Final Exam 842 Study Guide

Final Exam 842 – Dr. Leiva’s portion – 94 out of 125 questions Old Material (50%) – 32 Questions CINV (4) • Safety profiles of the drugs we discussed – no IV Anzemet in cancer patients, Aloxi vs. Zofran differences in administration, dosing, and safety. • Oral: given 40 to 60 minutes before chemotherapy • Dolasetron (Anzemet) • CINV → PO ONLY • IV: given 20 to 30 minutes before chemotherapy Ondansetron • Dose: • CYP3A4 substrate (Zofran) • IV: 0.15 mg/kg every 4 hours up to 3 doses or • Dronedarone C/I with max 16 mg Zofran • PO: max dose 24 mg/day • QTc prolongation • Breakthrough/delayed: 8 mg PO BID – TID • Torsade de Pointes (TdP) • Pts at risk: • Congenital long QT syndrome • Hypokalemia • Hypomagnesemia • Taking other meds that lead to QTc prolongation Palonosetron (Aloxi) • IV ONLY • DO NOT take Zofran within • More expensive than Preferred: delayed nausea 3 days of Aloxi ondansetron Dose: 0.25 mg IV push over 30 seconds single • Does NOT cause QTc dose 30 mins before chemo prolongation Be able to determine risk of emetogenicity when given a percentage or tell me the percentage when given a high, moderate, low, or minimal regimen. Risk Level Emetogenic Agents • • • High (>90%) Cisplatin, Carboplatin AUC ≥ 4, Cyclophosphamide > 1500 mg/m², Ifosfamide ≥ 2 g/m² Moderate (30-90%) Carboplatin AUC < 4, Cyclophosphamide ≤ 1500 mg/m², Oxaliplatin, Methotrexate > 50 mg/m² Low (10-30%) • 5-FU, Methotrexate ≤ 50 mg/m², Vinblastine, Vincristine Minimal (<10%) Bleomycin, Rituximab, Trastuzumab Risk factors for the different CINV types and what kinds are there – (acute, delayed, anticipatory, refractory, breakthrough) Acute Emesis Delayed Emesis Anticipatory Breakthrough Emesis Refractory Emesis Emesis ≤ 24 hours during or post chemo > 24 hours after chemo • • • Risk Factors • • • Drug dependent/s pecific, dose related Anxiety Carmustine, etc. • • • • Complicated Often missed by providers Cisplatin • Max intensity 4872 hrs post administratio n • Can last up to 7 days Carboplatin • Day 2-3, up to 5 days post chemo • • • • Complicated conditioned response Nausea > vomiting Younger patients more susceptible, more aggressive chemo, anxiety, and poorer emesis control Typically after negative chemo experience Incidence 1857% Nausea > vomiting Younger patients Occurs within 5 days of treatment despite prophyl actic tx and/or requires rescue with antiemetic agents N/V occurring during subsequent tx cycles when antiemetic ppx an d/or rescue has not been effective in earlier cycles Oxaliplatin Irinotecan Cyclophosphamide Doxorubicin Be able to recommend an appropriate antiemetic regimen based on a patient’s individual risk factors and based on the emetogenicity risk of their regimen. Scenario Best Option Avoid • • • • • Long QT Syndrome Palonosetron Ondansetron, Dolasetron Diabetes 5-HT3 antagonists Dexamethasone (↑ BG) Substance Use History Olanzapine Warfarin Patient • • • • Cannabinoids, Benzos Dexamethasone, 5-HT3 antagonists Aprepitant (↓ INR) Acute → 5-HT3 antagonist (Ondansetron, Granisetron) Delayed → NK-1 receptor antagonist (Aprepitant, Fosaprepitant) Breakthrough → Olanzapine or Dopamine Antagonists Anticipatory → Lorazepam CIA (3) • Know the causes of anemia in cancer patients; including the pathophysiology associated with anemia o Anemia present in 30-90% of cancer patients (due to): ▪ Bleeding ▪ Hemolysis ▪ Renal insufficiency ▪ Nutritional deficiencies ▪ Cancer cells • Suppress hematopoiesis • Cytokines → iron sequestration ▪ Radiation ▪ Chemotherapy • Impairs hematopoiesis o Synthesis of RBC precursors in bone marrow • Alkylating agents (docetaxel, cabazitaxel, topotecan) • Platinum-based regimens o Nephrotoxic effects (Cisplatin) o Decreased production of erythropoietin in kidney • • o Cause What Happens o Chronic inflammation Hepcidin ↑ → Iron blocked → ↓ RBCs o Bone marrow invasion ↓ RBC production o Chemo/radiation Myelosuppression → ↓ RBCs o Deficiencies Iron/B12/folate low → faulty