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Acute myelogenous leukemia (AML)

Uncontrolled proliferation of myeloid blast cells in marrow and peripheral blood associated with anemia, thrombocytopenia and neutropenia.

A heterogenous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues.

Defined as the presence of at least 20% myeloblasts or equivalents in the blood or bone marrow, with a localized accumulation of myeloblasts in tissues, so called myeloid sarcoma.

Blast  counts include myeloblasts, monoblasts and megakaryoblasts.
Evaluation includes past history to reveal antecedent bone marrow disease and previous exposure to radiation, chemotherapy, or leukemogenic toxins such as benzene and organochlorine insecticides.
Assessment includes a bone marrow aspirate for cytology and cytochemistry, including Sudan Black B, myeloperoxidase and esterase staining, immunophenotyping in the trephine biopsy for histology at diagnosis.
Bone marrow biopsy is mandatory in patients with a dry-tap.
Flow cytometry is required for diagnosis of specific AML entities.
Cytogenetic classification is based on the valuation of at least 20 metaphase.

Certain cytogenic abnormalities including t(8:21), inv(16), and t(15:17) is sufficient to establish the diagnosis without the blast threshold of 20% having been reached.

Genetically heterogeneous clonal disorder characterized by accumulation of somatically acquired genetic alterations in hematologic progenitor cells that alter self renewal, proliferation and differentiation (Frohling S et al).

Molecular studies are necessary to detect mutations and should be tested for FLT 3 gene, NPM1, PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11, double CEBPA,IDH1and IDH2.

Increased numbers of cases of AML can be categorized on the basis of underlying genetic defects and define clinical/pathological entities.

Approximately 18,120 individuals affected per year in the U.S.(3800 will be children), with approximately 10,000 deaths per year.

Estimated 21,380 individuals in United States wiere diagnosed in 2017, with 10,590 deaths.

Constitutes roughly 1.3% of all new cases of cancer and the incidence is approximately 4.2 per hundred thousand persons per year.

Most patients with AML die of their disease.

Approximately 90% of AML patients diagnosed with the disease after age 60 will ultimately experience a relapse after having an initial remission using intensive chemotherapy.

Clonal evolution, epigenetic alterations leading to aberrant DNA methylation, and persistence of leukemia initiating cells despite chemotherapy,  contribute to disease recurrence.

Age dependent.
With advanced age, the relative incidence of AML with generic abnormalities decreases, while  the relative increase of other AML categories such as AML with Myelodysplasia or therapy related AML increases with age, comprising about 19% and 17%  of AML cases, respectively.

Most common form of acute leukemia among adults, and accounts for the largest number of deaths annually from leukemia is in the US.

Median age of presentation about 70 years.

Elderly patients with AML are much more likely to have unfavorable risk factors, either unfavorable cytogenetics or unfavorable molecular genetics which makes their disease more resistant to induction type of chemotherapy.

The longer duration of first remission is associated with better survival outcomes.

Median age at death 72 years.

Five-year survival is about 26.6% (NCI).

Long term survival is approximately 35-40% of adults who present at age 60 years or younger, but only 5 to 15% of those older than 60 years at presentation will achieve long-term survival.

Survival rates among patients 65-74 years is approximately 5.3% those 75 years or older 1.6%.

Patients have relatively high early mortality rate of 37.5 percent at 8 weeks as well as a high overall mortality rate of 76% at 3 years (Oran B, Walter RB).

Accounts for 80% of adult acute leukemias.

Incidence increasing.

Incidence 3-4 new cases per 100,000 persons per year.

Rare in children and young adults.

Accounts for 1.5% of cancer deaths.

Most common type of acute leukemia in adults.

An estimated 21,380 people were diagnosed with AML and 10,590 patients died in 2017.

Patient 60 years of age and older fare worse than younger counterparts, with five-year survival rates of only 3-8% in older patients compared with up to 50% in younger patients.

SEER data suggest current five-year survival rate of only 26.6% for all subtypes combined.

sperm cryopreservation should be proposed before starting therapy, especially in patients due to undergo allogeneic hematopoetic stem cell transplant.

In females ovarian tissue cryopreservation maybe carry out before hemopoietic stem cell transplant if patients are in complete remission.

Treatment related disease, which occurs after cytotoxic chemotherapy accounts for approximately 15% of new cases.

