequently tumor cell death Myelodysplasia with 5q minus and response to lenalidomide is an example of synthetic lethality that could be necessary in order to make repurposing feasible for patients.

It is likely that development of more molecules targeting the E3 ubiquitin ligase cereblon and its related pathways may provide us with efficient therapeutic targets. Valproic acid n-dipropylacetic acid, 2-propylvaleric acid, or 2-propylpentanoic acid derived from valeric acid naturally produced by the flowering plant valarian valeriana officinalis was first synthesized by Beverly S. Burton in This branched short-chain fatty acid was used as a physiologically inert solvent for organic compounds for nearly a century before the discovery that valproic acid had an anticonvulsant activity on its own Clinically, valproic acid Orfiril, Deprakine, Depakote, Convulex, Epilim, Stavzor is used today as an long-term treatment of anticonvulsant in epilepsy and mood stabilizing drug for bipolar disorder Valproic acid is administered orally with available routine measurements of serum levels and has a low toxicity profile.

DNA hypoacetylation of histone-associated proteins leads to tight chromatin packaging resulting in repression of genes involved in differentiation, proliferation, and apoptosis. Preclinical studies showed enhanced differentiation and apoptosis in AML cells when combining valproic acid with other drugs 59 , 93 — Valproic acid is currently involved in many different anticancer clinical trials Furthermore, valproic acid often enhance or synergize with a numerous of drugs Recently, valproic acid was combined with standard induction therapy in elderly AML patients, and although not resulting in an overall improved clinical outcome, the 5-year relapse-free survival was significantly increased for the patients additionally treated with valproic acid Interestingly, the AML patients that particularly benefited from the additional valproic acid treatment were NPM1-mutated We examined this antileukemic effect of valproic acid in AML in combination with all-trans retinoic acid and theophylline, aiming for a combined epigenetic, transcriptional, and signaling transduction effect that resulted in increased differentiation and programmed cell death of tumor cells 98 , Several combinations of valproic acid with new and old drugs appear attractive, like the well-tested antimetabolite hydroxyurea and the new class MDM2 inhibitor nutlin-3 58 , Novel low-toxic combinations with valproic acid are in development and may be feasible to test in patients.

However, the ability to perform substantial clinical trials with valproic acid that secure indication in cancer is challenging. Quinacrine mepacrine, Atabrine is an acridine dye developed in the US as an antimalarial agent at the beginning of the Second World War and used by millions of military personnel. This allowed for extensive registration of side effects and toxicity of three million soldiers taking quinacrine for up to four years. The toxicology profile is well known, dominated by gastrointestinal symptoms, dizziness and nausea, exanthema, and at doses, above mg daily reversible psychosis may occur.

Quinacrine is currently used off-label for diseases such as therapy refractory giardiasis and as therapy enhancer in systemic lupus erythematosus The mechanisms of action for quinacrine have been extensively explored together with other acridine molecules. The DNA intercalating property of quinacrine is not associated with DNA damage, in contrast to the anthracycline chemotherapeutics, but has been used to stain chromosomes for G-banding where placental transfer of leukemic cells from fetus to mother was demonstrated.

Early works also indicated that quinacrine accumulates in tumor tissue in mouse and rat models, including leukemic spleen Quinacrine was recently selected as the number one hit in a drug screen searching for compounds with high antileukemic activity and low toxicity toward healthy peripheral mononuclear cells where ribosome biogenesis was found to be the target of quinacrine Thus, ribosome biogenesis inhibition will result in the release of ribosomal proteins binding to the E3 ubiquitin ligase MDM2, thereby blocking p53 ubiquitination.