RBCs o Blood loss Iron loss → ↓ RBCs o Hemolysis RBCs destroyed early Dose adjust and evaluate ESAs for response or lack of response o Epoetin alpha (Procrit, Epogen), Epoetin alpha-epbx (Retacrit) and Darbepoetin alpha (Aransep®) ▪ Epoetin alfa: • 150 units/kg SQ 3x/week • 40,000 units SQ once weekly ▪ Darbepoetin alfa: • 2.25 mcg/kg SQ once weekly • 500 mcg SQ once every 3 weeks ▪ Darbepoetin alfa 300 mcg = darbepoetin alfa 500 mcg for initial dosing (equivalent effiacy) ▪ No response defined: • Hb increase < 1 g/dL + remains < 10 g/dL after initial 4 weeks of epoetin, or 6 weeks of darbepoetin • Discontinue therapy after 8 weeks if no response o According to PI: Initiate ONLY if Hb <10 g/dL and anticipated duration of myelosuppressive chemotherapy is at least 2 additional months. o Titrate dosage to use the minimum effective dose that will maintain a Hb level sufficient to avoid RBC transfusions ▪ Dose should be adjusted to maintain lowest Hb level sufficient avoiding RBC transfusion ▪ If Hb reaches level needed to avoid transfusion or increases > 1 g/dL in any 2-week period... • Reduce dose by: o 25% for epoetin alfa(-epbx) o 40% for darbepoetin alfa MOA and ADRs associated with ESAs and precautions with their use o MOA: Regulates production of RBCs by stimulating division and differentiation of committed erythroid progenitor cells in bone marrow o ADRs: ▪ Generally when targeting Hb > 11 g/dL ▪ Cardiovascular events (HTN, VTE, MI) ▪ Cancer progression and decreased survival FN (3) • Define FN Febrile Neutropenia (FN) • • • • • • • • • Fatigue ANC < 500 Febrile: > 100.5ᴼF (38°C) • ≥ 38.3°C within next 48 hours or • ≥ 38.0°C for duration of over 1 hours Chills SIRS (in this case the patient may NOT be febrile due to sepsis but infection is present) Other symptoms depend on the bug(s) causing infection(s) – respiratory, sore throat, diarrhea, discharge, pain on urination, redness/swelling around port, etc. MOAs of GM and GCSFs as well as major ADRs o GCSFs ▪ MOA: stimulates the maturation and differentiation of neutrophil precursors ▪ ADRs • Bone pain (25%) • Acute Respiratory Distress Syndrome (ARDS) • Splenic rupture (rare) When and how do we use GM and GCSFs o Granulocyte Colony Stimulating Factors (GCSFs) ▪ Indication: decrease incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever ▪ Filgrastim (Neupogen) ▪ Pegfilgrastim (Neulasta®, Onpro®) ▪ Start Claritin or Zyrtec day before for 2-3 days after beginning GCSF for ppx bone pain How do we determine the risk of febrile neutropenia in a regimen? High, moderate, low percentages o High (> 20%) → GCSFs o Intermediate (10-20%) → Consider GCSFs based on pt’s risk factors o Low (< 10%) → No GCSFs BCA (5) • Liposomal vs. conventional doxorubicin Doxorubicin Preoperative/Adjuvant (Adriamycin) Chemo for HER2- • • • • Moderate (<60 mg/m2) to Highly emetogenic especially when combined with Cytoxan Administration • Vesicant → Dexraxozane • Mucositis → Ice chips • Alopecia – cooling caps (controversial) • May discolor urine Dose: • Depending on your institution, the LIFETIME CUMMULATIVE DOSE could 550 MG/M2 and if XRT to the chest 450 MG/M2 OR 450 MG/M2 regardless of XRT to the chest. You were taught 450 in calculations, so this is the number I will test on. Nadir: • 10-14 days, recovery by Day 21 → Need growth support if dose dense • • All anthracyclines toxicities • Myelosuppression • Nausea/vomiting • Alopecia • Discoloration of body fluids o Doxorubicin, daunorubicin, idarubicin, epirubicin – red secretions o Mitoxantrone – blue-green secretions • Vesicant • Secondary leukemia Major: Cardiotoxicity (life-threatening) • observed: o Early transient EKG changes ▪ Uncommon ▪ Not related to cumulative dose patient received ▪ Arrhythmias ▪ Pericarditis • Late Onset o More common, requires careful monitoring o May develop several years or even decades after therapy o Manifests as ventricular dysfunction, CHF, conductible disturbances and arrhythmias. o Occurs more