Treatment of Acute Myeloid Leukemia that develops after Myelodysplastic Syndrome &

Supportive CareJoseph Helms

Wingate University School of Pharmacy Oncology Rotation

Novant Health Presbyterian Medical Center

Objectives1. List pertinent patient information2. Describe the definition, clinical presentation, pathophysiology, risk

factors, and staging/diagnosis of Acute Myeloid Leukemia3. Discuss most recent guidelines and primary literature relating to

Acute Myeloid Leukemia4. Discuss supportive care and treatment of Acute Myeloid Leukemia

What is Acute Myeloid Leukemia?• Acute form of Myeloid Leukemia• Can occur as a result of Myelodysplastic Syndrome (MDS may develop into AML)• Uncontrolled growth of blasts in the bone; “crowds” the bone marrow • In general, treatment based on if < or > 60 years of age• Diagnosed usually in the elderly• Classic treatment: “7+3”

• Cytarabine + anthracycline (often daunorubicin)• HiDAC is the high dose form • Elderly patients may have trouble tolerating regimen

• Difference between AML and MDS? Hypercellular vs. Hypocellular• Difference between AML and ALL? CD13, CD34, and CD117• Difference between AML and APL? Subtype of AML and many pre-myelocytes

Patient Case• CC: Was diagnosed with AML after admission; Neutropenia fever, Pancytopenia, Fatigue• HPI: Nausea & Vomiting for 2 weeks, Weight loss• Admit Date: 8/27/16• PMH:

• Hypertension• Dyslipidemia• Hypercalciuria

• Allergies: losartan, lisinopril, cyclobenzaprine, pravastatin, simvastatin, ezitimibe• Family History: Breast Cancer (Daughter)• Social History: Former smoker (Quit 2007; pack years not listed)• BMI: 19.61 kg/m^2• No ECOG score or PPS2 recorded

Patient: Bone Marrow Aspirate and Biopsy

• Deletions at chromosomes 5 and 17 (5 and 7: not a favorable outcome)• CSF1R/RPS14 on Chromosome 5 (42%)

• Bone Marrow Aspirate: 30% blasts• Bone Marrow Biopsy: Hypercellular (70%); higher number of blasts• Know it’s Acute Myeloid Leukemia vs. Acute Lymphocytic Leukemia,

because tested positive for CD13, CD34, CD117, HLA-DR, CD-45, CD71, CD38, and MPO• No Auer Rods Were Noted

Patient Case: Home Medications• Amlodipine besylate 5 mg tablet daily• Aspirin 81 mg tablet daily• Lovastatin 20 mg tablet daily• Mometasone 0.1% ointment• Vitamin D3 5000U tablets daily• Zolpidem tartrate 10 mg tablet

Patient Case: Admission Vitals and Labs

_________________________ 102

4.3 25 1.1146 104 14

Vital Measured

Value

Temp 97.9-101

HR 82

RR 16

BP 100/60

SpO2 Sat % 96%

Definitions• Induction therapy- first treatment in cancer therapy with goal of sending the patient into remission• Consolidation therapy- after induction therapy; agents may be different from those used in induction

therapy; goals: prevent disease from recurring• Complete Remission:

• No Auer rods• Bone Marrow blasts <5%• ANC> 1,000/mcl• Platelets > 100,000/mcl

• Partial Remission: • 50% reduction in blasts to within the 5-25%• ANC> 1000/mcl• Platelets> 100,000/mcl• Evidence of disease (residual) outside of the bone marrow

• Treatment Failure: • Complete Response not achieved

Epidemiology of AML & MDS• There has been an increase in MDS as the elderly population has

increased in number• Incidence is 3.5 per 100,000 per year• Incidence is higher in men than in women• <65: incidence of 1.7 • >65: incidence of 15.9

Marcucci G, Bloomfield CD. Acute Myeloid Leukemia. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine [Internet]. 19 e New York (NY): McGraw-Hill; c2015. Chapter 132. [cited 2016 September 13]. [Incidence]; AccessMedicine. Available from: http://accessmedicine.mhmedical.com/content.aspx?sectionid=79731765&bookid=1130&Resultclick=2