The result implies that quinacrine indirectly inhibit MDM2, thereby stabilizing p53 protein that induces pdependent gene expression 6. A novel use of quizartinib is suggested through the use for preventing chemotherapeutic myelosuppression Myelosuppression is regarded as a natural and unsuspendable process in intensive AML therapy. By protecting normal hematopoietic stem cells from FLT3 ligand signaling, the myeloablasive phase could be significantly shortened. Bromocriptine was recently identified in a screen of FDA-approved drugs searching for drugs with potential of differentiation of AML cells Serotonin receptor agonists are frequently used in the treatment of depression and migraines.

Interestingly, the serotonin receptor type 1 HTR1 was demonstrated expressed on AML cells and addition of HTR1 antagonist induced differentiation, increased cell death, and impaired clonogenic capacity Leukemic stem cells play a central role in relapsed and refractory AML and, therefore, developments of low-toxicity compounds targeting these cells are needed.

Ongoing research is studying several compounds derived from natural sources such as plant extract from parthenolides with efficacy toward AML stem cells Leukemic progenitor cells are known to hide in stem cell niches of the bone marrow. In this situation, the leukemic cells are protected by stromal cells that directly or indirectly provide survival and protective factors that blunt the effect of chemotherapy Inspired by the observation that antibody blockage of certain homing factors to the bone marrow niche, like CXCR4, may provide mobilization of hematopoietic stem cells, these blockers of niche homing have been proposed to mobilize leukemic cells before chemotherapeutic therapy Obviously, the experimental backbone of repurposing drugs in cancer therapy is challenging, followed by demanding clinical trials that need a sophisticated biomarker program for identifying therapy responders Figure 1.

If successful, the data obtained should solve the obstacle related to the approval mechanisms and regulations by medicines agencies. These hurdles could be solved if the development program has financial muscles, which is not very likely in projects emerging from smaller laboratories and academic institutions. Furthermore, if the sale on a particular label or indication is limited, the producer may withdraw the marketing approval. In extreme examples, a drug alemtuzumab, anti-CD52 against relapsed B-cell chronic lymphatic leukemia; CLL was withdrawn from the initial cancer indication and reapproved for a larger market in multiple sclerosis , At the same time, the company introduced the Campath Distribution Program www.

System biology approaches has recently been used in a drug sensitivity test of AML cells from patients 9. Initiatives for advanced collections coupled with drug response mapping, e. We have seen these developments be rewarding in orthotopic small animal models of AML, where collections of libraries of molecules coupled with advanced bioinformatics tools may improve the probability of discovering novel combinations of therapeutics authorized for other diseases than AML More advanced in silico tools are on the brink to facilitate this development Combination of miniaturization, microfluidics, and bioinformatics with artificial intelligence may represent the novel tools needed to answer the overdue question in chemotherapy repositioning: which patients will be optimal responders.

At one end of the drug development spectrum, repurposing has the potential to bring old drugs rapidly into use for new diseases. At the other end, repurposing could serve to identify lead compounds being chemically modified in order to increase target affinity and reduce necessary dosing and toxicity. Novel formulations may add more dimensions to drug delivery and tissue targeting that make repurposing of medicines highly attractive.

Widespread use of repurposing in therapy development may need regulatory steps to move forward, securing approved indications, safety data, and allowing insurance reimbursement. This needs international regulations that take into consideration the global need for cancer therapy. Cancer therapy needs a larger therapy toolbox and effective repurposing may be one important tool that increases the number of therapy responders in cancer.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. New sources of drugs for hematologic malignancies. Blood — Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci — Repurposing drugs in your medicine cabinet: untapped opportunities for cancer therapy? Future Oncol —4. Drug repurposing in cancer.

Pharmacol Res — Nosenga N. Can you teach old drugs new tricks? Nature —6. Gurova K. Other states in which the white count can be high include leukemoid reactions, chronic myeloid leukemia CML , or lower grade indolent lymphoproliferative neoplasms such as chronic lymphocytic leukemia or hairy cell leukemia. The latter entities are generally easily distinguished because of the characteristic mature appearing lymphocytes. In chronic phase CML, or leukemoid reaction there should be few or no blasts and a preponderance of mid-range myeloid cells such as bands, myelocytes, metamyelocytes, and promyelocytes.