often in childhood / adolescence cancer survivors who received anthracyclines. o Common and life threatening. o Liposomal Doxorubicin (Doxil) NOT interchangeable w/ doxorubicin • Reformulated to reduce vesicant and cardiotoxicity potential (less but still possible) • Monitoring: • Baseline ECHO/MUGA, CBC w/diff, LFTs, periodic ECHO if high risk of cardiac toxicity • • Lot less nausea – Low emetic risk Infusion reactions • premedicate with Benadryl first time and slower infusion; most patients do fine and don’t require further premedication. MAJOR ADR • Hand and foot syndrome can be severe in patients. Usually mild and starts about 5-6 weeks but often requires a dose reduction or treatment break. • • • Related to cumulative dose patient received Preventing mucositis o → ice chips/cryotherapy Toxicity profile of anti HER2 drugs o Fetal toxicity o Pertuzumab (Perjeta) ▪ ADRs: • DIARRHEA, Cardiomyopathy, infusion reactions, peripheral edema, rash, neutropenia, insomnia • BBW: Cardiomyopathy and fetal toxicity o Trastuzumab (Herceptin) ▪ ADRs: • Cardiomyopathy, infusion reactions, pulmonary hypertension or fibrosis, rash, neutropenia ▪ BBW: Cardiomyopathy, Infusion rxns, ARDs, and fetal toxicity o Docetaxel (Taxotere) ▪ Toxicity Profile • Myelosuppression • Hypersensitivity • Fluid retention • • • Skin changes – Onycholyis Ribociclib contraindications o 21 days on, 7 days off o QT prolongation ▪ Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors – DO NOT USE WITH TAMOXIFEN Monitoring patients on tamoxifen o Monitoring: LFTs, CBC, pregnancy testing, lipid profile, gyn exam Q 12 months if patient still has uterus PCA (5) • How do we prevent tumor flares with drugs like Lupron o Use anti-androgens for at least 7 days before and after starting Lupron ▪ Bicalutamide (Casodex) ▪ Flutamide ▪ Nilutamide (Nilandron) • Treatment criteria for Provenge o Cell-based cancer immunotherapy for mCRPC o FDA approved for asymptomatic or minimally symptomatic mCRPC ▪ No liver metastases ▪ ECOG 0-1 ▪ Greater than 6-month life expectancy • Taxane toxicities o peripheral neuropathy, myelosuppression, infusion reactions • PSA for screening and levels for a transwoman • o Prostate CA Screening consists of PSA ± DRE in asymptomatic patients ▪ Screening refers to tests and exams used to find a disease, such as cancer, in people who do not have any symptoms. o For transfeminine persons ▪ Prostate-specific antigen 1 ng/mL is upper limit of normal if patient is on estrogen therapy. Novel hormone therapies and counseling points o 1st line Hormone therapy: Androgen Deprivation Therapy (ADT) = GOLD STANDARD LNRH Agonist LNRH Antagonist • • • AEs • Dosage forms • • • Leuprolide (Lupron, Eligard) Goserlin (Zoladex) Triptorelin (Trelstar) Tumor flare, loss of BMD, hot flashes, impotence, gynecomastia, bone pain, injection site pain, QT prolongation, dyslipidemia, hyperglycemia Pretreat w/ antiandrogens for 7 days for symptoms of flare ↑ cardiovascular risk Hepatotoxicity Eligard – SQ injection Zoladex – SQ implant Lupron – IM Depot • • Degarelix (Firmagon) Relugolix (Orgovyx) • PO med approved Dec 2020 • NO tumor flare ↓ in T on day 1 • • Orgovyx – PO tablets Firmagon – SQ injection GYN (4) • Carboplatin clinical pearls o Dosed using Calvert formula: Dose = AUC × (GFR + 25) o Main toxicity: Thrombocytopenia (↓ platelets) o Less kidney, nerve, and hearing toxicity than cisplatin o No need for aggressive hydration o Hypersensitivity reactions common after multiple cycles o Commonly used in ovarian, lung, breast cancers o Monitor CBC and renal function • Cervical cancer screening – how do we improve screening in a transmasculine person o Testosterone use thins vaginal lining and decreases natural lubrication ▪ Can pretreat with 2 weeks of vaginal estrogen ▪ Use lots of lubrication and consider topical lidocaine o In one study, self-collected vaginal swab for high risk HPV DNA was 71.4% as effective as the HCP performed swab LCA (4) • EGFR clinical