Clinical Presentation of AMLFatigue HeadacheAnorexia Sweating

Weight Loss Bone Pain

Bleeding/Bruising Anemia (often normocytic); low RBCs, low platelets (thrombocytopenia) ; platelets

adherence properties may change

Fever & Infection WBC:25-40% < 5000/microliter,20% >100,000/microliter

Median: 15,000/microliterLymphadenopathy Elevated Uric Acid

Cough

Marcucci G, Bloomfield CD. Acute Myeloid Leukemia. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine [Internet]. 19 e New York (NY): McGraw-Hill; c2015. Chapter 132. [cited 2016 September 13]. [Hematologic Findings]. AccessMedicine. Available from: http://accessmedicine.mhmedical.com/content.aspx?sectionid=79731765&bookid=1130&Resultclick=2

Pathophysiology of AML

http://www.cancer.gov/images/cdr/live/CDR526538.jpg National Cancer Institute. Cancer.gov [Internet]. National Cancer Institute (NIH); c.2015. Cancer Types: Acute Myeloid Leukemia Treatment-Patient Version; 2016 [cited 2016 September 13]; [Leukemia May Affect Red Blood Cells, White Blood Cells and Platelets]. Available from: https://www.cancer.gov/images/cdr/live/CDR526219.jpg

• Mutations of cells cause myeloblast to not mature• Bone Marrow gets

“crowded” with blasts• Begin to see immature blasts

in the cells

Risk Factors of AMLAML:• Anticancer agents

• Alkylating Agents: 4-6 years after exposure; chromosomes 5 & 7• Topoisomerase II Inhibitors: 1-3 years after exposure; chromosome 11q23• Anthracyclines• Others: Benzene, Chloramphenicol, phenylbutazone, chloroquine, and methoxypsoralen

• Age> 65: disease becomes more resistant as age• Men>Female• Previous Cancer History• Down’s Syndrome• Radiation (high dose or with use of alkylating agents), Chemicals (Ethylene), Smoking

Diagnosis of AMLTests: Bone Marrow Aspiration, Bone Marrow Biopsy, Peripheral Blood Smear for diagnosis, and to monitor response to treatment

• Usually performed on the hip (pelvic bone)

• Not as Commonly Used: Lumbar puncture (if suspect spread to CNS)

• Peripheral Blood Smear tells you if blood cells changing in numbers or in profile

MDS:

• Low RBCs, <20% blasts, and may have low WBC and platelets; may have anemia

• May want to rule out Vitamin B12, Folate deficiency, or other causes of decreased blood cells

AML:

• Not listed in NCCN Guidelines

• Generally known to be the following:• >20% blasts • Auer Rods • Cells turn black with AML• Cytochemistry

American Cancer Society [Internet]. Atlanta Georgia: American Cancer Society/Cancer.org. c. 2016. How is Acute Myeloid Leukemia Diagnosed?; 2016 February 22 [cited 2016 September 13]; [Complete Blood Cell Count and Peripheral Blood Smear; Cytochemistry]. Available from: http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute-myeloid-myelogenous-diagnosed

Prognostic Factors of Remission for AML

• Chromosomes: Most Important Prognostic Factor:• Good Impact on Prognosis: NPM1 mutations (5q35. 1), CEBPA mutations (19q13. 1),

and miR-181a overexpression (1q32. 1 and 9q33.3)

• Bad Impact on Prognosis: FLT3-ITD (13q12), KIT mutation (4q12), FLT3-TKD (13q12), RUXN1 mutations (21q22. 12), WT1 mutations (11p13), ASXL1 mutations (20q11. 21), DNMT3A mutations (2p23. 3), IDH mutations (IDH 1 and IDH 2) (2q34 & 15q26. 1), MLL-PTD (11q23), TET2 mutations (4q24), BAALC overexpression (8q22. 3), ERG overexpression (21q22. 3), MN1 overexpression (22q12. 1), EV1 overexpression (3q26.2), miR-155 overexpression (21q21.3), and miR-3151 (8q22.3)

• If achieve Complete Remission after one cycle, the patient is more likely to have a longer complete remission than a patient requiring multiple cycles

Marcucci G, Bloomfield CD. Acute Myeloid Leukemia. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine [Internet]. 19 e New York (N: http://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=98711279&gbosContainerID=0&gbosid=0Y): McGraw-Hill; c2015. Chapter 132. [cited 2016 September 13]. [Table 132-3: Molecular Prognostic Markers in AML]. AccessMedicine. Available from: http://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=98711279&gbosContainerID=0&gbosid=0