Incidence increases with age from approximately 1 per 100,000 in the 25-29 year age group to 23 per 100,000 among people 75-79 years of age.

Approximately 55% of cases diagnosed in persons 65 years or older.

Slight increase incidence in males and in individuals of European descent.

The risk is increased in patients with Hodgkin�s disease having had a splenectomy.

Risk increased with exposure to ionizing radiation and benzene.

Radiotherapy especially in the context of myeloablative therapy given before hematopoietic cell transplantation may also increase the risk for therapy related AML.

Can be the end result of myelodysplastic and myeloproliferative disorders.

The presence of MDS associated genetic abnormalities, or greater than 50% dysplastic cells in the bone marrow suggestive diagnosis of myelodysplastic related AML.

Prototypical disease linked to environmental, occupational exposure.

About 15% result from treatment with alkylating agents or exposure to topoisomerase II inhibitors.

Treatment with antimetabolites, such as the purine analogue fludarabine is associated with AML.

With exposure to alkylating agents there is a medium latency period of 3-6 years and a myelodysplastic phase prior to transition to AML.

Associated with alkylating agents associated with a deletion of all, or the long arm of chromosomes 5 or 7.

Associated with etoposide or other topoisomerase II inhibitors have a shorter latency period than that with alkylator exposure and is not associated with a myelodysplastic phase.

Associated with topoisomerase inhibitors have MLL/ALL-1 gene rearrangements on chromosome 11q23.

The disease course of therapy related AML is generally more resistant to conventional treatment.

Approximately 5-10% of patients have aberrations of chromosome band 11q23.

In adults it is a complex group of malignancies with diverse genetic causes.

Associated with perturbation or arrest of programs that involve differentiation of cells, and acquisition of the ability of malignant cells to ignore cues to constrain total production of cells.

As a result of the two factors above leukemic clones are produced with the accumulation of nonfunctional blasts resembling primitive cells, but they cannot for the most part divide.

Suspected that malignant cells initiated and maintained by self-renewing leukemic stem cells that comprise a subset of the total leukemic burden.

Mutations NPM1, CEBPA, and FLT3 mutations aid in diagnosis, risk assessment and guide therapy decisions and these mutations should be analyzed in patients particularly with cytogenetically normal AML.

BCL2 expression is increase in AML blasts, and the majority of AML stem cells express high levels of BCL2 and are dependent on BCL2 for survival.
Hi expression of BCL2 is associated with poor response to chemotherapy and poor survival in AML.

AML genomes average 13 mutated genes per case.

An average of only 5 genes are recurrently mutated in AML.

The top 10 genes mutated at higher than 5% frequency include: FLT3, NPM1, DNMT3a, IDH1, IDH2, TET2, RINX1, p53, NRAS, CEBPa, and WT1.

FLT3 internal tandem mutations are associated with poor outcomes compared to the wild type FLT3.

In AML FLT3-TKD and NPM1 mutations, when they occur  together indicate a better prognosis.

NPM1 mutations have improved survival compared to wild type NPM1.

CEBPA mutations are associated with improved outcomes

NPM1 mutations is a mislocalization in the exon 12 of the gene.

NPM1 mutations are found in approximately 1/3 of adult cases of AML, and is the most frequent mutation in the disease.

NPM1 mutations are associated with other genetic changes such as secondary chromosomal abnormalities like +8, +4, del((q), and additional gene mutations most frequently FLT3 and IDH1.

Approximately 20-25% of patients with AML have an IDH1 or IDH2 mutation.

IDH2 mutations  are more common than IDH1 mutations in AML, occurring in approximately 15-20% of patients.

Patients with IDH mutations and NPM1 mutations usually do well.

Patients with mutations in IDH & FMS-like tyrosine kinase e  (FLT 3) do less well.

The presence of IDH mutation is prognostic and predictive of a response to certain kinds of therapy.

RUNX1, the runt-related transcription factor 1 gene is associated with chromosomal rearrangements or intragenic mutations in acute leukemia.

RUNX1 mutations are associated with resistance to therapy and inferior outcome, and was found to be present in 5.6% of younger adult patients with AML (Gaidzik VI et al).

RUNX1 mutations are associated with undifferentiated morphology and with specific chromosome abnormalities including trisomy 21 and trisomy 13.

