Acute Lymphoblastic Leukemia (ALL) & Acute Myeloid Leukemia (AML) PDF

PHAR 6477: Integrated Systems-Based Pharmacotherapy IIIB1Module 2: Oncology/HematologyIntroduction: Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML)Denise I. Pinal, PharmD, BCPPSClinical Assistant Professor –UTEP School of PharmacyAdjunct Asst. Prof. –TTUHSC Paul L. Foster School...

PHAR 6477: Integrated Systems-Based Pharmacotherapy IIIB1Module 2: Oncology/HematologyIntroduction: Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML)Denise I. Pinal, PharmD, BCPPSClinical Assistant Professor –UTEP School of PharmacyAdjunct Asst. Prof. –TTUHSC Paul L. Foster School of Medicine INTRO TO ACUTE LEUKEMIAS•Heterogeneous hematologic malignancies characterized by unregulated proliferation of the blood-forming cells in the bone marrow.•Immature proliferating leukemia cells (or blasts) crowd out normal cell maturation in marrow •Thisleads to anemia, granulocytopenia, including neutropenia, and thrombocytopenia•Blasts may also infiltrate other tissues: lymph nodes, skin, liver, spleen, kidney, testes, and the central nervous system (CNS)4/21/202 INTRO TO ACUTE LEUKEMIASacute lymphoblastic (or lymphocytic) leukemia (ALL)acute myeloid (or myelogenous) leukemia (AML)chronic lymphocytic leukemia (CLL)chronic myeloid leukemia (CML)4 major leukemias4/21/203 INTRO TO ACUTE LEUKEMIAS•Epidemiology•2019U.S. estimates show 27,380 new cases of acute leukemia diagnosed—21,450 (AML) and 5,930 (ALL) OR about 1.5% of total # of cancers diagnosed•~12,420 deaths per year, representing about 2% of all cancer deaths, are caused by acute leukemias•leading cause of cancer-related death in age <20 years•~75% of pediatric patients with leukemia have ALL•leading cause of cancer death for males 20-39yrs •AML(most cases are in adults)•80% AML vs 20% ALL4/21/204 INTRO TO ACUTE LEUKEMIAS•World Health Organization Classification of Acute Myeloid Leukemia and Related Neoplasms (table 151-2)•ALL is classified based on lymphoblast analysis.•Immunophenotype defines the cell of origin•major phenotypes are mature B-cell, precursor B-cell, and T-cell disease, but the WHO classifies ALL as either B lymphoblastic or T lymphoblastic.•80% of childhood ALL derives from precursor B cells•In adults, ~75% of ALL is B-cell lineage and ~25% are T-cell lineage ALL.4/21/205 INTRO TO ACUTE LEUKEMIASGeneralSigns/SymptomsLab TestsOther Diagnostic Tests§history of vague symptoms (tiredness, lack of exercise tolerance, weight loss, “feeling unwell”)§Common: pallor, malaise, palpitations, and fatigue, bruising, ecchymoses, petechiae, fever, bone pain§Other: epistaxis, dyspnea on exertion, seizures, headache, splenomegaly, hepatomegaly, and/or lymphadenopathy are common in patients presenting with ALL; rarely, small, blue-green collections of leukemia cells under the skin (chloromas). In AML have gum hypertrophy/bleeding.§CBC w/dif: Anemia, Thrombocytopenia leukopenia or leukocytosis; about 20% of patients will present with a WBC count ≥50,000 cells/mm3and 53% of ALL and 20% of AML cases with a WBC <10,000 cells/mm3§Uric acid may be elevated due to rapid cellular turnover (more common in ALL).§Electrolyte abnormalities§Elevated PT, PTT§Bone marrow aspirate and biopsy§ALL –lumbar puncture to assess CNS involvement4/21/206 REFERENCES•DeRemerD, Higgins T.Acute Leukemias.In:DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V.eds.Pharmacotherapy: A Pathophysiologic Approach, 11eNew York, NY: McGraw-Hill; .http://0accesspharmacy.mhmedical.com.lib.utep.edu/content.aspx?bookid=2577&sectionid=237233312.Accessed April 19, 20204/21/207 PHAR 6477: Integrated Systems-Based Pharmacotherapy IIIB1Module 2: Oncology/HematologyAcute Lymphoblastic Leukemia (ALL)Denise I. Pinal, PharmD, BCPPSClinical Assistant Professor –UTEP School of PharmacyAdjunct Asst. Prof. –TTUHSC Paul L. Foster School of Medicine OBJECTIVES•Brieflyreviewpediatriccancerand pediatric chemotherapy dosing pearls •Highlightsomerelevantsupportivecareconsiderations for