Prognostic Factors (con’t)• Poor performance status• High leukocyte count• If obtain Complete Remission after first induction cycle, more likely to

have longer duration of Complete Remission

Treatment Induction of AML: NCCN Guidelines

O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, Bixby D, Blum W, Borate U, Coutre SE, Lima MD, Fathi AT, Foran JM, Gore SD, Lancet J, Maness LJ, Maricucci G, Martin ME, Martin, MG, Moore JO, Olin R, Pollyea DA, Pratz K, Ravandi-Kashani F, Shamji PJ, Stone RM, Strickland SA, Wang ES, Weiduwilt M. NCCN Clinical Practical Guidelines in Oncology: Acute Myeloid Leukdemia. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]: Title Page- MS-73, , Treatment Induction, AML mm,lllI > 60, (AML-11). Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

Treatment Post-Remission

O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, Bixby D, Blum W, Borate U, Coutre SE, Lima MD, Fathi AT, Foran JM, Gore SD, Lancet J, Maness LJ, Maricucci G, Martin ME, Martin, MG, Moore JO, Olin R, Pollyea DA, Pratz K, Ravandi-Kashani F, Shamji PJ, Stone RM, Strickland SA, Wang ES, Weiduwilt M. NCCN Clinical Practical Guidelines in Oncology: Acute Myeloid Leukdemia. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]: Title Page- MS-73, AML Post-Remission Therapy: Age > 60 y: (AML-13). Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

Relapse Treatment/Monitoring (In General)

Relapse Treatment: If had remission1. Clinical Trial2. Chemotherapy----- RIC (Reduced

Intensity Conditioning) allogeneic HCT (only if in remission)

3. If initial induction regimen was effective for patient for a prolonged initial remission (>12 months), then can re-try the regimen

4. Supportive Care5. Lower dose of cytarabine

Monitoring: In General• CBC with platelets 1-3 months for 2

years, then 3-6 months up to 5 years• Will be at least 12 weeks before get a

bone marrow with decitabine; for surveillance guidelines recommend bone marrow biopsy/aspirate if peripheral smeer is abnormal or cytopenias develop

• Bone marrow donor search

O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, Bixby D, Blum W, Borate U, Coutre SE, Lima MD, Fathi AT, Foran JM, Gore SD, Lancet J, Maness LJ, Maricucci G, Martin ME, Martin, MG, Moore JO, Olin R, Pollyea DA, Pratz K, Ravandi-Kashani F, Shamji PJ, Stone RM, Strickland SA, Wang ES, Weiduwilt M. NCCN Clinical Practical Guidelines in Oncology: Acute Myeloid Leukdemia. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]: Title Page- MS-73, Surveillance vvv (After Completion of Consolidation): (AML-14). Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

Supportive Care• Bacterial Prophlyaxis: Fluoroquinolone• Fungal Prophylaxis: Posaconazole• Voriconazole better if used for treatment, though guidelines say equivalent

• Viral Prophylaxis: acyclovir (HSV, VZV), famciclovir (HSV, VZV), ganciclovir (HSV, VZV, CMV, HHV-6)• Hydration to prevent crystal nephropathy; has renal adjustments• Famciclovir has no data for viral prophylaxis in oncology• Ganciclovir may cause myelosuppression

Baden LR, Sankar S, Angarone M, Blouin G, Camins B, Casper C, Cooper B, Dubberke ER, Morris A, Freifeld AG, Greene JN, Ito JI, Kaul DR, Lustberg ME, Montoya JG, Rolston K, Satyanarayana G, Segal B, Seo S, Shoham S, Taplitz R, Topal J, Wilson JW. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prevention and Treatment of Cancer-Related Infections. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]. Title page- MS 114, Prevention of Herpes Simplex Virus and Varicella Zoster Virus (VZV) Reactivation or Disease, (INF-3). Available from: https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf

Supportive Care (Con’t)• Tumor Lysis Syndrome Prophylaxis: Not needed unless stronger

chemo agents• Hydration• Diuresis• Rasburicase or Allopurinol

• Would Consider Rasburicase: Hyperuricemia, poor renal function, high percentage of blasts