pearls o Acneiform Rash EGFR-induced ▪ Prevention • Topical corticosteroids: Hydrocortisone 2.5%, Alclometasone 0.05% • Oral ABx • • • CRC (3) o Minocycline o Doxycycline o Other antibiotics covering skin flora o Taken twice daily for at least the first 6 weeks of EGFR therapy o May cause severe diarrhea o Sensitive to small molecule TKI – erlotinib, gefitinib irAEs in immunotherapy – managing hypothyroidism o Cause “Anything-itis” o Diarrhea/Colitis o Pneumonitis o Endocrinopathies ▪ Hyper, hypothyroidism (NO steroids for this) ▪ Type I Diabetes ▪ Adrenal insufficiency ▪ Treatment is with high dose steroids tapered over 4-6 weeks Lung cancer screening criteria o Smoking history of 20 pack-year or more o AND smoke now or have quit within past 15 years o AND b/w 50-80 years old ▪ Pack year: smoking an average of one-pack of cigarettes/day x 1 year • Ex: 20-pack year history by smoking 1 pack/day x 20 years or 2 packs/day x 10 years o When should we stop screening? ▪ Yearly lung cancer screening stop when: • 81 y/o • Not smoked in 15 years or more • Develops health problem and unable to have surgery if lung cancer found Immunotherapy in NSCLC o Immunotherapy → PD-L1 single agent or combo w/ systemic chemotherapy ▪ PD-1 inhibitors • Pembrolizumab monotherapy (PD-L1 ≥ 50%, if 1-49% → immune therapy + chemo) • Nivolumab (+/- ipilimumab) ▪ PD-L1 inhibitors • Atezolizumab • Durvalumab • MOA of Oxaliplatin o Platinum-based alkylating agent o Cross-linking of DNA strands (both intra- and inter-strand) o Disruption of DNA replication and transcription o Leads to cell cycle arrest and apoptosis (cell death) • Clinical Pearls of EGFR inhibitors EGFR Inhibitors Cetuximab (Erbitux) Cetuximab (Erbitux) • Indications: • Only efficacious in KRAS/NRAS WT/BRAF • Monitoring: Mg, K+, Ca2+ o KRAS/NRAS/BRAF WT Left WT patients with Left-sided • ADRs: 88% of patients get acneiform sided Tumors or In tumors UNLESS it’s given with rash w/in first 2 weeks of therapy, combination with encorafenib if BRAF V600E Mutation diarrhea, bone pain, and fatigue; encorafenib for patients with • Administration: Severe ALL reactions in the Southeast BRAF V600E mutations. o Premed w/ Diphenhydramine due to alpha-galactose cross-reactivity • Drugs o First dose higher (LD); if concurrent from tick bites (Alpha-gal syndrome) o Cetuximab w/radiation, loading dose must be and other potential antigen exposures o Panitumumab given 7 days prior to XRT. • Class ADRs o Use in-line filter to administer o Acneiform rash, infusion o NTE 10 mg/min infusion rate reactions, electrolyte ▪ Loading Dose given over 2 abnormalities, cardiac hours arrest ▪ Subsequent doses given over 1 hour Panitumumab (Vectibix) Panitumumab (Vectibix) • Monitoring: Mg, K+, Ca2+ • Only efficacious in KRAS/NRAS WT/BRAF • ADRs: 74% of patients get acneiform WT patients with Left-sided tumors rash, fatal infusion reactions, eye UNLESS it’s given with either Dabrafenib + toxicities, pulmonary fibrosis, and Trametinib OR Vemurafenib if BRAF V600E fatigue mutation • Administration: o In-line filter for administration o Infuse over 60-90 min New material (50%) Heme Malignancies – 62 questions HL (10) • Symptoms associated with lymphomas, know Reed-Sternberg as the difference between HL and other blood cancers o B symptoms: ▪ Fever ▪ Drenching night swears ▪ Weight loss o Presence of Reed-Sternberg is definitive for HL (large, abnormal lymphocytes that contain more than one nucleus) • Key points about ABVD and safety (bleo toxicities, dacarbazine dispensing, doxorubicin vesicant, vincas, etc) Adriamycin (Doxorubicin) • Administration • Monitoring: • MOA: intercalates DNA and • Vesicant → Dexrazoxane • Baseline ECHO/MUGA, CBC interferes with topoisomerase • Can cause mucositis → Ice chips w/diff, LFTs, periodic ECHO if high II • Alopecia – cooling caps risk of cardiac toxicity • Moderate (<60 mg/m2) to • May discolor urine • ADRS: radiation recall, mucositis, Highly emetogenic especially • Dose: Depending