conditions being discussed today•Discuss the etiology, epidemiology, clinical presentation and risk factors for ALL•IntroducegeneraltreatmentapproachesforALL4/21/20 PEDIATRIC CANCER•Rare (~1% of all cancer diagnoses)•Decliningmortality•1969: 6.5 per 100,000•2009: 2.1 per 100,000•2ndleading cause of death in children (after car crashes/accidents)4/21/20 PATIENT CASE•Yo u a r e w o r k i n g a t a h o s p i t a l p h a r m a c y a n d r e c e i v e c h e m o t h e r a p y orders for patient PL. PL is an 8-month-old male and weighs 7kg.Whichsetofordersismostappropriate?a)Vincristine 0.05mg/kg;dactinomycin0.045mg/kgb)Vincristine0.05mg/kg;dactinomycin1.35mg/m2c)Vincristine 1.5 mg/m2; dactinomycin 0.045 mg/kgd)Vincristine1.5mg/m2;dactinomycin1.35mg/m24/21/20 PEDIATRIC CHEMOTHERAPY DOSING •Dosed by patient weight (mg/kg)•Dosed by BSA (body surface area)•Mosteller method4/21/20 INFANTSANDCHEMOTHERAPYDOSING•For <12months of age and <10-12kg, common to convert from mg/m2dosing to mg/kg dose using factor of 30.•Assumes that patient who is about 1m2will typically weigh ~30kg•E.g.,doxorubicin30mg/m2=doxorubicin1mg/kg•Good clinical pearl to keep for any pharmacist!4/21/20 Nausea and vomitingTu m o r l y s i s syndromeMucositisHemorrhagic cystitisCardiotoxicityNephrotoxicityThis is not an all-inclusive pie4/21/20SUPPORTIVE CARE CONSIDERATIONS ANTINEOPLASTIC-INDUCED NAUSEA/VOMITINGMinimal emetogenic risk•No routine prophylaxisLow emetogenic risk•Single agent (ondansetron or granisetron)Moderate emetogenic risk•Dexamethasone + ondansetron or granisetron•*Ondansetron or granisetron + chlorpromazine, metoclopramide, or nabiloneHigh emetogenic risk•Dexamethasone + ondansetron or granisetron•Aprepitant added if no interactions •*Ondansetron or granisetron + chlorpromazine or nabilone4/21/20*if corticosteroids are contraindicated FEVER AND NEUTROPENIA•Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer•Potentialremovalofcentralline•High-risk patients: IV empiric antibiotic monotherapy w/antipseudomonal beta lactam (e.g., cefepime, carbapenem, imipenem/cilastin) or pip/tazo•Va n co myc i nNOTroutinelyrecommendedforinitialregimenbutconsider for specific situations (e.g., suspected catheter infection, SSTI, hemodynamic instability)4/21/20 •Cultures, imaging•High risk: antipseudomonal beta lactam or carbapenem•Add 2ndgram negative agent or glycopeptide if high resistance rates or for clinically unstable patients•Low risk: initial or step-down outpatient management Initial presentation (1st24hrs)•d/c double gram neg. coverage or glycopeptide, if possibleOR•Add on for unstable patients•d/c empiric abx if cultures negative x48hrs, afebrile x24hrs, and evidence of marrow recovery•low risk: consider d/c empiric abx at 72hrs if negative cultures regardless of marrow recoveryOngoing management (24-72hrs)•recent joint ASCO/IDSA guideline recommends antibacterial and antifungal prophylaxis in high-risk neutropenic patients (<100 cells/mm3[0.1 ×109/L] for 7 days)Empiric Antifungals4/21/20International Pediatric Fever And Neutropenia Guideline Panel For Initial And Ongoing Treatment Of Children With Cancer Or Undergoing Hsct MUCOSITIS•POGO Mucositis Prevention Guideline for oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing HSCT •Prevention•Routinelyassessforpresenceandseverity•Good oral hygiene•Keratinocyte growth factor (palifermin) considered in children receiving HSCT conditioning w/regimens associated with a high rate of severe mucositis •Tr e a t m e n t•Oral/IV pain management•IV hydration•PN4/21/20 TUMOR LYSIS SYNDROME•Massive release of intracellular contents after tumor cell death•Spontaneousoccurrence,eitherbefore firstchemoorafterinitial therapy•Potentially severe, life-threatening hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypercalcemia•Must prevent development of urate nephropathy4/21/20 4/21/20JAMA Oncol.2018;4(6):895. doi:10.1001/jamaoncol.2018.0613 Low Risk•Diagnoses:•Most solid tumors; indolent NHL, HL•AML with WBC <25,000 cells/mm3 and LDH <2x the upper limit of normal (ULN) ••Prophylaxis: Hydration with or without allopurinolIntermediate Risk••Diagnoses:•Select solid tumors with bulky or advanced-stage disease•ALL with WBC <100,000 cells/mm3 and LDH <2x ULN•AML with WBC 25,000–100,000 cells/mm3 or AML with WBC <25,000 cells/mm3 and LDH ≥2x ULN •Anaplastic large cell leukemia (ALCL) (stage III or IV only)•Intermediate-grade NHL with LDH <2x ULN (stage III or IV only)•Burkitt lymphoma with LDH <2x ULN•Lymphoblastic lymphoma, stage I or II, with LDH <2x ULN ••Prophylaxis: Hydration plus allopurinol High Risk••Diagnoses:•ALL with WBC of ≥100,000 cells/mm3 and/or LDH ≥2x ULN•AML with WBC of ≥100,000 cells/mm3•Burkitt lymphoma, stage III or IV, and/or LDH ≥2x ULN•Lymphoblastic lymphoma, stage III or IV, and/or LDH ≥2x ULN•Any intermediate-risk patient with renal dysfunction, renal involvement•Any intermediate-risk patient with serum uric acid, potassium, or phosphate above the ULN ••Prophylaxis: Hydration plus rasburicase (allopurinol in patients with glucose-6 phosphate dehydrogenase deficiency 4/21/20TUMOR LYSIS SYNDROME ACUTELYMPHOBLASTIC LEUKEMIA (ALL)4/21/20 PATIENT CASE •KLisa3.5-year-old male who presents to the emergency department with fatigue, petechiae, pallor, and pancytopenia. He undergoes diagnostic workup and is found to have standard-risk ALL. His white blood cell count is 12,000 cells/mm3. Which of the following would be the most appropriate induction therapy for this patient?a)Vincristine,dexamethasone,andpegaspargaseb)Vincristine, prednisone, and pegaspargasec)Vincristine, dexamethasone, pegaspargase, and daunorubicind)Vincristine,prednisone, pegaspargase, and daunorubicin4/21/20 PEDIATRIC LEUKEMIA•Leukemia àmost common malignancy in children (~1/4 of all cancers in children)•2majortypes•Acute lymphoblastic leukemia (ALL)•Acutemyeloidleukemia(AML)•ALL àremains leading causeofpediatriccancerdeathsdespite improving outcomes and survival rates4/21/20 PEDIATRIC ALL•Etiology generally unknown•proliferation of abnormal lymphoblasts of precursor B-cell or T-cell lineage •Genetic aberrations (lead to subtypes)•Epidemiology•2-4yrs (peak incidence)•Males>females•Whites/Hispanics > African Americans•Presentation•Non-specific•Fever, lymphadenopathy, bone pain, hepatosplenomegaly4/21/20 ALL PROGNOSTIC FEATURESAge at diagnosisLeukocyte count at diagnosisGenetic abnormalitiesResponse to inductionCNS statusHigher risk if <1yr or >10yrs of age at diagnosisHigher risk if total leukocyte count > 50K/mm3 at diagnosisUnfavorable: MLL rearrangement, BCR/ABLFavorable: Trisomy 4 and 10Lower risk if low to absent level of minimal residual disease (MRD,0.01%) following initiation of inductionHigher risk if CNS disease at diagnosis4/21/20 National Cancer Institute (NCI) Risk Classification for Pediatric Acute Lymphoblastic LeukemiaRisk GroupStandard RiskHigh RiskAge (years)1− <10<1 or ≥10WBC count (×103cells/mm3or ×109/L)<50≥50KaryotypeNo t(9;22) or t(4;11)t(9;22) or t(4;11)4/21/20This classification system uses the NCI-risk assignment to initially categorize patients into standard-or high-risk groups Risk Classification•Following induction therapy, risk is reclassified based on:•completeness of response to therapy•presence or absence of cytogenetic abnormalities•CNS involvement•Patients are then reclassified as:•low risk, standard risk, high risk, or very-high risk4/21/20 Citation: Acute Leukemias, DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. Pharmacotherapy: A Pathophysiologic Approach, 11e;2020. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=237233312 Accessed: April 20, 2020Copyright © 2020 McGraw-Hill Education. All rights reservedFor visual learners4/21/20 ALL –TREATMENT APPROACH4/21/20 STANDARD RISK ALLThree Drug InductionEligible Patients§Vincristine, dexamethasone, pegaspargase§CNS prophylaxis with IT therapy§Age 1-9.9yrs§WBC < 50K/mm3§No high-risk genetics§No CNS disease4/21/20ØPost-induction treatment will be based on MRD and other patient characteristics HIGHRISK ALLFour Drug InductionEligible Patients§Vincristine, steroid, pegaspargase, daunorubicin§<10yrs old: dexamethasone§>10yrs old: prednisone§CNS prophylaxis with IT therapy§>1yr of age§Not standard risk§Other criteria based on cytogenicity and MRD features4/21/20anthracylclines-cardiotoxicity POST-INDUCTION TREATMENT / OUTCOMES•What happens after induction?