• Do not need to alkalinize urine (can cause Calcium Phosphate precipitation due to hyperphosphatemia)

• Growth Factors: • Do Not Use in AML

General Toxicities of All Chemotherapy

•Chemotherapies in general target the rapidly dividing cells of the body which explain the following toxicities:•Myelosuppression• Nausea and Vomiting• GI toxicity• Diarrhea• Alopecia• Nails may fall off

Decitabine (Dacogen)• Uses: • FDA: Myelodysplastic Syndrome• Off-Label: AML

• Renal Adjustments: No renal adjustments except during treatment when SCr >2 mg/dL (hold until SCr resolves)• Hepatic Adjustments: No hepatic adjustments except when ALT or

Bilirubin >2 ULN during treatment• Blood: ANC < 1000/mm^3 and platelets <50,000, reduce or give dose

later

Decitabine (Dacogen) (con’t)• Dosed off of Body Surface Area (BSA)• 20 mg/m2/day days 1-5 for one hour infusion

• MOA: Hypomethylating agent• Time to Effect: 3-4 cycles before see response• Given Every 28 days• Metabolism: cytidine deaminase (possibly)• Half-life elimination: approximately 30 minutes• Cost: ~$2,000 for 50 mg vial (IV)

Adverse Effects of Cytarabine + Anthracycline (Daunorubin, Idarubicin) vs. Decitabine

• Cytarabine: Conjunctivitis, “hand-foot” syndrome, neurologic toxicity• Anthracyclines:• Cardiotoxicity: dose-related; becomes irreversible at 300-500 mg/m^2 (450

mg/m^2 is usually limit); monitor left ventricular ejection fraction with EKG; permanent; usually takes 5-10 years to develop• Vesicant• Infertility• Secondary AML and MDS

Bone Marrow Transplant• HLA typing should be done at diagnosis• Usually bone marrow transplants done in younger patients• Donor needed; does not have to be a family member• RIC (Reduced Intensity Conditioning) allogeneic for >60 years of age: • Option especially for patients with first complete remission, and few other

disease states• 1.) If in Complete Remission as post-remission therapy• 2.) Failed induction: Only in clinical trials, and must not have a large quantity

of disease

Primary LiteratureKantarjan HM, Thomas XG, Dmoszynska A, Wierbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J, Kuo C-Y, Oriol A,

Ravandi F, Faderl S, Delauny J, Lysak D, Minden M, Arthur A. Multicenter, Randomized, Open-Label, Phase III trial of Decitabine

Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly

Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology [Internet]. 2012 July 20 [cited 2016 September 13]; 30(21): 2670-2677.

Available from: http://jco.ascopubs.org/content/30/21/2670.long

Primary Literature• Multi-center, randomized, open label• Phase III, Alpha 0.05, Power: 80%• Enrollment: 485 patients > 65 were assigned in 1:1 ratio; 28 patients in supportive care

• Patients were intermediate or high risk• Treatment groups: decitabine vs. (Treatment choice: cytarabine or supportive care)

• Primary Endpoint: Kaplan Meier Curve• Overall Survival: decitabine 7.7 months vs. Treatment choice 5.0 months• Non-significant difference in overall survival: P=0.108

• Secondary Endpoint: Logistic Regression• Complete Remission plus Complete Remission without plate recovery (>100,000 platelets wasn’t

required): decitabine 17.8% vs. Treatment choice 7.8%

• Safety: Thrombocytopenia: decitabine 40% vs. cytarabine 35%, anemia: decitabine 34% vs. cytarabine 27%, febrile neutropenia: decitabine 24% vs. cytarabine 16%

Kantarjan HM, Thomas XG, Dmoszynska A, Wierbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J, Kuo C-Y, Oriol A, Ravandi F, Faderl S, Delauny J, Lysak D, Minden M, Arthur A. Multicenter, Randomized, Open-Label, Phase III trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology [Internet]. 2012 July 20 [cited 2016 September 13]; 30(21): 2670-2677. Available from: http://jco.ascopubs.org/content/30/21/2670.long

Primary Literature: Baseline Characteristics

Categories Total Treatment Choice (n=243) Total Decitabine (n=242)