on your institution, alopecia, N/V/D, LFT elevation, bone when combined with Cytoxan the LIFETIME CUMMULATIVE DOSE marrow suppression, CARDIOTOXICITY could 550 MG/M2 and if XRT to the cardiomyopathy, VESICANT; secondary chest 450 MG/M2 OR 450 MG/M2 malignancies → MDS/AML, etc. regardless of XRT to the chest. • Nadir: 10-14 days, recovery by Day 21 → Need growth support if dose dense Bleomycin • MOA: cell cycle specific; induces DNA strand breaks • • Vinca Alkaloids: Vinblastine • Administration: • Usually given IVP over 10 minutes • Premedicate with Tylenol • Test dose of 1 unit over 3-5 seconds o Monitor vitals q15 minutes and administer remaining dose after 1 hour • Irritant Dose Modifications: • CrCl <50 mL/min dose reduce • Cumulative dose of 400 Units IV, IM, or SC (route does not matter) • Administration: • • Monitoring Parameters: • CBC w/diff, SrCr, BUN • Pulmonary Function tests (Baseline and periodically) ADRs: interstitial pneumonitis, skin hyperpigmentation, alopecia, anaphylaxis, fever Monitoring Parameters: • • • • Bind to tubulin, the structural protein that polymerizes to form microtubules → mitotic spindle Disrupt the normal balance between polymerization and depolymerization of microtubules → inhibits formation of mitotic spindle→ cells arrest in the M phase All vinca alkaloids are vesicants. → Treat with hot compresses. Cannot be administered intrathecally o Causes fatal ascending myeloencep halopathy Dacarbazine • Highly Emetogenic • Alkylating agent: Purine analog • • • • Brentuximab vedotin (Adcetris®) • CD30directed antibodydrug conjuga te (ADC) • Chimeric monoclonal antibody, combined with a microtubule disrupting agent MMAE, and a protease cleavage linker that covalently attaches MMAE to cAC10 IVPush and a potent vesicant Never ever give intrathecally! Nadir: 5-10 days; recovery 7-14 days Dose Modifications: • Reduce in hepatic impairment not renal • • • CBC w/diff, LFTs, serum sodium ADRs: “the penias,”peripheral neuropathy, severe constipation/ileus, alopecia, bone and joint pain • • Administration: • Protected from light during infusion • Irritant to vein (can cause phlebitis) Nadir: 7-10 days; recovery 21-28 • Primary G-CSF prophylaxis is recommended with Brentuximab vedotin + chemotherapy • • • Monitoring parameters: • CBC w/ diff, LFTs, SrCr ADRs: Alopecia, the “penias,” hepatic toxicity, acute N/V* Common adverse reactions (20%) • neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia. Warnings and Precautions • Pulmonary toxicity, SJS, hyperglycemia, hepatoxicity Etoposide (Vepesid) [as part of BrECADD] • Epipodophyllotoxin: Derived from mayapple or mandrake plant • Forms complexes with topoisomerase II and DNA to inhibit strand rejoining after breakage • • Checkpoint Inhibitors in HL • Nivolumab (Opdivo) • Pembrolizumab (Keytruda) • • • • • • Important points: • Hypotension occurs with rapid infusion (need to give over at least 60 minutes) • Secondary malignancies may develop 5-8 years later • Has concentration dependent stability. o Solutions prepared at < 0.4mg/mL are stable for 24 hours o Solutions > 0.4mg/mL are very unstable and may precipitate within a few minutes Solubilized in Polysorbate 80 which may leach plastic → Must use low sorbing tubing Reed-Sternberg cells overexpress PDL1 ligands in 65-100% of cases through amplification of chromosome 9 Epstein-Barr virus, which is prevalent in cHL, also increases the expression of PD-L1 cHL may be genetically susceptible to blockade of the PD-1 pathway Brentuximab safety considerations – warnings and precautions o Primary G-CSF prophylaxis is recommended with Brentuximab vedotin + chemotherapy o Warnings and Precautions ▪ Pulmonary toxicity, SJS, hyperglycemia, hepatoxicity Bleomycin and GCSFs o NCCN guidelines: DO NOT recommend routine use of growth factors during any regimen containing Bleomycin Long term concerns from treatment o Radiation o Acute effects o o o o o • Anorexia Xerostomia Odynophagia (painful swallowing) Skin