•Several phases of therapy thatarebased on the patient’s end of induction risk category•Consolidation•Delayed intensification •Interim maintenance•Maintenance (targeting ANC with thiopurines) •To t a l t h e r a p y d u r a t i o n à2.5-3yrs•Pediatric ALL 5yr event-freesurvival rates vary w/risk category (about 90% on average)4/21/20 LEUCOVORIN RESCUE –PA U S E A N D C O N S I D E R4/21/20•Children with Down syndrome and ALL have an increased sensitivity to methotrexate and a resultant increased risk of mucositis. •Oral leucovorin is often given after intrathecal methotrexate during induction and consolidation. •WHY? ALL IN ADULTS•National Comprehensive Cancer Network (NCCN) guidelines recommend different strategies for Adolescent and Young Adult (AYA), adults, and adults ≥65 years with substantial comorbidities•Most commonlyàanthracycline,vincristine, anasparaginaseformulation, and a corticosteroid•Poorer outcomes in adults 4/21/20 ADOLESCENTS/YOUNG ADULT ALL•Improved outcomes when adolescents and young adults (AYA) are treated on pediatric protocols vs. adult protocols •Increased risk of osteonecrosis with use of dexamethasone in this age group•Hence, prednisone seen in induction4/21/20 PATIENT CASE •KLisa3.5-year-old male who presents to the emergency department with fatigue, petechiae, pallor, and pancytopenia. He undergoes diagnostic workup and is found to have standard-risk ALL. His white blood cell count is 12,000 cells/mm3. Which of the following would be the most appropriate induction therapy for this patient?a)Vincristine,dexamethasone,andpegaspargaseb)Vincristine, prednisone, and pegaspargasec)Vincristine, dexamethasone, pegaspargase, and daunorubicind)Vincristine,prednisone, pegaspargase, and daunorubicin4/21/20 PHAR 6477: Integrated Systems-Based Pharmacotherapy IIIB1Module 2: Oncology/HematologyAcute Myelogenous Leukemia (AML)Denise I. Pinal, PharmD, BCPPSClinical Assistant Professor –UTEP School of PharmacyAdjunct Asst. Prof. –TTUHSC Paul L. Foster School of Medicine OBJECTIVES•Define AML and possible implicated etioligies•Discuss the risk classification and prognostic factors for AML in adult and pediatric patients•Introduce general treatment approaches for AML in adult and pediatric patients4/21/202 AML -INTRO•Acute myeloid leukemia (AML) -a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. •Underlying pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development•Most AML subtypes are distinguished from other related blood disorders by the presence of >20% blasts in the bone marrow•Implicatedetiologiesincludeantecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures•Still mostpatientshavenoidentifiable risk factors4/21/203 AML -INTRO•Adult acute myeloid leukemia (AML) is the most prevalent kind of acute leukemia in adults in the US•Patients present with symptoms resulting from bone marrow failure, from organ infiltration with leukemic cells, or both•Tre a t m e n t options can be comprised of variety of chemotherapy regimens, biologic agents, and stem cell transplantation4/21/204 AML RISK CLASSIFICATION•World Health Organization Classification of Acute Myeloid Leukemia and Related Neoplasms (table 151-2)•Divided into patient-related and disease-related factors that influence response totherapy•Key prognostic factor for AML is age•>/=60yrs of age have significantly worse outcomes•Due to differences in tumor biology (confers resistance) and patient characteristics (can reduce treatment tolerance)4/21/205 AML RISK CLASSIFICATION•Additionalnonfavorableprognostic factors in adult AML•multidrug-resistance gene expression•WBC >100,000 cells/mm3(100 ×109/L) •therapy-related