RUNX1 mutations have been detected in almost half FAB M0 cases and in 80% of cases of trisomy 13.

RUNX1 mutations found to be present in 13.2% thyroid is adult patients with AML (Tang JL et al).

CDKN2A gene mutations linked to poorer survival.

Leukemic stem cells are among fraction of cells with positive CD34 and negative CD38 expression and give rise to leukemic progenitor cells positive for CD34 and CD38, which further differentiate into negative CD34 leukemic blast population.

Less than 1% of undifferentiated blast AML cells are capable of further division and <0.01% of blasts can cause the development of leukemia in suceptible mice when injected intravenously (Wang, Y).

11q23 genetic lesions occur de novo as well as therapy related to use of topoisomerase II inhibitors, such as Etoposide.

11q23 aberrations commonly affect the MLL gene and most such genetic changes are reciprocal chromosomal translocations t11q23.

Incidence per 100,00 persons is 1.2, 2.3., 7 and 21.3 at age 20, 45, 60, and 80 years, respectively.

Incidence appears to be rising with increasing myelodysplasia, and as a result of leukemia in survivors of childhood solid cancers, Hodgkin’s disease, breast cancer, sarcoma, lymphomas and testicular cancers.

Characteristic finding is a leukemic bulge which is the appearance of immature leukemic cell in the blood and bone marrow without terminal maturation.

Promyelocytic and oncotic leukemias are associated with a coagulopathy.

Blasts proliferate from autocrine production of myeloid growth factors.

About 10% of cases present with a white blood cell count higher than 100,000/microL.

Goal of therapy to reduce blasts to undetectable levels in the bone marrow (less than 5%) and peripheral blood (no circulating blasts), and to reconstitute normal hematopoiesis.

Aim of treatment is to induce a complete remission.

Despite aggressive therapy most patients eventually die of AML, as a consequence of impaired hematopoiesis, organ infiltration by malignant cells, or treated related toxicities.

Induction failure results can be assessed and defined either on day 15 of first induction therapy during aplasia with persistence of significant blast population, at blood count recovery after induction therapy between day 21 and day 35 when less than 50% reduction of blast percentage and a blast percentage above 25%, or in cases of partial response after first induction persistence of more than 5% blasts in the bone marrow after a second induction therapy.

Standard induction therapy with an anthracycline plus cytarabine has a rate of complete remission of 60-80% in patients younger than 60 years and a rate of approximately 50% in older patients. (cytabrine arabinoside by continuous infusion over 7 days and anthracycline daily times 3 days).

Combination of an anthracycline and cytabrine is standard therapy for the induction of remission (3+7 regimen).

Treatment of patients 60 years or younger with AML is divided into two phases: induction of remission and post remission therapy.

The death rate within 30 days of receiving traditional induction chemotherapy ranges from 5-10%.

The goal of induction chemotherapy in AML is to lower the presumed 10 to the 12th cells which are present at the time of diagnosis to an undetectable status by morphological analysis of the blood, bone marrow to 10 to the 9 cells which I felt to be present at the time of complete remission.

Options for postcondition therapy includes highly myelosuppressive chemotherapy for 3-4 cycles, or high-dose chemotherapy with autologous stem cell transplantation, or allogeneic stem cell transplantation

In a phase 3, randomized trial of 667 patients between the ages of 17 and 60 years with untreated AML to receive three days of standard dose daunorubicin or high dose 90 mg per square meter, combined with standard dose cytosine, arabinoside by continuous infusion: the high dose daunorubicin regimen resulted in a higher rate of complete remission of 70.6% vs. 57.3% and the overall improved median survival of 23.7 vs. 15.7 months with similar rates of serious adverse events (Fernandez HF).

In the above study, high dose daunorubicin did not improve the benefits in patients over the age of 50 years, those with unfavorable cytogenetics, and those with FLT3-ITD mutation or the MLL-TDT mutation.

In patients with AML or high risk refractory anemia, ages 60 to 83 were randomly assigned cytosine at 200 mg per meter squared by continuous infusion for seven days plus daunorubicin for three days at conventional doses or an escalated dose of 90 mg for me square and the treatment was followed by a second cycle of cytosine at 1 g per meter squared. for six days: the complete remission rate in the high dose daunorubicin group was 64% vs. 54% in the group that received the conventional dose,and the rate of remission after the first cycle of induction chemotherapy were 52 and 35%, respectively (Lowenberg).

