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Oncology Exam 4
Frei ACUTE Leukemia E
| Question | Answer |
|---|---|
| once again, Leukemia is an umbrella term for which other leukemias? | Acute Lymphocytic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Chronic Mylogenous Leukemia (CML |
| Epidemiology of Acute Leukemia | -Acute leukemias make up about 2% of all cancers ⭐️ and 2% of all cancer deaths -AML accounts for 80% of acute leukemias -ALL is primarily a pediatric disease and AML more common in older adults |
| ALL may manifest as? | -T-cell or B-cell (B-cell most common) ⭐️ -Philadelphia chromosome + or neg |
| What is the prognosis of Acute Leukemia? | -Cure rate in 1960’s in children ~10% for ALL (Today cure rate in children >80%) -Adult cure rates: 20 years ago cure rate ~35% adults; Today, survival rates > 60% -Treatment protocols developed in pediatrics -Most benefit has been derived from systematically modifying and improving the way chemotherapy is given *Complete response is obtained in 65-85% Disease free survival--> 35-50% (hasnt't come back but could) |
| Prognosis, need to know | -poor outcomes with unfavorable cytogenics (translocation 9:22) associated with the worst outcomes and harder to treat cancers |
| ALL risk factors include? | Chemical Exposure (pesticidses, beneze and petroleum produtcs, hair dyes, smoking, nonionic radiation, occurs after 10-30 years of exposure) -Preveious chemo (Alkaylting agents (cyclo and mlphalen) occurs after 3-5 years of expisure -Genetic disorders (Down's syndrome) |
| S/Sx of ALL? | -Abrupt onset with symptoms (days/wks) related to suppressed bone marrow -Fatigue -> anemia/extreme tiredness; -Fever or infection--> leukopenia -Bleeding, bruising-> thrombocytopenia -Bone pain and tenderness (More common in children) -WBC-> may be increased (>50) or decreased (<10) -Peripheral blast cells (immature cells) -Increased LDH -Increased uric acid |
| Findings on a physical for ALL are the following? | -Pallor, increased petechiae -Hepatosplenomegaly -Lymphadenopathy (about 50% on presentation) -Musculoskeletal pain -Mediastinal mass (more common in T-cell ALL) |
| Work-up and diagnosis of ALL: | -Physical exam and history -CBC -Peripheral blood smear -To examine for blast cells, platelet counts, WBC count -Bone marrow biopsy ± lumbar puncture -Cytogenetic analysis -Immunophenotyping |
| Immunophenotyping is used to? | -determine the presence of cell markers ⭐️ -Assists in determining lineage (B cell vs. T cell)⭐️ -Assists in determining prognosis⭐️ -B-cell is more common |
| Risk Stratification of ALL? remember VERY HIGH: Chromosomal variation? Translocation? | -Hypodiploidy (<45 chromosomes) -t(9:22) Phladelphial chromosome (when present-->confers a high risk of resistance or poor response to our treatments. |
| History of ALL therapy | -1962--> St. Jude’s Children Hospital founded -Initiated the concept of treatment “phases” -Remission induction – usually 3-4 drugs -Intensification /Consolidation – different agents (combo) -Prevention of meningeal disease – CNS prophylaxis (chemo is intrathecal for BBB) -Maintenance therapy Primary goal is CURE! *research protocols (initiated idea of giving heavy dose for remission reduction (different types for remission reduction) big de-bulking of cancer cells) |
| ALL Therapy consists of? | Induction (4-6 wks)-> HyperCVAD/ HD/ MTX/ ARA-C Intensification & Consolidation (20-30 wks)-> HyperCVAD HD MTX/ ARA-C/ Asparaginase Maintenance (2+ years) POMP (Puinethol (6-MP) Oncovin (Vincristine), M (MTX), P (Prednisone) *CNS Prophylaxis is used throughout |
| Induction in ALL goal? Remission? | -Goal: to rapidly kill most tumor cells and obtain Remission (100% to less than 5%) -Remission: Less than 5% leukemic blasts in the bone marrow Normal blood cells (getting back to normal count) Absence of tumor cells in blood (peripheral) Absence of other signs and symptoms of the disease (wont have fatigue, and relative free) |
| Remission Induction in Adult ALL? built about 3-4 drug regimen consisting of? | -Anthracyclines -Vincristine -Corticosteroids -Asparaginase |
