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March 21, 2019 Overview of Acute Leukemia Vinod Pullarkat, MD Clinical Professor Department of Hematology and Hematopoietic Cell Transplantation City of Hope Medical Center

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Page 1: Overview of Acute Leukemia - CME Syllabuscmesyllabus.com/wp-content/uploads/2018/03/08.-Pullarkat-_Dunca… · • Remains the standard of care at the current time for younger patients

March 21, 2019

Overview of Acute LeukemiaVinod Pullarkat, MDClinical ProfessorDepartment of Hematology and Hematopoietic Cell TransplantationCity of Hope Medical Center

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Disclosures

Consultancy and Advisory Boards: Abbvie and Jazz Speakers Bureau: Jazz and Servier

Presenter
Presentation Notes
While I have nothing to disclose, I will show photos of products with brand names. I do not work for those companies; do not consider this an advertisement.
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Hematopoiesis

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Acute myeloid leukemia

• Heterogeneous clonal stem cell malignancy in whichimmature myeloid cells proliferate and accumulate in bonemarrow and other tissues

• Most common type of acute leukemia in adults

• Median age is 67 years

• Survival remains poor

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Risk factors

• Exposure to chemotherapy• Alkylating agents• Topoisomerase II inhibitors

• Ionizing radiation• Toxins

• Benzene

• Inherited BM failure syndromes • e.g. Fanconi anemia

• Genetic disorders • e.g. Down syndrome, germline RUNX1 mutation etc.

• Myelodysplastic syndrome /Myeloproliferative neoplasm

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Presentation

• Constitutional symptoms

• Signs and symptoms of BM failure related to anemia, infection and thrombocytopenia

• Leukocytosis

• Other tissue infiltration e.g. skin, CNS

• Disseminated intravascular coagulation

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Classification

WHO classification 2016

• Incorporates epidemiology, clinical features, biology,immunophenotype and genetics

• Includes multiple subtypes

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Diagnosis

• ≥20% myeloblasts and/or monoblast/promonocytes and/or megaryoblasts in the peripheral blood or/and bone marrow

• Detection of t(8;21), inv(16), t(16;16), and t(15;17) irrespective of blast count

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Myeloid blasts

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Risk Stratification

• Clinical features• Advanced age• Extramedullary disease• History of antecedent hematological disorder• WBC# >50,000 at diagnosis

• Cytogenetics

• Molecular markers

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Acute Leukemia Work Up

• Bone marrow aspiration/biopsy• Immunphenotype (flow cytometry)• Cytogenetics• FISH studies• Mutation analysis (Next Generation Seq)• Assessment of comorbidities• Lumbar puncture• Biobanking

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Risk status Cytogenetics MolecularFavorable •CBF: t (8;21), inv(16),

t(16;16)•t(15;17)

•Normal cytogenetics with NPM1mutation or CEBPA mutation inthe absence of FLT3-ITD

Intermediate

•Normal karyotype•t(3;5)•+8•t(9;11)•Other non-defined

•c-kit mutation in CBF

Poor •Complex karyotype•MK+•-5, -7•Other 11q23 [non-t(9;11)]•Inv(3)•t(3;3)•t(6;9)•abn(17p)

•Normal cytogenetics with FLT3-ITD in the absence of NPM1•High EV11 expression

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AMLSurvival by karyotype in pts <60 yrs

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AML: Overview of Treatment

• Induction• 7+3 days of anthracycline and cytarabine. Hypomethylating agents

(azacytidine/decitabine) + Bcl-2 inhibitor (venetoclax) for older andunfit patients

• The 7+ 3 regimen was introduced over 4 decades ago• Remains the standard of care at the current time for younger

patients

• Post-remission• Age-adjusted high-dose cytarabine x 3-4 cycles vs. allogeneic

HSCT• Based on risk stratification, donor availability and patient eligibility

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AML: Relapsed/Refractory

• Carries poor prognosis

• Allogeneic HSCT if possible after achieving CR with salvage chemotherapy

• Salvage treatment with chemotherapy, hypomethylating agents + venetoclax and supportive care

• Targeted therapies for driver mutations: FLT3 inhibitors , IDH1/2 inhibitors

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AML Therapy: Side Effects

• Anthracyclines:• cardiotoxicity, myelosuppression, extravasation, and secondary

leukemia

• Cytarabine:• myelosuppression, neurotoxicity, chemical conjunctivitis, rash and

fever

• Hypomethylating agents:• well-tolerated, pancytopenia, constipation

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Acute Promyelocytic Leukemia