In the above study patients 60 to 65 years of age receiving the higher dose had a higher rate of complete remission 73% vs. 51%.

Liposomal daunorubicin and cytarabine had a better response rate and survival rate then standard 7+3 induction therapy.

Approximately 2-3 weeks after standard chemotherapy 3+7 the bone marrow is assessed and if the bone marrow continues to show blasts the patient typically receives a second course of the same treatment.

If the bone marrow after standard chemotherapy shows hypoplasia the second course of treatment is delay until evidence of disease reemerges.

In situation where complete remission is not reached, or who have an insufficient early effect on bone marrow blasts, induction should be repeated.

Complete remission is defined as having less than 5% blasts in the bone marrow, no blasts in the peripheral blood, adequate granulocytes of greater than 1500/microL and platelets greater than 100,000/microL counts.

CR with platelet recovery >400,000/mcl at day 30 associated with better outcomes (Mangaonkar, A et al).

Following a complete remission a consolidation treatment is administered and is associated with a median duration of remission of 12-15 months.

The fraction of patients that become long-term survivors increases with the intensity of consolidation management.

Standard treatment cures about half of children with AML.

Among patients aged 60 years or older have an induction mortality ranging from 10-82% with increasing age and worsening performance status.

Older patients have a worse prognosis due to disease biology and individual patients factors.

Mortality reflects inherent resistance to therapy and in part the deleterious and at times lethal effects of treatment.

Supportive care of AML patients undergoing aggressive curative intent chemotherapy has improved substantially in recent years.

A review of 1,834 patients with de novo AML found that patients older than 60 years had a worse outcome with worse karyotypes, higher LDH levels, elevated WBC counts and day 16 blasts (Buchner).

Approximately 50% of patients fail the induction regimen because of resistant disease, and half fail secondary to major complications of treatment.

Approximately 50% of patients fail the induction regimen because of resistant disease, and half fail secondary to major complications of treatment.

Myeloid growth factors G-CSF or GM-CSF administered after chemotherapy shorten the period of neutropenia, especially in older patients.

Use of myeloid growth factors does not decrease the rate of complete remission, and does not improve the overall prognosis of the disease.

5-15% of children treated with chemotherapy succumb to toxic effects of treatment.

In childhood 29-60% experience at least 1 microbiologically documented infection (Riley LC).

Increased incidence seen in patients with excessive chromatin fragility including the Bloom syndrome, Fanconi�s anemia, Wiskott-Aldrich syndrome Kostmann syndrome and ataxia telangiectasia syndrome.

Higher incidence of AML in Down syndrome (trisomy chromosome 21), Klinefelter�s, syndrome (XXY) and Patau syndrome (trisomy chromosome 13).

The diagnosis requires the presence of 20% blasts a number enumerated from all nucleated cells in the blood and bone marrow  in most cases.

The blast count should be obtained from at least a 200 cell count of all nucleated cells in the blood and a 500 cell count of all nucleated cells in the bone marrow.

French-American-British (FAB) classification based on morphology, cytochemical stains and incorporating immunophenotyping to differentiate cells into 8 different subtypes.

French-American-British (FAB) classification:

M0-myeloblastic with minimal differentiation and must demonstrate CD13 or CD 33 accounting for 3% of cases.

M1-myeloblastic without maturation, minimal evidence of granulocytic differentiation myeloperoxidase positive azurophilic granules and Auer rods. Accounts for 15-20% of cases.

M2-myeloblastic with maturation beyond promyelocytes, promonocytes and monocytes <20%, cells contain azurophilic granules and Auer rods. Accounts for 25-30% of cases.

M3-promyelocytic type with heavy granulation. Accounts for 5-10% of cases.

M5-monoblastic type with large blasts with delicate lacy chromatin and occasional prominent vesicular nucleoli with basophilic cytoplasm. Accounts for 2-9% of cases.

M6-erythroblastic disease with erythropoiesis component exceeding 50% of all nucleated cells. Accounts for 3-5% of cases.

M7-megakaryoblastic type with blasts that look like megakaryocytes and stain positive for factor VII, often with bone marrow myelofibrosis and Aaccounts for 3-12% of cases.

