Advances In The Treatment Of Acute Leukemia

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Acute Leukemia in the Adult:Current and EvolvingApproaches to Diagnosis andManagementU.S. Department ofHealth and HumanServicesNational Institutesof HealthWarren Grant MagnusonClinical CenterSandra Mitchell, CRNP,MScN,AOCNPre-Doctoral Fellow, Warren Grant MagnusonClinical Center, National Institutes of Health,Bethesda, MDDoctoral Student, University of Utah College ofNursingAdvances in the Treatment ofAcute Leukemia!!!!Transfusion supportNew antimicrobialsNew chemotherapeuticagentsAdvances in high dosetherapy withautologous orallogeneictransplantationEpidemiology of AcuteLeukemiasOverview of Acute Leukemia!!!!!Leukemias are clonal, neoplastic proliferations ofimmature cells of the hematopoietic system, which arecharacterized by aberrant or arrested differentiationAccumulate in the bone marrow, and replace normalhematopoietic cellsCirculate in the blood and may infiltrate other tissues (skin,gingiva, spleen, testes, central nervous system)Classic signs and symptoms are the result of bone marrowfailure (neutropenia, anemia, thrombocytopenia), and fromresultant hemorrhage, infection and anemiaAcute leuekmias can be broadly grouped based onphenotype and genotype into:!!!!– Myelogenous– LymphoblasticIncidence of leukemia is approximately 3% of all cancers,or approximately 15,000 new cases each yearApproximately 4000 new cases of acute lymphoblasticleukemia, and about 11,000 new cases of acutemyelogenous leukemiaALL has a bimodal distribution with peak occurrences inadolescence and again after age 70.Median age of onset for adult AML is 60-65 yearsScheinberg DA, Maslak P, Weiss M (1997). Acute leukemias. (p. 2293-2320). In:Devita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice ofOncology, 5th ed. Philadelphia, Pa: Lippincott.Pluripotent Stem CellEtiology!!!!Cause is generally unknownHistory of prior chemotherapy (especially carboplatin,etoposide, procarbazine, cyclophosphamide, CCNU) andradiation therapy increases riskEnvironmental/occupational exposures – ionizingradiation, cigarette smoking (20% AML), benzeneIncreased risk of leukemia with Down syndrome,Fanconi’s anemia, Bloom’s syndrome, or ataxiatelangiectasiaMyeloid Stem lastEosinophilBasophilB Stem CellT Stem CellPre B CellProthymocyteB LymphoblastT LymphoblastB CellT CellScheinberg DA, Maslak P, Weiss M (1997). Acute leukemias. (p. 2293-2320).In: Devita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles andPractice of Oncology, 5th ed. Philadelphia, Pa: Lippincott.Monocyte1