burns Taste changes o Delayed effects o o o o o o Pneumonitis Pericarditis Cardiovascular disease Herpes zoster Infertility Subclinical hypothyroidism o Chemotherapy ▪ Immunologic dysfunction ▪ Myelosuppression → Routine use of growth factors is not recommended with ABVD ▪ Nausea/vomiting → Dacarbazine, doxorubicin ▪ Gonadal dysfunction → Alkylating agents ▪ Secondary malignancies Cumulative lifetime doses – bleomycin, doxorubicin – be able to calculate as you did in class o Bleomycin: 400 units o Doxorubicin: 450 mg/m2 NHL (10) • Key points about R-CHOP o Highly emetogenic and often requires G-CSFs for prevention of febrile neutropenia • Safety concerns with CAR-T cell therapy and addressing ICANS, CRS o Toxicities complex ▪ Short-term complications • Tumor lysis syndrome (5-17%)) • Infections and sepsis (>30%) o 80% occur w/in the first 10 days • Cytokine Release Syndrome (CRS) o Systemic inflammatory reaction ▪ Flu like, hypoxemia, hemodynamic instability ▪ > Grade 2 in 30% of patients ▪ Usually within first 14 days • Immune effector cells associated neurotoxicity syndrome (ICANS) o 2nd most common ADR can occur w/without CRS o Mental status changes, aphasia, seizures o 30% of patients and occurs within 3-5 days • • • Main points about lymphomas – DLBCL as an aggressive lymphoma o Whether or not it is a Hodgkin lymphoma ▪ Presence of Reed-Sternberg is definitive for HL o Whether the cell that is replicating is a T cell or B cell ▪ B-Cell Leukemias (Non-Hodgkin) → Chronic Lymphocytic Leukemia ▪ HL → infiltrating CD4+ T cells o The site from which the cell arises TLS as a consequence of bulky disease How does CAR-T cell therapy work? Know brand names of the CAR-T cell therapy we discussed o CAR-T cell uses your own immune cells (specifically, T cells) to find and kill cancer o Axicabtagene ciloleucel (Yescarta) o Brexucabtagene autoleucel (Tecartus) o Lisocabtagene maraleucel (Breyanzi) o Tisagenlecleucel (Kymriah) CLL (8) • BTKi – MOA, safety profiles Ibrutinib (Imbruvica) Acalabrutinib (Calquence) Zanubrutinib (Brukinsa) • MOA: Potent and irreversible Bruton’s tyrosine kinase (BTK) inhibitor, which shuts down constitutively active b cell receptor signaling Acalabrutinib (Calquence®) • MOA: Selective and irreversible second generation BTK inhibitor • FDA approved for treatment of CLL/SLL • • Administration: • Ibrutinib: PO Qday without regard to food • Acalabrutinib: PO BID without regard to food • • • • Dose: 100mg p.o. q12 hr. • Used as single agent or in combination with obinutuzumab BCL2i – MOA, safety profiles (ramp up dosing to prevent TLS) • • Drug Interactions: CYP3A4 substrate – NO GRAPEFRUIT JUICE Monitoring: EKG prior to initiation if cardiac risk, SrCr, signs/symptoms of TLS, CBC w/diff, LFTs ADRs: Afib, headache, edema, fatigue, rash, diarrhea, thrombocytopenia, GI bleeding, subdural hematoma, and skin cancers. Adverse Effects: Hemorrhage, infection, cytopenias, second primary malignancies, atrial fibrillation and flutter Initial lymphocytosis seen with ibrutinib does occur with acalabrutinib and zanubrutinib, but not to the same degree or duration Venetoclax (Venclexta) • Cytotoxic activity in CLL cells which overexpress BCL-2. BCL-2 mediates survival and helps cells survive chemotherapy. • Venetoclax binds to BCL-2 protein and restores apoptosis • • • • Administration: • PO QD with food • MUST DO RAMP UP Dosing to prevent tumor lysis syndrome • Week 1: 20 mg Qday • Week 2: 50 mg Qday • Week 3: 100 mg Qday • Week 4: 200 mg Qday • Week 5 and beyond: 400 mg Qday • • • Drug Interactions: CYP3A4 substrate – NO GRAPEFRUIT JUICE Monitoring: • Tumor Lysis Syndrome – requires dose escalation and highest risk w/in the first 2-3 weeks of therapy. ADRs: fever, hyperkalemia, neutropenia, thrombocytopenia, infections, back pain, fatigue, and headache. Risk of disease transformation to DLBCL o Richter’s Transformation: CLL can sometimes transform to DLBCL B-2 microglobulin as a tumor marker Mainstays of