Two important other related entities to AML in which peripheral myeloblasts can be seen include myelodysplastic syndromes MDS and myeloproliferative neoplasms. The myeloproliferative neoplasms, particularly myelofibrosis MF , can present with elevated white counts, some degree of peripheral blasts, and abnormal platelet and white counts. However, bone marrow examination in the case of MF would show a relatively small number of myeloblasts in the context of infiltration with fibroblasts.

The most important risk factor for AML is age, probably due to aging of the bone marrow-stem cell compartment including the accumulation of genetic lesions over time. Most patients with AML have no predisposing factors, however, chemotherapy for other cancers, particularly alkylating agents or topoisomerase II inhibiting drugs can be leukemogenic. In the case of alkylating agents, patients usually have a 5 to 8 year latency period and often have a myelodysplastic prodrome. In the case of the topoisomerase inhibitors such as etoposide, patients tend to have a shorter latency period 2 to 3 years and often present with a monocytoid type of AML which has a characteristic translocation involving the long-arm of chromosome 11 at the MLL gene locus.

Recent molecular data also suggest that not every patient with so-called therapy-related AML has genetic changes suggestive of a chronic marrow stem cell disorder. Other risk factors for AML include exposure to ionizing radiation from military, industrial, or therapeutic sources and exposure to certain industrial solvents such as benzene. The most important laboratory studies in a patient with known or suspected AML are bone marrow aspirate and biopsy.

One should first review routine laboratory studies including a chemistry panel and complete blood count CBC. Particular attention should be paid to the serum potassium which can be elevated due to tumor lysis, or depressed due to myeloblast usually monocytoid blasts -induced renal tubular electrolyte losses. The serum phosphate and uric acid may be quite high in tumor lysis syndrome, with hyperphosphatemia leading to hypocalcemia. There are many reasons why the hepatic transaminases could be elevated in AML, including infection or leukemic infiltration of the liver.

In the latter case, the serum alkaline phosphatase are elevated. Direct hyperbilirubinemia may occur due to biliary stones or infections; rarely indirect hyperbilirubinemia can indicate tumor cell-mediated hemolysis due to antibody elaboration. A low serum albumin might indicate a more chronic presentation with evidence of malnutrition at the time of diagnosis. Moreover, anthracyclines, which are required for induction therapy in AML, are excreted hepatically; direct hyperbilirubinemia would require at least consideration for dose modification unless the abnormal liver tests can be definitively shown to be due to leukemic infiltration.

Renal failure could indicate underlying renal dysfunction, especially in older patients, or, if acute, could indicate renal damage from uric acid released in the context of tumor lysis syndrome. The CBC is a critical test in patients with known or suspected leukemia. Profound anemia, leukocytosis, and thrombocytopenia are common, although leukopenia can sometimes occur particularly in older adults with smoldering leukemia or in a patient who presents with APL. It is very important to review the peripheral blood smear because there are often circulating tumor cells myeloblasts , which can be noted on a standard Wright-Giemsa stain.

Auer rods are concretions of peroxidase-containing granules. AML blasts tend to have more nucleoli, more open chromatin, and somewhat granulated and more abundant cytoplasm than would be seen in patients with ALL. Especially in patients with APL, but in all patients, an INR international normalized ratio , partial thromboplastin time, and fibrinogen should be checked.

Almost all patients with APL and a minority of patients with other types of AML will present with disseminated intravascular coagulopathy DIC due to the release of pro-coagulant granules from the malignant cells. In full-blown cases of DIC, the thromboplastin time will also be elevated. The degree of hypofibrinogenemia correlates with the severity of the DIC.