| Example regimens for induction in ALL to know is the? | Hyper-CVAD (MD Anderson) |
| ⭐️HYPER refers to? CVAD? | hyperfractinated--> High dose MTX and Ara-C (High dose MTX IV) and High dose ARA-C (cytarabine) IV -C for cylophosphamide and Mesna (given for prevention of the hemorrhagic cystitis that occurs with both Cyclophosphamide and Ifosfamide due to the acroline metabolite) -V for Vincristine IV -Doxorubicin (Adriamycin IV) -Dexamethasone 40 mg daily for 4 days *CNS prophylaxis: Intrathecal (IT) Cytarabine and IT Methotrexate given every cycle both parts (IT throughout) |
| MTX remember the acronym METHO! for AE which stands for? | M: Mouth ulceration E: End of WBC; leukopenia T: Tiredness/ Fatigue H: Hepatotoxicity O:Fibrosis of the lung |
| MTX is a high dose tx in the Hyper CVAD regimen for induction of ALL. It requires | Requires hospitalization, Rigorous hydration, Leucovorin rescue |
| SE of MTX consists of? | Myelosuppression (Low red blood cells, white blood cells, and platelets); Severe diarrhea; Mouth sores; Stomach ulcers; Kidney Damage; Liver Damage |
| DI of MTX are? | -Dec MTX excretion - non-steroidal inflammatory drugs (NSAIDs⭐️), aspirin, penicillins, proton pump inhibitors -Interfere with folate antagonism – Phenytoin and (Bactrim⭐️) (trimethoprim component) and see increased MTX tox. -Do NOT be used the day before or the day of therapy with methotrexate |
| Vincristine drug info? | Administer IV -Never administer intrathecally (IT)⭐️ : Can result in death -Unique and specific ADRs: Myelosuppression, Peripheral neuropathy, Constipation Generally, dose is capped at 2 mg |
| After induction, the next step in therapy for ALL is Intensification/Consolidation, what are we doing in this step? | -Goal: Eradicate residual measurable leukemia cells -Using high doses of multidrug chemotherapy to further reduce tumor burden -HyperCVAD is given again for months 6 and 18 -MTX and L-asparaginase administered on months 7 and 19 |
| Asparaginase Toxicities and management drug info? | -Hypersensitivity: Premed with steroids, diphenhydramine, acetaminophen; If rxn occurs, give more of above meds and slow infusion -Thrombosis/bleeding: Monitor fibrinogen 2x weekly and replace if low -Hypertriglyceridemia: Treatment may be necessary, hold tx if trig > 1000mg/dL ⭐️ -Pancreatitis If patient develops pancreatitis, will discontinue treatment |
| Other Toxicities and management of Asparaginase are? | -Hyperammonemia (asaparaginase blues): from Immediate infusion reactions; delayed- fatigue, somnolence; Monitor ammonia in patients exhibiting mental status changes (not common) -Hyperglycemia: Educate patients to monitor glucose; If stop treatment, glucose should normalize -Hepatotoxicity: Prevention: need cautious dosing in AYAs(adolescent/young adults/adults (especially if obese); Hold until bilirubin < 2 mg/dL (can rechallenge when resolved) |
| Continuation/Maintenance (2+ years): Goal? Remember the maintenance regimen: POMP which stands for? | -Goal-->prevent disease relapse; if any cells left, they will cause relapse if not eradicated; P: Purinethol (6-MP) O: Oncovin (Vincristine) M: MTX P: Prednisone *Ph + --> HSCTl imatinib/dasatinib (both are preferred TKI) means Philadelphia chromosome + and expect them to relapse (we know cancer will come back and those pts will be sent to transplant (Hematopoietic...); Ph + will not get POMP regimen⭐️ then placed on Imatinib/dasatinib (either for a couple of years since they target the phily) |
| Remember that CNS prophylaixis occurs in all phases of therapy (induciton, intesification/consilidation, and Maintenance)--> usually consits of _______ chemo, such as MTX or cytarabine/ Administered either through lumbar puncture or _____ ______ | intrathecal; Ommaya reservoir |
| Supportive care in ALL therapy consists of? | -Anti-infective prophylaxis: Ciprofloxacin BID or; levofloxacin daily; Fluconazole daily; Acyclovir daily or valacyclovir daily -Growth factors: G-CSF was given on day 5 of HyperCVAD first part and day 4 of high dose MTX-araC therapy |