World Health Organization (WHO) classification includes prognostic factors with molecular markers, chromosome translocations, and evidence of dysplasia with 17 subclasses.

WHO classification incorporates cytogenetic data and defines 4 major types of AML.

WHO classification requires a minimum criterion of 20% blasts, including cases previously identified as high-grade myelodysplasia (MDS).

Chromosomal abnormalities that target the core binding factor leukemia include t(8;21)(q22;q22) and inv(16)(p13;q22).

Good risk cytogenetics is associated with the core binding factor translocations including t(8:21) and inv16 and t(15:17).

In core-binding leukemias, high dose cytarabine-based regimens can result in cure rates of 60-80%.

Translocation(8:21) and inversion 16 associated with 80-90% remission rates and prolonged disease survival, especially with the use of high dose cytabrine at postremission.

Poor risk cytogenetics associated with -5, -7,del(5q), abn(3q),the(9:22) or combination of three or more abnormalities.

Molecular studies to detect the presence of mutations in the FLT3 Jean or tyrosine kinase domain is carried out immediately to allow timely initiation of FLT3  inhibitor.

Deletions of chromosomes 5 and 7 as well as deletions of other chromosomes and certain translocations are associated with a poor prognosis.

Normal karyotype associated with intermediate prognosis.

Multidrug resistance over expression(MDR1) occurs less frequently in young patients with acute myelogenous leukemia.

Multidrug resistance over expression(MDR1) in older patients with acute myelogenous leukemia have a high rate of MDR1, 71%,.

Multidrug resistance over expression(MDR1 increased expression in AML in patients with favorable or intermediate cytogenetics have a decreased complete remission rates and, in some studies, poorer survival.

MN1 overexpression with a normal karyotype characterized by an intermediate prognosis.

Patients with high MN1 expression have a worse prognosis than patients with low MN1 expression.

Good, standard and poor risk cytogenetic individuals have complete remission rates of 80-90, 70-80- and 50-60%, respectively, with event free survival rates of 40-60, 30-40, and 5-20%, respectively.

Persistent cytogenetically abnormal cells after complete remission after induction therapy predicts for shorter relapse free interval, and overall survival (Chen Y et al).

Patients who have persistent cytogenetically abnormal cells after chemotherapy induction should be considered for HSCT in first remission.

Among intermediate and poor risk groups fewer than 20% of patients achieve long term event free survival with no significant improvement in decades of care.

t(8;21)(q22;q22) occurs in 8% of patients with AML, and in most cases associated with M2 FAB subtype with granulocytic maturation and in a minority of case with marrow eosinophilia or mastocytosis.

t(8;21)(q22;q22 associated with extramedullary leukemia involving the orbit or head and neck sites in children and paraspinal sites in adults.

Extra medullary AML involvement has been found in 70% of patients when using pet scans.

A 29 fold higher level of complex aberrant karyotypes among patients over the age of 60 years compared to individuals 20-29 years of age (Shoch).

About 50% of newly diagnosed cases are in a cytogenetically normal subgroup.

A second subgroup of AML patients are characterized cytogenetically by translocations of the core binding factor genes AML-1 (21q22) and CBFB (16q22): t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(q13;q22)-with modestly improved prognosis compared to other subgroups.

A third cytogenetic subgroup involve chromosomes 3,5 and 7 abnormalities or complex cytogenetic changes with a poor outcome.

Cytogenetics helps in the recognition of the prognosis and can help choose appropriate post remission consolidation management: high-dose cytarabine useful for consolidation for core binding facto AML and allergenic hematopoietic stem cell transplantation for adverse risk karyotype AML in first complete remission.

In patients older than 60 years high rates of treatment related mortality and neurotoxicity from cytarabine, at all dose levels, in the postremission setting, and a continued complete remission at 4 years of less than 16% (compared to 24-44% in patients younger than 60 years) (Mayer RJ et al).

Incidence peaked 5-7 years in survivors of atomic bombs in Japan.

Isocitrate dehydrogenase (IDH) mutations in AML may promote leukemogenesis and are associated with AML progression.

Therapeutic radiation, particularly with the use of alkylating agents increases the risk of AML.

Median age at onset ranges from 65-70 years of age.

