ACUTE LEUKEMIAS PART 1 2023.pptx

ACUTE LEUKEMIAS Laura Cannon, PharmD, MPH, BCOP September 30, 2023 1 ACUTE LEUKEMIA OBJECTIVES ● Compare and contrast the pathophysiology and trends in epidemiology for AML, ALL, and APML ● Relate disease risk factors and patient characteristics to goals of treatment & treatment choice ● Design a...

ACUTE LEUKEMIAS Laura Cannon, PharmD, MPH, BCOP September 30, 2023 1 ACUTE LEUKEMIA OBJECTIVES ● Compare and contrast the pathophysiology and trends in epidemiology for AML, ALL, and APML ● Relate disease risk factors and patient characteristics to goals of treatment & treatment choice ● Design appropriate treatment plans based on disease & molecular targets AML = Acute Myeloid Leukemia ALL = Acute Lymphoblastic Leukemia APML = Acute Promyelocytic Leukemia 2 ADULT LEUKEMIAS OVERVIEW 3 PATHOPHYSIOLOGY 4 ACUTE LEUKEMIAS - CLINICAL PRESENTATION Nonspecific symptoms ● Fatigue ● Weight loss ● Bruising/bleeding ● Infection/fevers ● Bone pain ● Feeling unwell 5 REMINDER - TUMOR LYSIS SYNDROME ● Fast cell growth = fast cell death ○ General rule of thumb, but there are always exceptions! ● Increased cell death leads to: ○ ○ ○ ○ ● ● ● ● Increased uric acid Increased potassium Increased phosphorus Decreased calcium Risk of renal failure from uric acid crystals FLUIDS, FLUIDS, FLUIDS Treatment → Rasburicase Prevention → Allopurinol 6 DIAGNOSIS 7 ACUTE MYELOID LEUKEMIA 8 EPIDEMIOLOGY - INCIDENCE & SURVIVAL 9 https://seer.cancer.gov/statfacts/html/amyl.htm EPIDEMIOLOGY - AGE 10 https://seer.cancer.gov/statfacts/html/amyl.htm ACUTE MYELOID LEUKEMIA ● Most common form of adult leukemia accounting for largest number of deaths ● Rapid clonal expansion of myeloid blasts ● Considered a medical emergency ○ Immediate treatment necessary ● Goal is Complete Remission (CR) ○ Induction - to induce remission ○ Consolidation - to maintain remission & prevent relapse 11 NCCN Guidelines Acute Myeloid Leukemia Version 3. CYTOGENETICS & MOLECULAR MUTATIONS 5-YEAR SURVIVAL: 55-65% 24-41% 5-14% 12 NCCN Guidelines Acute Myeloid Leukemia Version 4.2023 DIAGNOSIS MYELOID MORPHOLOGY + OR 13 NCCN Guidelines Acute Myeloid Leukemia Version PROGNOSTIC FACTORS ● Patient specific factors ○ Age, ECOG, WBC at diagnosis ○ Extramedullary disease or CNS involvement ● Cytogenetics and molecular mutations ● Treatment-Related AML ○ Associated with worse prognosis ○ Cyclophosphamide, doxorubicin, etoposide, etc. ● Response to induction treatment ○ Lack of Complete Remission after first induction ○ Duration of remission < 6 months 14 NCCN Guidelines Acute Myeloid Leukemia Version TREATMENT SELECTION FACTORS ● TWO MOST IMPORTANT FACTORS ○ Age ○ Cytogenetic & molecular abnormalities (risk group) ● Other factors ○ Fit vs. unfit → can they tolerate intensive chemotherapy? ■ ECOG (can an be a grey area especially around age 60-65) ● May have a very fit patient that is 70 or a very unfit patient that is 55 ■ Comorbidities 15 AML TREATMENT STRATIFICATION AGE < 60 CANDIDATE FOR INTENSIVE THERAPY AGE > 60 AGE > 60 CANDIDATE FOR INTENSIVE THERAPY NOT A CANDIDATE FOR INTENSIVE THERAPY 16 REMISSION INDUCTION AGE < 60 Age < 60 + Candidate for Intensive Therapy ● Backbone of Therapy is “7+3”across ALL risk groups ○ Cytarabine 100-200 mg/m2 IV continuous infusion x 7 days ○ Idarubicin or daunorubicin 60-90 mg/m2 x 3 days ○ May include additional targeted agents based on disease characteristics! ● Given INPATIENT ● Goal is to induce Complete Remission (CR) 17 PRACTICE RS IS A 42 YOM PRESENTING WITH EXTREME FATIGUE HE NOTICED RECENTLY WHEN MOWING HIS YARD. HE ALSO REPORTS A RECENT COLD HE CAN’T GET RID OF AND ABNORMAL BRUISING ON HIS ARMS AND LEGS. BONE MARROW BIOPSY SHOWS 23% MYELOBLASTS; CYTOGENETICS IDENTIFIED AS INTERMEDIATE RISK, FLT3-ITD MUTATION POSITIVE. WHAT THERAPY SHOULD RS RECEIVE FOR REMISSION INDUCTION? Please go to: https://www.nccn.org/ 18 MIDOSTAURIN (RYDAPT) ● FLT3 Inhibitor = Fms-like tyrosine kinase 3 inhibitor ○ Inhibits FLT3 receptor signaling & cell proliferation → apoptosis in leukemic cells ○ Patients must have FLT3 mutation ● Dose: 50 mg by mouth BID on days 8 to 21 of induction & consolidation ● Interactions & Toxicities: CYP3A4 substrate, QTc prolongation, N/V/D, headache, increased LFTs, pancytopenia, electrolyte disturbance, hyperglycemia 19 N Engl J Med 2017; 377:454-464 GEMTUZUMAB OZOGAMICIN (MYLOTARG) ● Mechanism of Action: ○ Antibody-drug conjugate that binds to the CD33 antigen, undergoes internalization, then releases calicheamicin which binds to and breaks DNA inducing cell cycle arrest and apoptosis ○ Patients must express CD33 ● Dose: ○ 3 mg/m2 IV (max 4.5 mg)on days 1, 4, 7 with 7+3 ● Toxicities: ○ Hepatotoxicity (BBW), pancytopenia, hemorrhage, infusion reactions, QTc 20 GEMTUZUMAB OZOGAMICIN (MYLOTARG) 21 Nat Rev Clin Oncol 16, 73–74 (2019) THERAPY FOR TREATMENT-RELATED AML ● Liposomal cytarabine + daunorubicin (Vyxeos) ● FDA approved for use in treatment-related AML to overcome chemotherapy resistance ● Mechanism of action: ○ ○ ○ Anthracycline + Antimetabolite Fixed ratio of daunorubicin:cytarabine (1:5) leads to synergistic effects in leukemic cell death that may overcome chemotherapy resistance Liposomes taken up to a greater degree in leukemia cells & degraded following internalization leading to more localized release ● Dose: Daunorubicin 44 mg/m2 & cytarabine 100 mg/m2 (liposomal) on days 1, 3, and 5 ● Toxicities: similar to toxicities of individual agent 22 Blood (2014) 123 (21): 3239–3246. THERAPY FOR TREATMENT-RELATED AML ● Liposomal cytarabine + daunorubicin (Vyxeos) 23 Blood (2014) 123 (21): 3239–3246. RESPONSE CRITERIA GOAL !! 24 So we have induced remission, now what? 25 Using the NCCN Guidelines, what are some options for Consolidation Therapy in patients <60 years old? ⓘ Click Present with Slido or install our Chrome extension to activate this poll while presenting. CONSOLIDATION THERAPY AGE <60 ● Goal is to prolong remission & prevent relapse! ● High-dose cytarabine (HiDAC) ○ 3 gm/m2 IV every 12 hours x 6 doses on days 1, 3, 5 ● Mechanism of action: ○ Antimetabolite ○ Pyrimidine analog that is incorporated into DNA ○ Inhibits DNA synthesis and repair ● Toxicities ○ Cerebellar toxicity -- requires neurologic checks ○ Ocular toxicity - prevent with steroid eye drops ○ Cardiovascular C’s of Cytarabine Toxicity Cerebella/CNS Cornea/Conjunctivitis Cardiotoxicity ● Consider Bone Marrow Transplant in place of chemotherapy 27 NCCN Guidelines Acute Myeloid Leukemia Version for intermediate & high-risk groups 3.2021 SUPPORTIVE CARE ● Tumor Lysis Syndrome ○ Prophylaxis → Allopurinol + Fluids ○ Treatment → Rasburicase ● Antimicrobial Prophylaxis ○ Posaconazole preferred for fungal prophylaxis in AML ○ Antiviral & antibacterial prophylaxis when warranted ● G-CSF use is controversial ○ Theory that you could potentiate spread of disease! 28 ACUTE PROMYELOCYTIC LEUKEMIA (APML) 29 ACUTE PROMYELOCYTIC LEUKEMIA (APML or APL) ● ● ● ● ● ● Accounts for 10% of all adult AML Median age of diagnosis: 44 years Higher incidence with obesity Cytogenetic hallmark of APML is t(15;17) Considered a medical emergency Goal is CURATIVE ○ Early mortality risk due to coagulopathy ● Treatment is risk stratified based on WBC 30 NCCN Guidelines Acute Myeloid Leukemia Version ACUTE PROMYELOCYTIC LEUKEMIA ● Treatment Options ○ ATRA + Arsenic Trioxide ○ ATRA = all-trans retinoic acid ■ Can be started before diagnosis confirmed on bone marrow biopsy ○ Arsenic Trioxide ■ Monitor for QTc prolongation!! ○ Could also include cytotoxic chemotherapy depending on risk ● Monitor for risk of differentiation syndrome ○ Could consider prophylaxis with corticosteroids 31 NCCN Guidelines Acute Myeloid Leukemia Version ACUTE LEUKEMIAS Laura Cannon, PharmD, MPH, BCOP September 30, 2023 32