Firstly, this is useful in cases where platelet allo-immunization becomes a problem, and it is necessary to transfuse HLA-matched platelets. Secondly, the majority of AML patients should be considered to be stem cell-transplant candidates, at least at diagnosis. A bone marrow biopsy and aspirate should be carried out in every patient with suspected AML. Myeloblasts can be distinguished by their characteristic appearance including prominent nucleoli, a few cytoplasmic granules, and open chromatin.

Definitive diagnosis of a myeloblast requires the presence of Auer rods, or cytochemical or immunophenotypic studies revealing myeloid derivation. In blasts that are cytochemically negative, a diagnosis of M0 AML according to the old FAB [French-American-British] classification system may be made if myeloid antigens with the absence of lymphoid antigens are noted on immunophenotypic studies.

Blasts occasionally display no lineage-specific markers, or markers indicative of both myeloid and lymphoid derivation mixed-phenotype acute leukemia. An aliquot of aspirate marrow should be sent for cytogenetic analysis. Cytogenetics remains a key test to establish prognosis, understand pathophysiology, and, in many cases, guide therapy. Two cytogenetic abnormalities, inversion of chromosome 16 and translocation t 8;21 , are characteristic of so called core-binding factor leukemias which have a favorable prognosis. Patients who have the type of chromosomal abnormalities seen in secondary AML or MDS, including loss of the long-arm or all of chromosome 5, loss of the long-arm or all of chromosome 7, and complex karyotype greater than three abnormal cytogenetic findings have a very poor prognosis.

Monosomal karyotype two chromosome deletions or one chromosome deletion plus structural abnormalities augers an inferior prognosis, even when compared to the average patient with adverse cytogenetics. Cytogenetics can be used to confirm the diagnosis of APL. In such cases where APL is strongly suspected and cytogenetics are not technically feasible or will take excessive time to obtain results, important alternative diagnostic studies include FISH fluorescence in situ hybridization and PCR polymerase chain reaction.

FISH technology does not require cells to go into cell division and can be done on non-dividing cells. Testing for certain genetic abnormalities at diagnosis is increasingly becoming the standard of care. Patients with normal karyotype can be parsed into different prognostic categories by mutations occurring in certain genes. This is an evolving field as new genes with prognostic impact are being rapidly discovered.

If this mutation is present in both alleles this predicts a very good prognosis. The list of genes that will be prognostically useful is expanding; ongoing studies are evaluating the prognostic and pathophysiological importance of genes that may epigenetically affect expression of multiple genes including TET2, IDH1, IDH2, and DNMT3A. Although some patients with acute leukemia present in an indolent fashion, particularly older adults, the majority of patients with AML present with issues that must be dealt with urgently. If there are any obvious infectious manifestations at presentation, appropriate antibiotics should be started.

Because of the neutropenia and the lack of inflammatory cells, it can sometimes be difficult to delineate the source of the infection. Broad spectrum antibiotics covering commensal organisms from the gastrointestinal GI tract and the skin should be initiated in case of neutropenia and fever. Patients who are bleeding and thrombocytopenic should be given platelet transfusions; prophylactic transfusions are indicated if the platelet count is less than 10, Efforts to lower the serum uric acid should be accomplished.

In cases where rapid reduction of the serum uric acid is not required, prophylactic allopurinol, a xanthine oxidase inhibitor, should be administered. Full-blown tumor lysis syndrome with ongoing or potential renal failure, or if the patient cannot take oral drugs, should prompt administration of recombinant urate oxidase. Most patients will have a rapid reduction in their serum uric acid with a single 6mg dose of recombinant urate oxidase, but the dose can be repeated in 24 hours if needed. These microthrombi, often accompanied by microhemorrhages, can lead to the clinical sequelae of altered mental status or respiratory failure.

If hydroxyurea cannot be given or if the patient has ongoing leukostasis and particularly if rapid reduction is needed, then leukopheresis should be initiated. Large bore intravenous therapy is required for this procedure which can rapidly reduce the white count, albeit temporarily, and improve central nervous system or pulmonary function.