therapy for CLL – treatment, surveillance, never surgery o Radiation ▪ Local palliation ▪ Alternative to splenectomy o Splenectomy ▪ Palliation ▪ Autoimmune hemolytic anemia refractory to immunosuppressive agents o Leukapheresis – Short term use with elevated lymphocyte counts o Chemotherapy o Biotherapy– monoclonal antibodies o Hematopoietic stem cell transplant MM (8) • Mainstays of therapy – proteosome inhibitors, immunomodulatory drugs, dexamethasone – safety considerations; concerns around contraception/teratogenicity Proteasome Inhibitors Bortezomib (Velcade) • Administration • Stop proliferation and induce apoptosis • SQ or IVPush in MM cell lines o SQ – dilute to 2.5 mg/mL o Activity enhanced w/ o IVPush – dilute to 1 mg/mL dexamethasone + overcame resistance to apoptosis conferred by IL-6 • Carfilzomib (Kyprolis) • • • 2nd Generation Proteasome Inhibitors Ixazomib (Ninlaro®) • • • IMiD (immunimodulatory drug) SQ preferred (improved efficacy + less incidence of neuropathy – still controversial) Dose Modification • Bilirubin > 1.5x ULN → reduce • Administration • Premedicate w/ dexamethasone 4 mg prior to each dose in Cycle 1 • Pre-hydration w/ 250-500 mL Dose schedule (Max BSA 2.2 m2) • Weekly or biweekly depending on regimen Dose Modification: numerous 1st oral proteasome inhibitor FDA approved for treatment of MM in combination with lenalidomide and dexamethasone in patients who have received at least one prior therapy Dosing: 4mg p.o. once weekly days 1,8,15 of a 28 day cycle Thalidomide (thalidomide®) • Inhibition of angiogenesis • Inhibition of cell adhesion to bone marrow • Altering production/activity of cytokines • Stimulation of T cells, induce secretion of IFN beta • Role in multiple myeloma • Used as both 1st line therapy and for relapsed/refractory disease Lenalidomide (Revlimid) • REMS • More potent than thalidomide • More tolerable SEs • Disadvantages: o Neutropenia • Administration • Take 1 hour after evening meal • TWO forms of contraception if reproductive potential!! • VTE prophylaxis required: ASA 81-325 mg PO May prevent adequate stem cell collection o Strict tracking by manufacturer (Revlimid REMS® ) o • Bone targeting agents – zometa vs. pamidronate vs Xgeva – which have anti-myeloma activity and OS o Equal at reducing skeletal events but zoledronic acid 16% mortality benefit and OS by 5.5 months Pamidronate Zoledronic Acid (preferred) Denosumab (Xgeva) • • • No anti-myeloma activity Used for bone mets/pain Dosed reduced for renal impairment • Daratumumab and premedication requirements o Daratumumab (Darzalex) ▪ MOA: monoclonal antibody against CD-38 ▪ Administration: • 1st couple infusions → severe reactions • Require premedication of H1, Tylenol, + corticosteroids What type of cells are affected in MM and how does it manifest? o MM is a Plasma Cell Malignancy ▪ Accumulation of malignant plasma cells within bone marrow ▪ Proliferating plasma cells → produce + secrete monoclonal antibodies contributing to the symptoms and disease of myeloma • • • • Has anti-myeloma activity Used for bone mets/pain Dose reduced for renal impairment MDS (8) • Potential etiologies o Multifactorial: Environmental, occupational, chemo, radiation o Treatment association ▪ 10-15% due to radiation, chemotherapy, or both ▪ Alkylating agents: busulfan, nitrosurea, procarbazine (5-7 years) ▪ DNA topoisomerase inhibitors (~2 years) • Ring sideroblasts as a definitive diagnosis of MDS • Hypomethylating agents – emetogenicity o DNA hypomethylating agents (azacitidine or decitabine) ▪ Azacitidine (Vidaza) – moderate • Preferred in pts w/ significant renal insufficiency • 3-4 antiemetic medications: Aloxi/Zofran/dexamethasone/NKI ("prepitant") Decitabine (Dacogen) – minimal • No antiemetic medications needed Risk of transforming to AML Deletion 5q mutation – preferred treatment o Lenalidomide ▪ • • AML (8) • Clinical presentation and etiology • Etiology • Chemical exposure • Benzene + petroleum • Pesticides • Onset: 