• Subtype of AML with distinctive biological and clinical features• Accounts for 10-15% of AML cases• Higher incidence in Latinos

• It is highly curable, without chemotherapy in Low/Int-risk• Balanced reciprocal t(15;17)

• Generates fusion transcript joining PML and RAR-α

• Leukemic cells have unique ability to undergo differentiation with exposure to ATRA, and differentiation/apoptosis when exposed to ATO

• Standard of care includes combination with ATRA and ATO, +/- chemotherapy

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APL blasts

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APL: Supportive Care

• Significant risk for DIC on presentation• Start ATRA on first suspicion of APL• BID-TID CBC and fibrinogen check

• Platelet transfusion to keep >50k• Cryoprecipitate to keep fibrinogen >150

• ATRA “differentiation” syndrome• SOB, fever, chest pain, leukocytosis and b/l infiltrate on CXR• Can be fatal• Steroid, consider holding ATRA/ATO when severe

• QTc prolongation with ATO• Weekly EKG• Keep K >4.0, Mg >2, avoid medications prolong QTc

• ATRA induced pseudotumor cerebri

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Acute Lymphoblastic Leukemia

• Most common cancer in children

• Uncommon disease in adults• Accounts for 10-20% of adult cases of acute leukemia

• Bimodal distribution; 4-10 and at age 50

• Outcomes have improved significantly in children with ALL,but less dramatic improvement seen in adults• CR; 100% vs. 65%-90%• 5-yr survival; >90% vs. 25-50%

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Presentation

• Non-specific constitutional symptoms, related to cytopenias, bone pain, splenomegly

• Mediastinal mass in T-cell disease

• Extramedullary involvement; CNS, testis

• Always needs a CNS evaluation at diagnosis

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ALL blasts

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Risk Stratification

• Clinical:• Age• Elevated WBC• Failure to achieve early CR, MRD

• Cytogenetics:• Philadelphia chromosome• Complex cytogenetics (>5 abn)• MLL mutation• Ploidy status

• Molecular:• CRLF2, IKROS, NOTCH, HOX11, etc.

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Classification

• Precursor B-cell:• 70-85% of ALL cases• + CD19, CD79a, TdT and HLA-DR• Burkitt’s leukemia/lymphoma is classified as mature B-lymphoid

neoplasm

• Precursor T-cell:• 15-25% of ALL cases• + TdT, CD7, CD3, co-expressed CD4 and CD8• Early thymic precursor ALL is a distinct subtype associated with

dismal outcomes

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CNS Involvement

• Only 5% of patients with ALL present with CNS involvement

• Third of adults in CR develop CNS relapse if no CNS-directed prophylactic therapy is given

• Cranial radiation is effective but carries significant risk of late toxicities

• Systemic chemotherapy alone is usually inadequate since it is difficult to maintain prolonged therapeutic concentrations of drugs in the CSF

• Combination of IT chemotherapy and systematic chemotherapy has emerged as most effective approach to prevent CNS relapse, rates 1-3%

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Treatment• The introduction of intensive and prolonged multi-agent

chemotherapy changed the natural history of pediatric ALL (over 90% cure rate)

• BFM regimen is widely used, tested initially in pediatrics, and then tested in modified fashion in adults

• Most modern ALL regimens include • Induction-anthracycline, vincristine, steroids, +/-cytoxan & ASP• Post-remission consolidation - 6-8 cycles• Maintenance therapy - 2-3 years

• No consensus of the optimal regimen in adults. Cure rates are 40-60%

• Allogeneic HCT remains recommended for high-risk and relapsed cases

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Drug Toxicities

• Anthracycline- cardiotoxicity, myelosuppression, secondary leukemia

• Vincrisitine- neuropathy, ileus• MTX- hepatotoxicity, nephrotoxicity, mucosititis, pneumonitis• Asparaginase- hepatotoxicity, pancreatitis, neurotoxicity,

coagulopathy, thrombosis, allergic reactions• Alkylating agents- myelosuppression, secondary MDS/AML• Intrathecal chemotherapy- headaches due to CSF leak,

arachnoiditis, N/V when given through Ommaya reservoir• Cranial irradiation- secondary cancer, cognitive impairment

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Ph+ ALL

• Ph-chromosome incidence increases with age• Represents 30-50% of adult ALL

• Ph+ ALL used to carry a poor prognosis, with low CR rateand short duration of remission

• The introduction of TKIs (imatinib, dasatinib, ponatinib)increased CR rate, more pts proceeding to alloHCT, andimproved OS compared to historical cohorts

• TKI therapy is well-tolerated and the majority of Ph+ ALLachieves CR nowadays with low intensity therapy

• TKIs toxicities: myelosuppression, QTc prolongation,dasatinib-pleural effusion, colitis

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ALL: Novel therapies for relapsed refractory disease

• New effective immunotherapies have been approved for ALL• Bispecific (BiTE) antibody• CAR T cells therapy

• There is risk of cytokine-release syndrome with immunotherapy• Manifestations: Fever, chills, hypotension, SOB, neurological

manifestations• Result of release of large amount of cytokines, IL-6, INF, etc.