| Response to ALL treatment consists of looking at bone marrow and blood evaluation and a complete response. Response is measured by? | -< 5% blasts in bone marrow -No abnormal peripheral blasts in blood -Resolution of signs and symptoms -Normal hematological response |
| Recurrent ALL can be seen with up to ___% adults with ALL are resistant to induction. Many adults who do obtain a clinical response, eventually relapse. Consider? | -25%; -re-induction with initial regimen unless patient was resistant initially (timing of relapse)--> stem cell transplant with high dose chemo -Consider: High dose chemotherapy with allogeneic (someone else gave a transplant) SCT(stem cell transplant) or try Blinatumomab; Clinical Trial *always allogeneic for ALL so long as they can find a donor |
| Acute Myelogenous Leukemia (AML) background? | -Most common myeloid malignancy -About 20,800 new cases of acute myeloid leukemia (AML). Most will be in adults. -More common among men -Incurable 50 years ago, AML is now cured in 35 to 40% of adults (<60 yrs old) -Older patients unable to receive intensive chemotherapy have a dismal median survival of only 5 to 10 months |
| AML-Etiology? Drugs? Viruses? | -Drugs: Topo II inhibitors, Alkylating agents; -Viruses: EBV, HTLV-1,-2 -Genetic conditions: Ataxia Tel, Bloom's syndrome, Down's, Fanconi, Kleinfelter's; -Social habits: Smoking, maternal marijuana, ethanol use; -Chemicals: Benzenel -Radiation: Ionizing radiation; -Pesticides; -Pyethroid based shampoo |
| S & Sx of AML are? | -Anemia -Thrombocytopenia -Fatigue -Fever -Night sweats -Unexplained weight loss -Weakness -Bone, back or abdominal pain -Easy bruising |
| Diagnosis of AML is? | -Peripheral blasts or bone marrow findings consistent with AML should be present -Greater than or equal to 20% blasts in peripheral blood |
| Risk Stratification of AML is measured by? | -Patient Age -Performance Status -Comorbidities -Treatment related AML/ prior hematologic disorders -Cytogenetics/molecular mutations |
| ML- Cytogenetics Risk group: unfavorable; Cytogenetic abnormality? Gene Mutations? | just know the t(9-22) poor outcome *also true in ALL (ph+ phily chromosome) |
| AML Therapy consists of? | induction (7 + 3) ⭐️ ; Consolidation (HiDAC then Transplant, usually Allo transplant) ⭐️; Maintenance⭐️ |
| Principles of adult AML therapy are? | -Stratify by intensity of remission induction: High Intensity for CURE: </= 60 years or > 60 but fit for intensive therapy (Goal is CR) -Low intensity for unfit (Goal is palliation): Majority of these treatments continue until disease progression; High intensity for > 65 years has poor long-term outcomes -Incorporate predictive markers where applicable |
| Adult AML "Induction" Tx: how do we manage induction? | 1. Manage life threatening complications 2. Complete workup 3. Determine “fitness”; intensive therapy eligible or ineligible 4. Select and manage therapy over ~ 1 month 5. Goal: complete response (CR) /remission (CR) (~day 28 at count recovery) |
| AML - Induction for healthy patients info? | -Kill all leukemic cells in blood and bone marrow -Standard of care = 7+3⭐️ -If FLT3 mutation, add midostaurin on days 8-21 to 7 + 3: Midostaurin addition improved OS, 74.7 months vs 25.6 months (placebo) p=0.009 (add midostaurin if they have the FLT3). overall survival got 74 months vs 25 months that didn't have it. extra 2 years. ⭐️ |
| 7 + 3 is standard of care for Intensive Induction Chemotherapy. What are the drugs in this regimen? | -Cytarabine (Ara-C) 100 mg/m2/d CIV days 1-7⭐️(continuous) -Anthracycline: Daunorubicin 60 – 90 mg/m2/d IV x 3 days OR Idarubicin 10-12 mg/m2/day x 3 days ⭐️ -If FLT3+ add midostaurin (as data matures with newer FLT3+ drugs may see more use) *this would start at day 8) |
| AML Treatment: Predictive Biomarkers: These consist of? Drug options to remember is _____ for FLT3 mutation | FLT3; IDH1 or IDH2; BCL-2 overexpression; CD33. -Midostaurin |
| AML - Induction for healthy patients: Day 14 marrow, if no leukemic cells, continue to ___ ____. If on Day 14, marrow shows leukemia, _-____ | post remission (re-assess and check blood); re-induction (repeat same regimen to get response |