Classification of AcuteLeukemiasPresentation!!!!!!!!Fatigue over 1 to 3 monthsBone marrow failureHemorrhageInfection / feverEasy bruisingMinimal to moderateweight lossBone thyWBC OR Chest mass ( T cell ALL)Organ infiltration ( ALL)Gingival infiltration( AML, M-5) Fibrinogen PT, PTTBlasts on peripheral smear!Three questions must be answered to diagnose andclassify an acute leukemia– What is the lineage?– What is the maturational stage?– What is the genotype?Mufti,G.J., Flandrin, G., Schaefer, H., Sandberg, A., &Kanfer, E.J.(1996). Acute leukemia. (p.1-134).In Malignant Haematology: Cytology, Histology and CytogeneticsBone Marrow Aspirate and Biopsyand Peripheral Blood Smear!!!!Evaluation of the morphology (microscopic appearance ofthe leukemic cellsProvides tissue for immunohistochemical stains to identifythe lineage of the cell (eg.lymphoid or myeloid)Provides material for flow cytometry to determine thepercentage of high immature cells, and the pattern ofexpression of cell surface or cytoplasmic markers (eg. CD20, TdT, CD 33, CD 34, HLA-DR)Provides tissue for molecular diagnostics [cytogenetics,RT-PCR, FISH] to determine if there is a chromosomalabnormality (eg. Philadelphia chromosome in ALL) ortranslocation [eg. t (15;17, t (8;21), inv (16)]Cytochemistry andImmunophenotyping Cell Surface Antigen TestingImmunofluorescence – flow cytometry blood andbone marrow aspirateImmunoperoxidase – tissue or bone marrow biopsy Cytoplasmic and nuclear antigen testingCytoplasmic immunoglobinTDT (Terminal deoxynucleidyl transferase) Flow Cytometry – provides quantitativevalues of immunofluorescence per cell.London: Lippincott-RavenMorphology! Morphologicexamination is performed toestablish the lineage– Peripheral smear– Bone marrow aspirate– Bone marrow biopsy– Tissue analysis (eg. lymph node, CSF)Cytogenetics/MolecularDiagnostics! Cytogeneticsare molecular diagnosticstudies which detect genetic rearrangementor deletion of a gene.! Metaphase cytogenetics! RT-PCR – reverse transcriptase polymerasechain reaction! PCR- polymerase chain reaction! FISH – fluorescence in situ hybridization2

French – American –British(FAB) GroupAcute LeukemiaAcute MyelogenousLeukemia! Acutemyeloid leukemia has beendivided into 8 FAB subtypes M0-M7!!!!! AcuteLymphoid Leukemia has beenclassified into 3 FAB subtypes L1- L3!!!!Prognostic Features ANLLAgeOnsetLDHWBCAdverse Prognostic Factors in Adult ALL!Remission InductionRemission Duration / SurvivalAntecedentmyelodysplasia!Age 60 yearsWBC 30,000Non – T cell phenotypeLack of mediastinal adenopathyPoor performance statusAge 35 yearsWBC 30,000Non – T cell phenotypet (9;22) or BCR/ABLrearrangementt(4;11)T(8;14) and variantsBurkitt cell (L3)Phenotype (Sig )Auer rods, M1 - 4M0,M6, M7MarkersLymphoid markers(CD34-, mdr- 1 -)CD2(CD34 , mdr- 1 )2 !!Rapid8;21, Inv.16, ,complexInitial Evaluation of the Patientwith Acute LeukemiaEvaluation of Minimal ResidualDisease!!!!!!!de novoMorphology!!L1 Childhood ( pre B-andT – cell)L2 Adult (Pre B – and T –cell)L3 Burkitt’s type ( B –cell) 60( 2)Inc/ 100,000/mm3Cytogenetics- mostpotent correlate! 45Nl / 25,000/mm3Cytoreduction - CRM0 UndifferentiatedM1 MyeloblasticM2 MyeloblasticM3 PromyelocyticM4 MyelomonocyticM5 MonocyticM6 ErythroleukemiaM7 MegakaryoblasticAcute LymphocyticLeukemiaMorphologyBone Marrow Aspirate and BiopsyFISH for specific translocationsPeripheral blood smearFlow cytometrySouthern blotPolymerase chain reaction!!!!!!!!!Physical examination and family historyDental evaluationViral serologies, including HSV,CMV, hepatitis and HIVCardiac status evaluated with MUGA or echocardiogramLeukapharesis if WBC 100,000 or symptomaticCoagulation screeningEstablish Central Venous AccessHLA typingSperm banking3