• Treatment include: aggressive supportive care, IL-6 monoclonal antibody, and steroid in severe cases

• Neurologic dysfunction also seen with immune therapies

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Treatment of refractory/relapsed ALL

• Goal is to achieve CR with minimal toxicity in order to proceed to allogeneic HCT in suitable candidates

• Options include chemotherapy reinduction, blinatumomab, CAR-T cells, immunoconjugates like inotuzumab

• Overall survival of relapsed ALL is dismal. New therapies may have impact

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Acute leukemia: Clinical Trials

• Patients with acute leukemia should preferably be managed in tertiary care centers

• Should be enrolled in clinical trials whenever possible

• Early referral improves access to clinical trials and curative treatments like allogeneic HCT

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Acute leukemia: Treatment challenges

• Patients treated outside of clinical trials and with suboptimal therapy

• Inadequate initial work up, particularly molecular risk stratification, early mortality

• Delayed referral to tertiary care centers• Toxicity of therapy, particularly in the older population• Financial toxicity• Transplant donor availability (improved with haploidentical

HCT)• Social and caregiver issues, transportation issues

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Click to edit Master Presentation Date

KATRINA DUNCAN, ACNPC-AG, MSNNURSE PRACTITIONER, HEMATOLOGY / HEMATOPOIETIC CELL TRANSPLANTATION

ACUTE LEUKEMIA :NURSING CONSIDERATIONS

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Disclosure

Speakers Bureau: Astellas Pharma

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Nursing Considerations - Supportive Care

“Supportive care is an integral component of an effective individualized cancer treatment plan that

minimizes potential toxicities, maximizes therapeutic outcomes, and maintains optimal quality of life for the

patient.”

Kurtin, S.E. Cancer Nursing: Principles and Practice. Chapter 57: Leukemia and Myelodysplastic Syndromes. 7th Edition; 2011: p1369-1398.

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Education: Patient and Family

• Provide a comprehensive explanation of leukemia, including: Definition Symptoms Treatment Adverse Effects Disease-related vs Therapy-related Recovery Subsequent Treatment

• Facilitate understanding of leukemia diagnosis and treatment plan, including: Consider literacy level of the patient and their family Consider utilization of various tools to provide to the patient and their family Consider education along the continuum of patient care

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Adverse Effects: Disease-Related

• Myelosuppression Neutropenia Fever, chills, pneumonia Prophylactic antimicrobial coverage, consider: Antibacterial prophylaxis Antifungal prophylaxis to prevent candida and aspergillus infections Patients with impaired cellular immunity (i.e. ALL), consider antiviral

prophylaxis to prevent HSV/VZV infections and pneumocystis prophylaxis to prevent PCP infections

Anemia Fatigue, dizziness, tachycardia, hypotension, palpitations Transfuse PRBCs per institutional guidelines – Irradiated, leukoreduced

Thrombocytopenia Petechiae, ecchymosis, epistaxis, hemoptysis, hematuria,

hematochezia Transfuse PLT per institutional guidelines – Plasma reduced For severe thrombocytopenia or platelet refractory, consider

antifibrinolytic therapy (i.e. aminocaproic acid)

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Adverse Effects: Disease-Related

• NeutropeniaAbsolute Neutrophil Count (ANC ) < 1500 CELLS/microLMild: 1000 – 1500 cells/microLModerate: 500-1000 cells/microL Severe: <500 cells/microLRisk for Infection Neutropenic fever Febrile with temperature 100.4 F or higher May or may not present with accompanying infectious symptoms Initiate diagnostic infectious disease evaluation Cultures Imaging Initiate empiric antimicrobial coverage until afebrile and culture-

negative

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Adverse Effects: Disease-Related

• Hyperleukocytosis White blood cell count > 50,000 cells/microL Evaluate the presence of blasts Consider treatment with hydroxyurea

• Leukostasis White blood cell count > 100,000 cells/microL Evaluate the presence of blasts Evaluate patient for symptoms of decreased tissue perfusion Respiratory status Neurologic status Consider treatment with hydroxyurea and leukapheresis

For any leukocyte presentation, initiate cytoreductive chemotherapy as soon as possible to treat the underlying leukemia and effectively reduce the burden of disease.