In general, no more than 2 to 4 leukopheresis procedures are needed to stabilize the patient until definitive anti-leukemic therapy can be given. Occasionally low-dose radiation therapy can be used urgently to lyse cerebral myeloblasts, in cases of mental status deterioration, when leukopheresis cannot be done, or is ineffective. The definitive therapeutic approach to AML depends on specific disease and patient-related features.

The treatment paradigm for AML is divided into two stages; the first is induction therapy, and the second is post-remission consolidating therapy. In the first stage, chemotherapy is given to reduce the tumor burden which is believed to be about 10 12 cells at diagnosis down to a level low enough so that a complete remission is achieved. Complete remission is defined as a state where leukemic cells are not detected by routine means in the bone marrow, peripheral blood, or extramedullary sites.

Theory suggests that remission occurs when there are still cells present; detectability is not straightforward.


The presence of such minimal residual disease MRD may portend a poor long-term outcome. If a patient does not receive additional therapy in the post-remission setting, relapse is inevitable. A major effort has been dedicated to determining which post-remission therapy option high-dose chemotherapy alone, high-dose chemotherapy with autologous stem cell support, or allogeneic stem cell transplantation is the optimal approach for a given patient. Moreover, younger patients with non-APL AML cannot be considered as a single entity since the current treatment algorithm indicates that post-remission therapy should involve a risk-adapted approach.

In general, this means that those with higher risk disease less likely to remain in long-term remission with a chemotherapy alone strategy should be allocated to receive an allogeneic stem cell transplant. Induction therapy should consist of an anthracycline-like agent for 3 days, in conjunction with cytarabine for 7 days. While various anthracyclines or anthracycline-like agents have been compared to standard daunorubicin, little consensus has emerged as to the optimal agent. Some studies suggest that idarubicin might be better than daunorubicin, but questions of dose equivalence made such comparisons difficult.

Patients who had an FLT3 ITD mutation, those with high white count, or those between ages 55 and 60 did not benefit from this more dose-intensive approach. An alternative induction including idarubicin alone and continuous infusion high-dose ara-C cytarabine is used at the MD Anderson Cancer Center. One problem with comparison of one drug to another is the question of dose intensity. The dose of cytarabine has also been investigated during induction. Another question has been whether or not intensifying cytarabine during induction might be beneficial. Replacing high-dose cytarabine with standard dose cytarabine has also been attempted, with results suggesting a possible benefit in disease free but not overall survival for those receiving a more intensive induction regimen.

Giving chemotherapy during leukemic stem cell recovery would presumptively be effective, since many cells would be going into S phase and be susceptible to chemotherapy. Although such a regimen in children seems to be highly effective, there are only uncontrolled reports of the efficacy of timed-sequential approach in adults.

Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety

This method has not been widely adopted. A variation of the timed-sequential approach is represented by administration of hematopoietic growth factors prior to chemotherapy, in an attempt to maximize the number of leukemic cells at S phase prior to the use of cytotoxic agents. While most randomized studies of using this so-called priming strategy have been negative, one important large prospective trial conducted by the HOVON group suggested pre-administration of granulocyte colony-stimulating factor GCSF would allow remission to occur at a lower level of tumor burden, thereby leading to superior long-term and overall survival rate.

The standard of care remains 3 days of anthracycline, 7 days of cytarabine, with reinduction in the event of positive leukemic cells in the adequately cellular marrow obtained 15 to 22 days after the start of induction.

Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics

For those who fail to achieve remission after one or two cycles of induction chemotherapy, the prognosis is poor. These so-called refractory patients are often salvaged with a high-dose ara-C based regimen. If the salvage attempt is successful, then they should be taken to allogeneic stem cell transplant using the best available donor, even if that is an alternative donor such as haplo-identical matched donor or a cord blood unit or units. For those who achieve remission, several potential strategies can be undertaken to try to reduce the leukemic burden down to a level compatible with cure.