AML•Additionally,genetic analysis provides important prognostic information (table 151-4)4/21/206 4/21/207Risk categoryGenetic abnormalityFavorablet(8;21)(q22;q22.1);RUNX1-RUNX1T1inv(16)(p13.1;q22) or t(16;16)(p13.1;q22);CBFB-MYH11MutatedNPM1withoutFLT3-ITDor withFLT3-ITDlow¶Biallelic mutatedCEBPAIntermediateMutatedNPM1andFLT3-ITDhigh¶Wild typeNPM1withoutFLT3-ITDor withFLT3-ITDlow¶(without adverse-risk genetic lesions)t(9;11)(p21.3;q23.3);MLLT3-KMT2AΔCytogenetic abnormalities not classified as favorable or adverseAdverset(6;9)(p23;q34.1);DEK-NUP214t(v;11q23.3);KMT2Arearrangedt(9;22)(q34.1;q11.2);BCR-ABL1inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);GATA2,MECOM(EVI1) –5 or del(5q); –7; –17/abn(17p)Complex karyotype,◊monosomal karyotype§Wild typeNPM1andFLT3-ITDhigh¶MutatedRUNX1¥MutatedASXL1¥MutatedTP53‡2017 European LeukemiaNetrisk stratification of acute myeloid leukemia by geneticshttps://0-www-uptodate-com.lib.utep.edu/contents/image?imageKey=HEME%2F111588&topicKey=HEME%2F4530&search=acute%20myeloid%20leukemia&rank=2~150&source=see_link&sp=0 ADULT AML TREATMENT•Short-term goal of treatment for AML is to rapidly achieve a complete clinical and hematologic remission. •Disappearance of all clinical and bone marrow evidence of leukemia•normal cellularity >20% with <5% blasts•restoration of normal hematopoiesis (neutrophils >/=1,000 cells/mm3[1 ×109/L] )•platelets >100,000 cells/mm3[100 ×109/L])•Partial remission •Adecrease of at least 50% of blasts•Considered a significant response, however, evidence of residual disease in bone marrow still remains(5%-25% blasts) •Considered treatment failure requiring additional therapy4/21/208 ADULT AML TREATMENT•Therapy for AML is divided into two phases:•Induction •Postremission(consolidation)•Selection of initial therapy is influenced by medical fitness, prognostic features of the AML cells, and goals of care•Usually needs to start as quickly as possible after diagnosis as it can progress very quickly4/21/209 ADULT AML TREATMENT•As with ALL, goal of remission induction for AML is to rapidly induce a CR with restoration of normal hematopoiesis•Compared to ALL, fewer patients with AML achieve CR •CR rate in AML is related to the intensity of the remission induction regimen•Therefore most drugs used in AML are given at doses that cause severe myelosuppression •Inability to give optimal doses (because of marrow toxicity), can contribute to lower CR rate •Patients may achieve CR after 1-2 courses of chemo •If additional therapy required to achieve CRàpoorprognosis4/21/2010 NEWLY APPROVED DRUGSGenomically-targeted personalize therapies•FLT3•Midostaurin•Gilteritinib•IDH•Enasidenib•IvosidenibNon-genomically targeted therapies•Intensive•Liposomal cytarabine and daunorubicin (CPX-351)•Gemtuzumabozogamiacin•Non-intensive•Glasdegib•Ve netoclax4/21/2011 ADULT AML TREATMENT•Standard therapy for adult AML has not changed in several decades•The most active single agents in AML are anthracycline antibiotics (daunorubicin,doxorubicin, idarubicin),mitoxantrone, and cytarabine•For medically fit patients with favorableprognosis AML most common regimen combines daunorubicin along withcytarabine (7+3 regimen)•consists of getting cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days.•In 2017, FDA granted approval to a liposome-encapsulated combination ofdaunorubicin-cytarabine (CPX-351) for treatment of adults with newly-diagnosed, therapy-related AML ORAML with myelodysplasia-related changes•Adverse events include hemorrhagic events, febrile neutropenia, rash, fatigue, and increased risk of infections•cardiotoxicity is still a concern (monitor cardiac function)4/21/2012 ADULT AML TREATMENT•For patientswhose leukemia cells have anFLT3gene mutation, the targeted therapy drugmidostaurin(Rydapt)maybe given along with chemo•Midostaurinàoral multitargeted TKI that is active against FLT3•Given twice daily as a pill•For patientswhose leukemia cells have the CD33 protein, the targeted druggemtuzumab ozogamicin (Mylotarg)might be added to chemo•NCCN guidelines recommend the standard 7+3 regimen for AML patients <60yrs4/21/2013 ADULT AML TREATMENT•For medically fit older patients (>60) with adverse cytogenetic/molecular features who are not candidates for intensive remission induction therapy•low-intensity therapy with low-dose subcutaneouscytarabine, azacitidine or decitabine, liposomal daunorubicin-cytarabine (CPX-351), a clinical trial, or best supportive care •Dismal outcomes and toxicity risks are associated with conventional chemotherapy in this population•Azacitidine and decitabine generally well-tolerated •Most significantADEismyelosuppression (supportive care includes the use of blood product transfusion support)•Either agent can be combined with venetoclax4/21/2014 ADULT AML TREATMENT•For patients with favorable or intermediate prognostic features of AML who are likely to tolerate intensive remission induction•7+3 therapy; liposomal daunorubicin-cytarabine•For patients with favorable or intermediate prognostic features of AML but less likely to tolerate intensive therapy•Hypomethylating agent(decitabine, azacytidine) or low dose cytarabine•Can combine these with venetoclax•For patients with adverse prognostic features of AML•Ivosidenibor enasidenib (for IDH1orIDH2mutation, respectively),decitabine, azacytidine, or supportive care alone.4/21/2015 ADULT AML TREATMENT•All adult patients presenting w/CNS symptoms or asymptomatic monocytic disease should have diagnostic lumbar puncture•Tre a t i f p o s i t i v e(methotrexate orcytarabine intrathecally twice a week until clearance of leukemic blasts from the CSF), then weekly for 4-6wks. •Continued secondary prophylaxis is recommended following treatment for CNS disease4/21/2016 ADULT AML -CONSOLIDATION•Adults <60yrs options:•Several cycles of chemo with high-dose cytarabine (ara-C) (sometimes known asHiDAC)•Allogeneic (donor) stem cell transplant•Autologous stem cell transplant•>60yrsorpoorhealth options:•Higher-dose cytarabine (not as high as younger patients)•Standard-dose cytarabine(+/-idarubicin, daunorubicin, or mitoxantrone)•Midostaurin (Rydapt) if given during induction•Non-myeloablative stem cell transplant (mini-transplant)4/21/2017 Patient Case•DL is a 35-year-old male with newly diagnosed AML. Cytogenetic analysis reveals a t(8;21) and mutational analysis reveals a biallelic CEBPA mutation. His FLT3-ITD is negative. Based on this information listed, what would be the most appropriate induction treatment regimen?A.Cytarabine3 g/m2IV every 12 hours on days 1, 3, and 5B.Veneto cl ax400 mg PO daily with low-dosecytarabine 20 mg/m2SQ daily on days 1-10C.Cytarabine100 mg/m2/day continuous IV on days 1 through 7 and daunorubicin 90 mg/m2IV on days 1 through 3D.Cytarabine100 mg/m2/day continuous IV on days 1 through 7, daunorubicin 90 mg/m2IV on days 1 through 3, andmidostaurin50 mg PO daily on days 8-214/21/2018 PEDIATRIC AML•Etiology •generally unknown•proliferation of abnormal myeloid, erythroid, monocytic, and megakaryocytic cell precursors•Genetic aberrations (can lead to abnormal clones)•Epidemiology•~700 children/adolescents affected in 2014•Hispanicchildrenpossibly> other races/ethnicities•Presentation•Can be similar toALL•Acute promyelocytic leukemia(APL) may present very differently4/21/2019 PEDIATRIC AML STRATIFICATIONLow RiskIntermediate RiskHigh RiskSpecial Groups§Core-binding factor (CBF) leukemias: t(8;21), inv16 §{Not meeting low or high riskcriteria} §Chromosomal deletions: monosomy 5 or 7, 5qdel, FLT3/ITD §APL, t(15;17) §Myeloid leukemia of Down syndrome (MLDS) 4/21/2020 PEDIATRICAML–TREATMENT/OUTCOMESTre at me ntOutcomes§Based on cytogenetic features and risk group§4-5 courses of intense chemotherapy§Each cycle includes cytarabine (plus other agents)§Allogeneic HSCT for those with high risk features post 2-3 courses of chemo§Maintenance therapy NOT an important component§Survival estimates show EFS >50% and overall survival (OS) at 60-70%4/21/2021 QUESTIONS4/21/2022