10-30 years • Environmental exposure • Hair dyes • Smoking • Non-ionic radiation • Prior chemotherapy • Alkylating agents: 4-8 years • Topo II inhibitors: 1-3 years • Prior XRT • Genetic Disorders • Down's syndrome • Fanconi's anemia • Bloom's syndrome • Clinical Presentation: "B-symptoms" • Weight loss • Fever • Night sweats • Most common cause of death during a blast crisis (Hyperleukocytosis) • White blood cell (WBC) count or blast count of > 100,000/mm3 • Symptoms • Intracranial hemorrhage + respiratory failure – most blast crisis deaths • Leukostasis • Rapid consumption of O2 by increased number of WBCs • • Definitions of induction, consolidation • Induction: 1st phase of treatment • Goal: kill as many cancer cells as possible and put the cancer into remission (no signs of cancer) • Consolidation: 2nd phase of treatment after remission achieved • Goal: “clean up” any leftover cancer cells that might still be hiding and reduce the risk of relapse 7+3 regimen, safety considerations, ADRs • Remission Induction • "7+3" combo of daunorubicin + cytarabine High-dose 7+3 Conventional 7+3 • • • • Pts < 60 y/o w/ good PFS Daunorubicin 90 mg/m2/day Days 1-3 Cytarabine 100 mg/m2 CIVI Days 1-7 CR 71% vs. 57% Daunorubicin (Cerubidine) • Moderately Emetogenic (3090%); highly in some patients • • • • Administration: Short infusion or IVPush in a free flowing IV • Vesicant: Extravasation→ tissue damage Cumulative Dose: • 550 mg/m2 IV or 450 mg/m2 IV in patients who received radiotherapy to chest Dose reductions: • Severe Renal and hepatic impairment (dose reduced or omitted) Nadir: 10-14 days; recovery 2124 days HiDAC supportive care requirements – eye drops Cytarabine • HiDAC (high dose cytarabine) • Antimetabolite; • GOLD-STANDARD for incorporates into DNA = post-remission therapy • • • Pts > 60 y/o w/ good PFS Daunorubicin 45-60 mg/m2/day Days 1-3 Cytarabine 100-200 mg/m2 CIVI Days 1-7 • Monitoring: CBC w/ diff, LFTs, SrCr, Echo/MUGA (baseline + periodically) Major ADRs: Alopecia (total and rapid), acute N/V, Bone marrow suppression, mucositis, phlebitis at injection site • • • • DLT (dose-limiting toxicity): myelosuppression Primary non-hematologic toxicities: cerebellar toxicity and chemical conjunctivitis inhibiting synthesis and function • < 60 years w/ favorable or intermediate risk o > 60 years and/or adverse risk = less clear High dose = ≥ 1,000 mg/m2/dose IV over 14 hrs for > 2 doses • • Cerebellar toxicity (HiDAC): ataxia, nystagmus, dysarthria o Occurs relatively soon upon starting highdose cytarabine o Frequent monitoring of neuromotor status (q 3-6 hr or 4-8 hrs) o Management ▪ Hold further doses • Symptoms often improve to baseline but permanent neuromotor damage may persist Ocular Toxicity (HiDAC) - 80% who do NOT receive eye drops o Prevention ▪ Topical eye drops need to have two mechanisms for success: • Dilute ocular concentration of cytarabine • Halt inflammation • Topical corticosteroids are the standard of care for prevention of cytarabineinduced ocular toxicity • Topical corticosteroids are required even if patient is receiving systemic corticosteroids • Dexamethasone is preferred over prednisolone due to higher potency and greater penetration into corneal epithelium ONC Emergencies (10) • Managing extravasations – hot vs. cold o Vinca alkaloids: warm compress + SC hyaluronidase o Anthracyclines: cold compress + IV dexrazoxane • Anthracycline antidote and management o Treatment must begin within 6 hours of the extravasation event • Drugs for hypercalcemia of malignancy – bone targeting agents and dosing and ADRs • • TLS – signs and symptoms, management and prevention (PhosCaUK) o Hyperphosphatemia o Hypocalcemia o Hyperuricemia o Hyperkalemia o Acute renal failure Signs and symptoms of SVC syndrome o Common: edema of the face, neck, or arms; dilatation of the veins of the upper body; cyanosis of the face • o Periorbital edema may be prominent Spinal cord compression steroid treatment o Dexamethasone