Concepts and Definitions!!!Induction TherapyGoal: rapid clearing of leukemic cells from peripheralblood with subsequent marrow aplasiaPost Remission TherapyGoal: prolong the duration of remissionPost Remission Therapy– Consolidation– Intensification– le Induction RegimenRegimenAML!!!!! Evenwith CR, estimated that 10 billionleukemia cells remain.! Some form of therapy required to preventdisease relapse! Stratify based on age and cytogenetic featuresCytarabine 1-3 gm/m2 IV over 2-3 hours every 12hours x 12 doses days 1-6PLUSDaunorubicin 45 mg/ m2/day Days 1-3ORIdarubicin 12 mg/ m2/day Days 1-3ORMitoxantrone 12 mg/ m2/day Days 1-3Options for PostPost-RemissionTherapyTherapy-AMLAcute Myelogenous LeukemiaRationale for Intensive Post-Remission TherapyIntermittent treatment for a prolonged period using lower doses of sameagents used in induction or other agentsSample Induction RegimenRegimenHIDAC(“7 and 3” Regimen)100-200 mg/m2/day bycontinuous IV infusion Days 1-7PLUS! Daunorubicin 45 mg/ m2/day Days 1-3OR! Idarubicin 12 mg/ m2/day Days 1-3OR! Mitoxantrone 12 mg/ m2/day Days 1-3Course of therapy given using different drugs, different schedule and higherdose intensity than those used for initial induction.Goal is that the agents used in intensification will not be cross-resistant withthe agents used in induction regimenearly intensification, if initiated immediately following remission inductionlate intensification, if given several months after remission inductionMaintenance:!! CytarabineOne or two courses of same agents and same dose intensity as used forinitial induction 60 years old, CR to induction, with good riskcytogenetic abnormalities!Consolidation with 4 cycles of high dosecytarabine (3 gm/m2) followed by 4 cycles ofmaintenance with cytarabine and daunorubicin!Alternative: 1-2 cycles of high dose cytarabinefollowed by autologous transplantation or matchedrelated transplantation4

Options for Post Remission TherapyTherapyAML 60 years old, CR to induction with intermediate risk or high riskcytogenetics! Consolidate with:1-2 cycles of high dose cytarabine, and proceed to autolgous orallogeneic transplantationOR– 4 cycles of high dose cytarabine 60 years!!Enroll in clinical trial if availableIf not available, consolidate with: 2 cycles of standard dose cytarabine100 mg/m2 anthracycline (Idarubicin, Daunorubicin orMitoxantrone)Salvage Therapy for DiseaseRelapseRelapse- AMLEarly relapse with low tumor burden and identifieddonor?! Allogeneic transplantationEarly relapse, but no donor?! Clinical trialRelapse after long remission?! Reinduction using original agents or clinical trial,followed by autologous or allogeneictransplantationTherapy of AcuteLymphoblastic ion MaintenanceandIntensification4-5 drug regimenIntrathecalchemotherapywithmethotrexate /Craniospinalirradiation4-5 drug incristineCytarabine (HD)Anthracycline3-4 drug regimengiven on monthlycycle for 2 yearsVincristine (IV)Prednisone (PO)Methotrexate (PO)6-Mercaptopurine(PO)Management of PrimaryInduction Failure/RefractoryDiseaseDisease-AML 60 years old with a related or unrelated donor?Related or unrelated allogeneic transplantation 60 years old without a related or unrelated donorClinical trial, monoclonal antibody therapy 60 years old?Clinical trial, monoclonal antibody therapy(MylotargR) or supportive careTherapy of AcuteLymphoblastic Leukemia! RemissionInductionProphylaxis! Consolidation and Intensification! Maintenance! CNSRemission InductionInduction-ALL! Vincristineand prednisone serve asbackbone of induction regimen 2 or moreadditional agents! Examples of other agents added to regimen:daunorubicin, doxorubucin, idarubicin, Lasparaginase, cyclophosphamide,cytarabine, methotrexate, 6-mercaptopurine,6-thioguanine5