These strategies include a chemotherapy-based approach, a high-dose chemotherapy approach with autologous stem cell rescue, or allogeneic stem cell transplantation. Chemotherapy is thought optimal if it includes high-dose ara-C. These regimens were then followed by a lower-dose regimen involving 1 day of daunorubicin and 5 days of subcutaneously administered low dose ara-C. This trial demonstrated that patients under age 60 who were randomized to the high-dose arm enjoyed a superior disease-free and overall survival, compared to those randomized to the lower-dose arms.

Importantly, this disease-free and overall survival benefit was only seen in patients under age Moreover, subsequent studies revealed that patients who benefitted the most from the intensified high-dose ara-C were those who had an inversion 16 or t 8;21 chromosomal abnormality, the so-called CBF or core binding factor leukemias. While subsequent studies have failed to demonstrate that high-dose ara-C is superior to other intensive regimens and that the very high doses used in CALGB are required, the overall point is that if chemotherapy is chosen, it should be given intensively.

The value of maintenance therapy is debated in AML and is not generally used, although one trial performed in Germany did suggest a benefit. While high-dose chemotherapy with autologous stem cell rescue has never been demonstrated to be superior to several cycles of an intensive chemotherapy regimen, proponents argue that the total time of myelosuppression is actually lower with a single cycle of the so-called autologous transplant.

On the other hand, it may be more difficult to salvage patients with an allogeneic transplant if they relapse after high-dose chemotherapy with autologous stem cell rescue, than if they were treated with an intensive chemotherapy-based approach. A very important post-remission strategy is allogeneic stem cell transplant. Omacetaxine and chemgenex are semisynthetic HHT derivatives that combined with imatinib showed promising activities. Histone deacetylases HDAC are the catalysts in deacetylation of lysine residues at the amino termini of core nucleosomal histones.

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Histone deacetylase inhibitors HDI such as suberoylanilide hydroxamic acid SAHA, vorinostat , generate hyperacetylated histones, causing transcriptional upregulation of the cyclin-dependent kinase inhibitor, p21, cell-cycle arrest and apoptosis in tumor cells. SAHA also induces expression of a key cell-cycle regulator p27, and its application is associated with downregulation of the p Bcr-Abl protein. The mentioned combination induces apoptosis in imatinib-resistant CML cell lines as well. A published study showed that when combined with imatinib, the HDI valproate can increase the antileukemic efficacy and sensitize imatinib-resistant CML cells Kantarjian, O'Brien et al.

Proteasomes are responsible for the degradation of different cellular proteins. However, if a low dose bortezomib exposure of CML cell lines is followed by imatinib, there are some additive effects. Semi-synthetic drugs flavone and flavopiridol are going through clinical trials. They target multiple cyclin-dependent kinases. Flavopiridol showed a very promising activity in combination with imatinib for inducing apoptosis in Bcr-Abl-positive CML cell lines Melo and Chuah Current FTIs under investigation and with a potential as antileukemic agents are tipifarnib and lonafarnib.

Abl through protein-protein interactions and to play a central role in leukemogenic transformation. The combination imatinib and tipifarnib was well tolerated and active in patients with imatinib-resistnat CML — a partial cytogenetic response was achieved in patients harboring the TI mutant. Lonafarnib is a selective inhibitor of primary progenitor cells derived from CML patients. It reduced colony formation of progenitor cells and showed activity in imatinib-resitant CML cell lines. However, the reports from a pilot study demonstrated that only 2 of 13 patients achieved a clinical response.

The combination between sorafenib and vorinostat HDAC inhibitor triggers cell dysfunction through Mcl-1 downregulation and p21 inhibition. The last two combinations were tested with a positive effect in patients with TI mutation. Because of the challenging pharamokinetic properties, clinical advancement is unlikely, but a derivate PD is under development Burke, Swords et al. Rapamycin sirolimus is the prototype compound of this group, but it has poor aqueous solubility and chemical stability, limiting its clinical usefulness. However, in a small clinical trial four out of six patients with imatinib-resistant disease responded to oral rapamycin.