Older patients have a high proportion of intermediate and unfavorable cytogenetics, a high incidence of antecedent hematologic disorders such associated myelodysplasia, a high frequency of the multi-drug resistance gene (MDR-1), a high incidence of trilinear dysplasia and an increased incidence of FLT3 internal tandem duplication, the most frequent gene mutation in AML accounting for poor prognosis.

FLT3-activating mutations occurs in 30% of patients and is associated with a poor prognosis.

FLT3 refers to fms-like tyrosine kinase-3 gene.

The overpresentation of internal tandem duplication relative to the wild type FLT3 allele is especially predictive of a poor outcome.

FLT3, a member of the class 3 tyrosine kinase family and is seen with normal karyotypes.

FLT3 expressed on early lymphoid and hematopoietic progenitors cells playing a role in myeloid differentiation and early stem cell survival.

FLT3 detected in about one quarter of patients with newly diagnosed disease and is associated with leucocytosis and increased risk of relapse.

In patients that have blasts with cuplike nuclei there is a high frequency of FLT 3 mutations with internal tandem duplication in the juxtamembrane domain and nucleophosmin 1 gene mutations in these leukemias.

Cytogenetics provides the most important prognostic information.

About half of adults lack clonal chromosome aberrations at the time of diagnosis and these patients have an intermediate prognosis with 40% long term survivorship.

Approximately 35-45 percent of younger patients can be cured with intensive chemotherapy.

In patients who are older than 60 years of age only 5 to 10 percent of patients are long-term survivors.

Poor survival in older patients reflects higher degree of adverse prognostic factors and comorbidities, as well as a preference not to treat such patients as aggressively.

Fewer than 15% of patients over the age of 60 years survive 2 years.

In a study of 3,439 patients with AML aged 65 years and older who received conventional induction treatment fewer than 7% were alive at 2 years (Lang).

The utilization of high dose ARA-C in consolidation therapy had led to an overall survival of 44% without relapse at 4 years.

Approximately 50% of older adults achieve complete remission while those with unfavorable cytogenetic will achieve a 30% complete response rate with conventional chemotherapy.

Post remission treatment is essential to increase remission duration and survival.

Patients who undergo complete remission and have consolidation therapy with an allogeneic transplant, autologous stem cell transplant or high-dose cytarabine have survival rates of 40-50% 4 years after treatment.

Hematopoetic cell transplantion early in the disease improves outcomes.

Hematopoetic cell transplantion is recommended for patients with intermediate and poor risk disease in first complete remission.

The anti-leukemic effect of allogeneic hematopoietic stem cell transplantation (HSCT) is provided by T cells and natural killer (NK) cells.

T cells recognize malignant cells with tumor antigens presented by HLA molecules.

NK cells recognize changes in HLA induced by transformation, stress, or infection.

For children and adolescents allogeneic transplant is the most effective treatment to achieve initial remission.

Only about 1/3 of patients with AML who have detectable amounts of cancer cells in their blood at the time of allogeneic hematopoietic transplantation will be alive 3 years later, compared with nearly 3/4 of those without minimal residual disease.

Achievement of measurable residual disease (MRD) is associated with superior disease free survival and overall survival in AML.

The estimated five year disease free survival is 64% for patients without MRD and 25% for those with MRD  and the estimated overall survival was 68th% for patients without MRD and 34% for those with him or decrease

Younger patients with favorable cytogenetic profiles t[8,21], inv[16], or t[15,17] have a CR rate of 80% and have a 40-50% chance of cure with chemotherapy alone.

Patients with unfavorable cytogenetics have initial rates of CR lower than 50% and the disease may be incurable if treated with standard therapy.

Among patients with no cytogenetic abnormalities the rate of CR is 60-70%, but the rate of long-term disease-free survival is only 10-20%.

Core-binding factor (CBF) acute myelogenous leukemias most commonly contain either t(8;21)(q22;q22) or inv(16)(p13q22) chromosome aberrations and constitute approximately 15-20% of de novo AML’s in patients under 60 years.

CEBPA mutations in AML patients with otherwise normal cytogenetics is a strong postive prognostic indicator.

All patients should be tested for FLT3 mutations as this marker is strong negative prognosticator.

Recommended that FLT3, CEBPA and NPM1 be tested on patients to categorize normal cytogentic patients with AML.