Central Nervous SystemProphylaxis! WithoutCNS prophylaxis, between 10-50%of patients will develop CNS nConsolidationALLaggressive systemic chemotherapyalso contributes to a reduced risk of CNSrelapseusuallyrequires the use of increased doses of drugsused in induction, or the addition of noncross-resistant new agents.! May be given early (for example 1 monthafter induction) and/or late (for example 5months after induction)! Allogeneic and autologous PBSCT haveimportant roles for those with high riskfeatures, who are younger and have a donor.Maintenance TherapyTherapy-ALLRefractory or Relapsed ALL! Craniospinalirradiation of 18-24 Gycombined with intrathecal methotrexate isthe standard! More! Typically,daily 6-Mercaptopurine (po)andweekly methotrexate (IV) for 18 to 36months! Vincristine! Intensification-consolidation! Significanceand management of relapseinfluenced by:– Duration of first remissionand prednisone pulses– Intensity of initial regimen used– Site of relapse! Optimaldrugs, doses and duration have notbeen determinedRelapsed ALL!Relapse on therapy or shortly after completion?– Reinduce with drugs not previously received– Give CNS directed therapy– Consider consolidation and intensification toRelapsed ALL!Isolated extramedullary relapse in CNS?Additional systemic therapy transplant!Isolated testicular relapse?Additional systemic therapy including CNSprophylaxis and testicular XRT!Late relapse?Reinduce with vincristine, prednisone,asparaginase and an anthracycline transplantprolong duration of 2nd remission– Best hope for long term survival is allogeneictransplant. Autologous transplant with cellscollected during second remission6

Therapy of AcutePromyelocytic Leukemia!Remission Induction TherapyTherapy of AcutePromyelocytic Leukemia! Relapse– Daunorubicin All-transretinoic Acid (ATRA)– Arsenic trioxide /- Ara-C!!– Reinduction with Anthracycline, CytarabineConsolidation with 3 courses of Ara-C andAnthracyclineMaintenanceand ATRA– Proceed with autologous PBSCT (if PCRnegative for PML-RAR), allogeneictransplantation or clinical trial– Vincristine– Oral maintenance therapy with 6-Mercaptopurine andATRAPatient Monitoring DuringTherapy!Slide Not Available!CBC, relevant chemistries (eg LFTs, tumor lysislabs, BUN/Cr)Bone marrow aspirate and biopsy– 14 days after treatment initiation, and every 7-14 daysthereafter until evidence of normal hematopoiesis orpersistent leukemia documented– Evaluate with cytogenetics (if there is an abnormality)or other method to detect minimal residual disease(MRD) eg. Polymerase Chain Reaction (PCR),Fluorescent Insitu Hybridization (FISH)!Response Criteria in AcuteLeukemia!Complete Response!Absolute neutrophil count1500/microliterPlatelets 100,000/microliterNo leukemic blasts in peripheralbloodNo extramedullary organinvolvement 5% blasts in bone marrow, andcellularity 20% 15% normal erythropoiesis 25% granulopoiesis!!!!!!!Partial Response!6-25% blasts in bone marrow 10% normal erythropoiesis 25% normal granulopoiesis!!History and physicalSupportive Care of the PatientUndergoing Treatment of an AcuteLeukemia7

Supportive Care of the PatientUndergoing Treatment of an icAntimicrobialsSteroid eye gtts forHIDACCytokine SupportBlood Products-Irradiatedand filteredMenses suppression!!!!Leukemia and Lymphoma SocietyAmerican Cancer SocietyNCI Cancer Information ServiceNational Marrow Donor ProgramTreatment of Acute Leukemiain the AdultSlide Not AvailableNew Strategies- New TargetsNew Agents for the Treatment of LeukemiaSlide Not AvailableCytotoxic Agents! Troxacitabine, Clofarabine! Arsenic Trioxide (TrisenoxTM)Monoclonal Antibody Therapies! Engineered antibodies that bind to cell surface antigens on malignant cells! Conjugated with cytotoxic molecules! Deliver targeted cytotoxicity to leukemic cells! Monoclonal antibody therapies include antibodies targetingCD33(MylotargR),CD52 (Campath-1H), others in developmentTherapies with Novel Targets/Mechanisms of actionInhibit multidrug resistance protein (MDR1-PGP)Cyclosporin, PSC 833Hypomethylating Agents (induces reactivation of tumor suppressor genes silencedby leukemia)Decitabine (DAC), 5-AzacytidinePromote Terminal Differentiation by Arresting Cell CycleATRA, Topotecan (CPT-11), Bryostatin-1Induce/facilitate apoptosis, inhibit cell growth signaling pathways, inhibitangiogenesisPS-341, SU5416, PTK 7878