The combination between imatinib and another mTOR inhibitor, everolimus, was associated with an increased expression of c-Abl and inhibition of Bcr-Abl. In the presence of inhibited Bcr-Abl, c-Abl enetrs the nucleus an modulates apoptosis. A Phase I trial with imatinib and everolimus has been completed while a study with temsirolimus is currently in accrual Burke, Swords et al. After interferon therapy they had disease-free survival beyond 10 years.

There are some clinical trials that showed succesful combinations between TKIs and interferon which provided an adjunct immunologic response during induction or maintenance therapies. Treatment with interferon after imatinib was shown to be followed by a possible remission status Burchert, Muller et al.

Howerver, additional data are required in order to clarify the role of interferon in conjunction to the TKI therapy. In the imatinib era, however, ASCT is becomning second or even third option for these patients if hematological, cytogenetic or molecular remission with imatinib is not achieved after 3,12 and 18 months, respectively Baccarani and Dreyling ASCT is still the only treatment that offers a definitive cure. The risks of ASCT are some mortality rate, graft-versus-host disease GVHD , potentially lethal acute or chronic infections death and risk of second malignancy.

There are no data about negative influence on ASCT of pre-treatment with tyrosine-kinase inhibitors.

This confirms the fact that the outcome of ASCT is highly dependent on risk factors. EBMT study showed that favorable factors are sibling donor, treatment at early stage of the disease, under 12 months after diagnosis, and younger age of the patient age under 20 years is better than years, and above 40 the risks are higher. If successful, ASCT can lead to long-lasting results. In a year study of patients transplantated with an allogeneic bone marrow from siblings, the mean time of hematologic or cytogenetic disease recurrence was 7.

National Marrow Donor Program institutions in the U. The results from this study confirm that patients transplantated with bone marrow from a non-relative donor have greater risk of complications. Imatinib is now the most common first line drug for the treatment of CML and is a hallmark of target drug therapies for malignant diseases. Single agent therapy with imatinib may not be the best long-term option in many of the CML patients and other approaches should be considered. There are many novel compounds that are in development and in preclincal and clinical trials, some of them showed very promising results.

It is very likely that new Bcr-Abl mutants will become resistant to these small-molecule inhibitors. Therefore, other therapeutic approaches are required. The combination of TKIs with other inhibitors of non-Bcr-Abl targets is needed to overcome the resistance. Help us write another book on this subject and reach those readers.

Login to your personal dashboard for more detailed statistics on your publications. Edited by Margarita Guenova. By Chandrika Gowda, Olivia L. Payne and Sinisa Dovat. We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists.

Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Zaharieva, G. Amudov, S. Konstantinov and M. Downloaded: Introduction Chronic myeloid leukemia is one of the most thoroughly studied and, undoubtedly, best understood neoplasms. First generation tyrosine-kinase inhibitors — Imatinib Imatinib was introduced for clinical use in for the treatment of CML. Second generation tyrosine-kinase inhibitors 2.

Nilotinib Nilotinib is a highly selective ABL inhibitor and derivative of Imatinib and can overcome some mutations that can cause imatinib resistance with the exception of TI. Dasatinib Dasatinib is another ABL kinase inhibitor that binds to the active conformation of the ABL-kinase domain and to the structurally related kinases of the Src-family. Daily b Salvage therapy: Dasatinib 70 mg mg b. Daily Nilotinib mg b. Daily Imatinib high-dose mg b.

Daily 2. Accelerated phase and blast crisis of CML: Imatinib mg p. Daily Dasatinib 70 mg b. Daily 3. Table 1. Treatment schedule with tyrosine kinase-inhibitors. Experimental drugs for CML therapy 3.