| Adult AML “Consolidation” Treatment. risk and tx option? | Risk stratify Chemo – favorable risk (no cytogenetic mutation i.e t(9-22) or not suitable for transplant. (chemo only for favraoble risk) or have a Transplant who are intermediate/ poor risk such as with the the 9-22 (along with Chemo) Goal: deepen remission/cure *Chemotherapy--> Allogenic transplant *Day 28 would move into consolidation which means achieved complete response and then move to allo transplant. *people that have that 9-22 would get that transplant. |
| AML - Consolidation: What is the standard of care of chemotherapy in this stage? | HiDAC (high dose (ara-C) (cytarabine) |
| HiDAC, used in consolidation in AML, consists of what agents? | -Cytarabine (Ara-C) 3 g/m2 iv q12h x 6 doses -Days 1 & 3 & 5 per cycle -4 cycles |
| Adult AML "Consolidation" Treatment Considerations? | -Identify patient who may benefit -Goal: maintain remission/prevent relapse *everyone gets the HiDAC (cytarabine) andn those elibible would get allogenic transplant such as pts with ph+ chromosome pts *induction: 7+3 +/- midostaurin (if they have the FLT3+ mutation) *Consolidation: High dose Ara (c) as well as allo transplant in genreally poor or high risk pts with ph+ chromosome t9-22) |
| Summary ALL--> | -ALL is primarily a disease of children, but can affect adults -ALL requires immediate treatment or prognosis is poor -Various regimens exist, most studies performed in pediatric ALL -Regimen with improved outcomes HyperCVAD -Refractory or relapsed disease requires consideration for HSCT or clinical trial |
| AML – Transplant | -Occurs after control of leukemic cells -Allotransplant is preferred treatment with matched sibling -Consolidation therapy may/may not be given depending on plans for transplant *Autograft from same individual) -Syngeneic graft (from identical twin) -Allograft (non-identical individual -Xenograft (different species) |
| AML - Maintenance: Allo Transplant If yes, do we give maintenace? | No maintenance |
| AML - Maintenance: Allo Transplant If no, do we give maintenance? What do we give? *intense regimen | Give Azacitadine (maintenance); Continue Azacitadine PO daily x 14 days fo 28 day cycle until no clinical benefit |
| AML – Low Intensity Induction for those not able to get a transplant, perhaps too old). What agents? | -Decitabine or 5-azacitidine (most often used) -May take up to 4-6 cycles to see benefit -Gemtuzumab ozogamicin (GO) monotherapy -Low dose cytarabine -Best supportive care |
| What are the major toxicities? | -Cytarabine -Anthracyclines -Midostaurin |
| Toxicities with Cytarabine include? | -Severe CNS toxicity with doses > 1 g/m2 (i.e. with the high dose Ara (c); monitor closely -Conjunctivitis (ophthalmic steroid use for prevention and treatment) |
| Toxicities with Anthracyclines include? | -DOSE LIMITING TOXICITY: Cardiotoxicity at cumulative doxorubicin dose equivalent of 550 mg/m2⭐️ ; dose dependent and permanent; delayed onset by years -Moderate/High N/V -Mouth sores -Extravasation risk *considered a vesicant |
| Toxicities with Midostaurin include? Overall survival with this agent? | -Pulmonary toxicity (including fatal events) -Nausea * (Statistically different than placebo) -Anemia * (Statistically different than placebo) -Rash -Prolonged overall survival with midostaurin given during induction and consolidation and maintenance vs standard of care 74.7 months vs 25.6 months, HR 0.78, CI 0.63-0.96 |
| Midostaurin (Capsules) Toxicities? DI? | -Can increase QTc (do not use if baseline QTc >500msec) Drug Interactions: -Avoid CYP 3A inducers -Monitor with given with CYP 3A inhibitors for increased neutropenia, anemia, thrombocytopenia -Be cautious if taken with other meds that prolong QTc |
| Conclusions: ALL? AML? | ALL – disease of children, treatment includes high dose combination chemotherapy AML – more common in adults, 7+ 3 regimen is standard induction regimen followed by HiDAC |
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Xander635
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