Therapies with Novel Targets!!!!!Promote Apoptosis (Cell Death)– Arsenic trioxideAngiogenesis Inhibitors– Thalidomide, SU5416, PTK 787Inhibition of Tyrosine Kinase (inhibits proliferation of cells containingBCR-ABL)– STI-571 (Gleevec )Farnesyl transferase Inhibitors (blocks cell signaling pathwayspreventing cellular changes associated with malignant cell growth)– R115777Promote tumor-specific T-Cell Activation– Vaccine-based strategiesBerman, E. (2000). Recent advances in the treatment of acute leukemia. Current Opinion inHematology, 7, 205-211.Cortes, J. & Kantarjian, H.M. (2000). Promising approaches in acute leukemia. InvestigationalNew Drugs, 18 (1), 57-82.Estey, E. (2000). New agents and new targets for the treatment of AML. Hematology 2000, 70-74.Leukemia in the Elderly!!!!AML- median age at diagnosis is 63 years.Older individual may be less able to tolerate intensivetreatmentAML appears to be biologically different in older adult! Cytogenetic abnormalities associated with resistantdisease! Increased expression of the multidrug resistantmarker, p-glycoproteinIntensifying induction or post-remission therapies are notthe answer. Novel strategies and clinical trials are urgentlyneededSecondary Acute Leukemias!!!!Secondary or therapy related AML accounts for10-20% of all AMLsMost pts with secondary acute leukemia have anunfavorable outcomePrior chemotherapy with alkylating agents ortopoisomerase II inhibitors such as etoposideAllogeneic PBSCT may be the treatment ofchoice, if donor is availableSlide Not AvailableCase Study! 46year old Caucasian male who presentedto family MD with nausea, vomiting, feversand weight loss! Sonogram of the abdomen shows spleen of15.5 cm (upper limit of normal 12 cm), withsome sludging in the gallbladder and fattyliver infiltration. Patient scheduled forcholecystectomy.Case StudyPreoperative CBC reveals:WBC 22.6 (4.5-11.5)Hgb 12.8 (11.9-15.7)Hct 31.6 (35-45)Platelets 74,000 (153,000-320,000)Differential: 60% blasts, and 4% nucleated RBCs!Antecedent CBC done three months earlier as part of routine care showeda WBC of 6.8, Hemoglobin of 15, and platelet count of 309,000 with anormal differential9

In addition to the presence ofcirculating blasts, what clinicalfeatures suggest the diagnosisof ALL?! Leukocytosis,What components deservespecial attention during review ofsystems in a patient withpresumed ALL?!Symptoms associated with neutropenia, thrombocytopenia,and anemia including infections, bleeding, bruising,fatigue, pallor, tachycardia or chest pain!Symptoms associated with hepatosplenomegaly such asnausea, vomiting, dyspepsia, abdominal pain, early satiety!Symptoms associated with CNS involvement and/orleukostasis including headache, visual changes, weakness,syncope, dizzinessanemia, thrombocytopenia! Hepatosplenomegaly! AdenopathyPhysical ExaminationWithin normal limits except for:! 1 cm right supraclavicular lymph node and 1 cm right!axillary lymph node. Shotty adenopathy along the inguinalligament that is not measurable. No other palpableadenopathy in the cervical, supraclavicular, axillary oringuinal regionsSpleen palpable 4 cms below the left costal margin. Liveredge palpable 1 cm below the right costal margin.Abdomen non-tender.What additional diagnosticstudies are required toevaluate this pt?! Bonemarrow aspirate and biopsy! CT of the head! CT of the chest/abdomen and pelvis! Lumbar puncture! Lymph node biopsyWhich of the followinglaboratory abnormalities mightyou expect to see in thispatient?! ElevatedLDH! Hyperuricemia! Renalfailure! HyperkalemiaCase Study!!!!The diagnostic work-up is complete, and thediagnosis of Philadelphia chromosome (Ph ), Blineage ALL is confirmed.Phenotyping of leukemic blasts demonstrate CD34, CD-38, CD 10, CD 20, and DR positive, butnegative for CD 13 and CD-33Chest CT demonstrates hilar lymphadenopthy.Analysis of the cerebrospinal fluid reveals totalprotein of 59, glucose of 49, 0 white cells, 0 redcells, and negative cytology10