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Adverse Effects: Disease-Related

• Tumor Lysis Syndrome Risk factors:

Intrinsic tumor-related features: High tumor cell proliferation rate, chemo-sensitive malignancy, large tumor burden

(bulky disease > 10 cm in diameter, WBC > 50,000/microL, LDH two times the upper limit of normal, organ infiltration, bone marrow involvement)

Predisposing clinical features: Pretreatment hyperuricemia/hyperphosphatemia, preexisting nephropathy, exposure

to nephrotoxins, oliguria, acidic urine, dehydration Manifestations:

Hyperuricemia -- risk of acute kidney injury Hyperkalemia -- risk of cardiac dysrhythmias, heart failure Hyperphosphatemia -- risk for hypocalcemia Hypocalcemia -- risk of acute kidney injury, cardiac arrhythmias, seizures, muscle

cramps, tetany Treatment:

Aggressive IV hydration Allopurinol Rasburicase ALL or AML and WBC > 50 K/Ul AND ldh > 2500 or serum creatinine > 1.5 mg/dL Unresponsive or allergic to allopurinol and/or febuxostat Uric acid level > 10 mg/dL or 7 gm/dL with renal dysfunction

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Adverse Effects: Disease-Related

• Disseminated Intravascular Coagulation Acute complication of a newly diagnosed malignancy, especially acute

promyelocytic leukemia (APL), causing thrombosis and hemorrhage Diagnostic manifestations: Thrombocytopenia Prolonged PT/PTT, low fibrinogen, Elevated D-dimer Increased thrombin time, reduced levels of procoagulant factors,

reduced levels of coagulation inhibitors antithrombin Clinical manifestations: Bleeding, thromboembolism, renal and hepatic

dysfunction, respiratory dysfunction, shock, central nervous system involvement

Treatment: Treat the underlying cause Supportive measures PRBC and/or PLT transfusions, cryoprecipitate, fresh frozen plasma Anticoagulation

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Adverse Effects: Therapy-Related

• Adverse Effects of Cytotoxic Chemotherapy Central Nervous System Toxicity (cytarabine) Ataxia, confusion, impaired hand-eye coordination, sensory deficits Cardiotoxicity (anthracycline) Congestive heart failure, cardiomyopathy, QT prolongation, Torsades

de pointe Gastointestinal Toxicity (multiple agents) Mucositis, nausea/vomiting, diarrhea, typhlitis Nephrotoxicity (multiple agents) Tumor lysis syndrome, co-administration of nephrotoxic agents,

dehydration Cutaneous Toxicity (cytarabine) Painful plantar/palmar erythema, blistering or desquamation if severe Ocular Toxicity (cytarabine) Keratoconjunctivitis Myelosuppression (multiple agents) Neutropenia, anemia, thrombocytopenia

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Adverse Effects: Therapy-Related

Acute Myeloid LeukemiaTargeted therapy toxicity: FLT3 inhibitors

Midostaurin : GI toxicity Gilteritinib : QT prolongation,

pancreatitis, PRES IDH 1 and IDH 2 inhibitors

Enasidenib and Ivosidenib : Differentiation syndrome

BCL-2 inhibitors Venetoclax : Tumor lysis syndrome

Acute Lymphoid LeukemiaTargeted therapy toxicity: Tyrosine kinase inhibitors

Dasatinib: Pleural effusion, pneumonitis

Monoclonal antibody Blinatumumab : Cytokine release

syndrome Chimeric antigen receptor

CAR T Cell therapy: Cytokine release syndrome, CNS toxicity

Acute Promyelocytic Leukemia

Targeted therapy toxicity: Arsenic trioxide : Cardiac toxicity All trans retinoic acid : Differentiation

syndrome

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Pre-Treatment Assessment

• Peripheral blood testing CBC w/Diff, CMP, Mg, Phos, LDH, Uric Acid, PT/PTT, INR,

Fibrinogen, Type and Screen• Bone marrow biopsy and aspiration

Next generation sequencing• HLA typing• Imaging

EKG, ECHO CT, PET/CT

• Vascular access PICC

• Fertility preservation

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Education: Patient and Family

• Patients: Understanding diagnosis Understanding therapy regimen Balancing personal life and responsibilities to accommodate your

diagnosis and treatment Patient activities and support groups

• Caregivers: Self-care and preventing burn out Legal and financial resources