The presence of inv3, the(6;9), t (9;22), monosomies of chromosomes 5 or 7 11q23 abnormalities and combinations of three or more different cytogenetic alterations predict for a poor prognosis.

Core-binding factor (CBF) acute myelogenous leukemias have a significantly better prognosis than that of patients with AML with other chromosome aberrations or a normal karyotype.

Unfavorable outcomes for patients with class M3, M5, and M6 AML, advanced age and high white blood counts.

Elderly are more likely to have resistant disease as a result of P-glycoprotein, more likely to have unfavorable cytogenetics, often have poor performance status and more comorbid medical conditions than younger patients.

Five-year survival for patients over the age of 65 is approximately 5%.

In a study of 3,439 patients with AML aged 65 years and older who received conventional induction treatment fewer than 7% were alive at 2 years (Lang).

Conventional chemotherapy in patients over the age of 75 years with poor performance status 3, the 30 day mortality is greater than 80%.

Southwest Oncology Group Committee study found 35% unfavorable risk cytogenetics in patients 55 years or less, and 51% of cases of those 75 years or older.

Southwest Oncology Group Committee study found favorable risk cytogenetics from 17% in patients 55 years of age or younger and 4% in those 75 years or older.

Southwest Oncology Group Committee study found patients overall survival with unfavorable cytogenetics was decreased from a median of 11 months for younger patients to 4 months for those 66 years or older.

Low dose ARA-C in elderly patients associated with a median survival less than 3 months.

Elderly patients have a poor prognosis with a 2 anf five-year overall survival rate of approximately 10% and 2%, respectively (Menzin J, SEER results).

Elderly patients receiving intensive chemotherapy at a median survival of only 5-13 months.

Treatment options for elderly patients: standard 3+7, low dose AraC 20 mg bid x 10 days, Azacitidine 75/m2/d, Decitabine 20 mg/m2 daily x 5days.

80-90% of AML blasts express CD33 cell surface marker.

Risk factors include exposure to high levels of ionizing radiation, long-term exposure to benzene, myelodysplastic disorder, myeloproliferative disease, and previous treatment for another malignant disease with alkylating agents or topoisomerase-2 inhibitors.

The use of high-dose cytabrine, autologous or allogeneic stem-cell transplantation soon after induction of a first remission have failed to improve the outcome in any substantial way in randomized trials.

The best predictor of outcome from transplantation is the status of the disease at the time of transplant: the 10 year overall survival is 17% for patients with induction failure or relapse, in patients in first complete remission it is 57% in the Stanford experience (Negrin RS).

Outcomes from transplantation vary with cytogenetics and molecular markers.

Patients with nucleophosmin gene (NPM1) have favorable prognosis and generally do not require a transplantation, while mutations of the FMS-like tyrosine kinase 3 gene (FLT3) have unfavorable prognosis with chemotherapy and may respond better with transplantation.

Cytogenetic and molecular markers should be done on all patients with AML.

Approximately 80-90% of children with AML attain remissions and 70% have long term remissions with chemotherapy or stem cell trnsplantation.

Allogeneic stem cell transplant is treatment of choice for patients with AML at high risk for relapse or have resistant disease.

Allogeneic hematopoetic cell transplant outcomes of largely dependent on remission status at the time of allografting, with anticipated overall survival rate of 15-30% in relapsed/refractory disease or primary induction failure and 50%-75% in patients who receive allograft during the first complete remission.

Allogeneic hematopoietic cell transplantation is preferred treatment for patients with AML and high risk cytogenetics as noted in the AML CG-99 study where patients were treated after induction therapy and in the first complete remission compared to conventional post remission management: Five-year overall survival 48% versus 60% in five-year relapse free survival 40% versus 13% (Stelljes M et al).

Cyclophosphamide combined with ablative doses of total body irradiation or the oral alkylating agent busulfan have been the main conditioning regimens for allogeneic hematopoetic stem cell transplantation for patients with acute myelogenous leukemia.

Intravenous busulfan has increasingly replaced oral busulfan in conditioning regiments for allogeneic hematopoietic stem cell transplant.

In myeloid malignancies a comparative study of survival of busulfan intravenous versus ablative total body radiation resulted in superior survival of busulfan with no increased risk for relapse or treatment related mortality (Bredeson C et al).