What other components willneed to be addressed/plannedfor as this pt begins definitivetherapy for his ALL?! HLAtyping of pt and siblingsbanking! Echocardiogram/MUGA! Establish vascular access! Hydration and allopurinol! Infection prophylaxis against Pneumocystiscarinii pneumonia with Bactrim 3 x/weekCase StudyThe patient begins induction therapy with thefollowing regimen:! SpermWhich of the following urgentproblems might you expect tosee in this pt?lysis syndrome! Leukostasis! Disseminated intravascular coagulation! Sepsis/Septic Shock– Cyclophosphamide 1200 mg/m2 on Day 1– Daunorubicin 45 mg/ m2 on Days 1, 2, 3– L-Asparaginase 6000 units/ m2 on Days 5,8,11,15,18,22– Vincristine 2 mg IV on Days 1, 8, 15, 22– Prednisone 60 mg/m2 on Days 1-21Case Study!! Tumor!!!This patient’s protocol requires monthlyintrathecal methotrexate prophylaxis but nocranial irradiation.Hospitalized for febrile neutropenia once duringthe past 2 months25 lb weight loss, fatiguedAbout to commence maintenance phase oftreatment with methotrexate and 6mercaptopurine, along with monthly intrathecaltreatments x 6How would this patient bemonitored at regular intervalsto determine his progress?What will be the most effectivemethod(s) for monitoring forMRD in this patient?! CBC! Bonewith differential q 2 weeks! Bone marrow aspirate and biopsy monthly! BUN/creatinine q 2 weeks! CT of the chest q 2 weeksmarrow biopsy! Cytogenetics! Molecular! Completediagnosticsblood count with differential11

Case Study!!8 months after diagnosis, routine evaluationreveals a sharp decline in the platelet count, andblasts are noted on the bone marrow aspirate andbiopsy. Molecular diagnostics confirm the reappearance of the BCR –ABL abnormality.Admitted for re-induction with M-Amsacrine andhigh dose Ara-C, and seen in consultationregarding possible allogeneic stem celltransplantation.Case StudyStudy- Conclusion! Afterobtaining remission with high dosecytarabine, the pt proceeds to allogeneicstem cell tranpslant from his 6/6 HLAantigen matched sister.! His preparative regimen for transplantincluded cyclphosphamide, thiotepa, totalbody irradiation, with a testicular boost.Case StudyStudy-Conclusion!!!Post transplant course complicated by CMV reactivationand Stage II graft versus host disease of the skin and gut.Remission status confirmed by recent bone marrowaspirate and biopsy which demonstrates 100% donorengraftment, and the absence of the Ph chromosome andthe BCR-ABL abnormalityHe is undergoing the second of six planned monthly cyclesof post-transplant intrathecal chemotherapy withmethotrexate.12

Epidemiology of Acute Leukemias! Incidence of leukemia is approximately 3% of all cancers, or approximately 15,000 new cases each year! Approximately 4000 new cases of acute lymphoblastic leukemia, and about 11,000 new cases of acute myelogenous leukemia! ALL has a bimodal distribution with peak occurrences in adolescence and again after age 70.!

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