American Society of Bone Marrow transplantation found no significant advanage of autologous SCT over chemotherapy in AML

Use of growth factors shorten the duration of neutropenia and reduce the incidence of neutropenia by a few days, they have no effect on the rates of remission or overall survival.

Postremission treatment with high-dose cytabrine produces longer relapse-free survival and survival than standard-dose cytabrine.

Postremission autologous transplantation results in superior relapse free survival when compared with intensive chemotherapy or no further treatment.

Postremission relapse free survival with allogeneic transplantation is significantly longer than that achieved with intensive chemotherapy.

Despite a remission rate of 60% for those older than 60 years only about 15% are alive at 3 years and the risk of relapse following remission is 80%.

Outlook for patients with relapse related to patients age, the length of initial remission, and cytogenetic findings at diagnosis.

Patients with first remission of 6 months or less do very poorly with a second complete remission rate of 10% compared to those whose first remission exceeded 18 months with a complete remission rate of greater than 50%.

Cells are not homogeneous, and leukemic stem cells may be in G0 stage of cell division rendering them resistant to cell cycle specific agents and may enable such cells to survive chemotherapy to develop dormancy and eventually cause relapse.

Patients in poor prognostic categories are recommended to have experimental treatment or hematopoietic stem cell transplants because of poor outlook with conventional therapy.

In relapsed or refractory patients have a poor prognosis with chemotherapeutic salvage regimens yielding a complete remission rates of less than 50% and an overall survival of less than 30%.

In AML significant heterogeneity in clinical outcome such that approximately 20% of patients are cured with the existing therapies, 20% of therapy refractory disease from the time of diagnosis, 50% relapse and die from refractory disease after initial response to leukemic treatment.

Azacitidine in older patients with low bone marrow blast count of 20-30% prolonged overall survival compared to conventional care regimens: With a median survival of 24.5 months compared to conventional therapy of 16 months, and a 2 year overall survival 50% compared to 16% for the conventional regimen. (Fenayx ).

Azacitidine In untreated patients with AML at least 65 years of age, is associated with an incidence of remission of 30% or less and survival of less than one year.

Patients with a first complete remission duration of less than 1 year or who do not receive a complete remission have a worse outcome.

Allogeneic stem cell transplant after myeloablative conditioning is a curative treatment option for younger patients with AML in first complete remission.

A systematic review and meta-analysis of prospective clinical trials comparing nonallogeneic stem cell transplant therapies to allogeneic stem cell transplants to patients with first clinical remission of AML resulted in significant relapse free survival and overall survival benefit for intermediate and poor risk AML patients but not for good risk patients (Koreth).

Gene expression score with leukemic stem cells in AML an independent prognostic factor, with a high score associated with poor overall survival, event free survival and relapse free survival in patients with normal karyotype, and inferior overall survival in patients with chromosomal abnormalities (Gentles AJ et al).

High leukemic stem cell scores (LSC) correlate with lower remission rates.

Most adopted therapy for post remission consolidation is high-dose ARA-C therapy given 3 g/ m squared over three hours every 12 hours on days one, three, and five for 4 courses.

The above therapy is for patients younger than 60 years of age who undergo non-transplant approaches to AML in first complete remission and it’s for patients with favorable chromosomal abnormalities.

FLT3 AML responds to acytidine 75mg/M IV x 7 days plus sorafenib 400 mg BID with A 46% response rate and 27% complete response rate.

((Midostaurin)) in combination with chemotherapy approved for FLT3 mutated AML.

Gilteritinib approved for management of FLT3 AML.

Enasidenib approved for AML with relapsed/refractory IDH2 disease.

IDH inhibitor ivosidenib targets IDH1 in AML.

IDH mutations occur in 20% of patients with a 40% overall response rate to enasidenib.

Venetoclax approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of adult patients with newly-diagnosed acute myeloid leukemia who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Venetoclax is a BCL-2 inhibitor that promotes apoptosis of AML cells.

In the trial of AML patients, untreated, with Ventoclax, and Azacitidine is associated with a longer survival in remission rate in those who received Azacitidine alone.

For FLT 3-mutated disease incorporating midostaurin added to standard therapy for AML.

Gemtuzumab ozogamicin approved for adults with newly diagnosed CD33 positive AML and adults and children age 2 years and older with relapse/refractory CD33 positive AML.

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