Median Age 73 73

Sex 37.9 Female, 62.1% Male 43.4% Female, 56.6% Male

Cytogenetics: Intermediate Risk 62.6% 63.6%

Cytogenetics: Poor Risk 36.9% 36%

ECOG Performance Status 0 or 1

76.3% 75.3%

ECOG Performance Status 2 23.7% 24.7%

Kantarjan HM, Thomas XG, Dmoszynska A, Wierbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J, Kuo C-Y, Oriol A, Ravandi F, Faderl S, Delauny J, Lysak D, Minden M, Arthur A. Multicenter, Randomized, Open-Label, Phase III trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology [Internet]. 2012 July 20 [cited 2016 September 13]; 30(21): 2670-2677, Table 1, Patient Demographics and Baseline Clinical Characteristics, (2672). Available from: http://jco.ascopubs.org/content/30/21/2670.full.pdf+html

Strengths and Weaknesses of StudyStrengths:• Studied in correct patient

population• Patients had a 2.7 month

longer survival with decitabine than cytarabine, but not statistically significant• More patients experienced

complete remission with decitabine• Showed good safety

Weaknesses:• Very Low power of 80%• Didn’t show any overall

survival benefit• Grouped supportive care

patients with cytarabine patients

• Showed to have CR in patients without platelet recovery

Patient’s Prognosis with AMLPatient Factors:• Elderly patient• Myelodysplastic Syndrome

Prognosis:• Prognosis is not good for patient, because patient is elderly patient

who had Myelodysplastic Syndrome and developed AML; usually these patients do not have a relatively good response to treatment due to treatment resistance

Patient Assessment:AML: The patient cannot tolerate the adverse effects of cytarabine and an anthracycline, so patient taking decitabine. The patient should be switched from piperacillin/tazobactam to ciprofloxacin and vancomycin for “bug-bite” cellulitis treatment as most bug bite infections are gram(+). Needs bacterial prophylaxis, fungal prophylaxis, and viral prophylaxis because has AML and is neutropenic. Cannot take DVT prophylaxis, because platelets <30,000. Does not require tumor lysis prophylaxis, because does not have highest intensity chemotherapy regimen. Should not take growth factors, because has Acute Myeloid Leukemia and may perpetuate cell growth.

Patient’s Treatment Plan• AML:

• Decitabine 20 mg/m^2 (32 mg) IV• Repeat cycle in 28 days

• Bacterial Prophylaxis: • Ciprofloxacin 500 mg tablet twice daily

• Bacterial Treatment (Skin Infection/Cellulitis): • Piperacillin-tazobactram 3.375 g IV three times daily

• Fungal Prophylaxis:• Posaconazole 300 mg delated release tablet daily (at bedtime)

• Nausea and Vomiting:• Ondansetron 8mg IV three times daily, promethazine 12.5 mg IV q4h prn

• Viral Prophylaxis: • Acyclovir 200 mg capsule twice daily

Patient’s Treatment Plan• Tumor Lysis Syndrome:

• Doesn’t need prophylaxis, because usually used with cancer drugs that cause a higher load of tumor burden in the blood

• Anemia: • Transfused RBCs

• Thrombocytopenia• Will give platelet transfusion if platelets fall below 10,000

• DVT Prophylaxis:• Not getting due to thrombocytopenia (<30,000)

• Urinary Incontinence: • Oxybutynin 5mg oral x 3 times daily

• Hypokalemia: • Potassium of 20 mEq and 40 mEq on order

• Diarrhea: • Loperamide 2 mg capsule every 4 hours as needed prn

Conclusions• AML is a leukemia in which the bone is “filled” with immature blasts

and “crowds” the bone marrow; >20% blasts and Auer Rods• Decitabine may have a better Complete Remission Profile than

cytarabine in older patients who do not have good prognostic factors for MDS• Do Not Give Growth Factors in AML • Give patients best supportive care

ReferencesGuidelines and Primary Literature:O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, Bixby D, Blum W, Borate U, Coutre SE, Lima MD, Fathi AT, Foran JM, Gore SD, Lancet J, Maness LJ, Maricucci G, Martin ME, Martin, MG, Moore JO, Olin R, Pollyea DA, Pratz K, Ravandi-Kashani F, Shamji PJ, Stone RM, Strickland SA, Wang ES, Weiduwilt M. NCCN Clinical Practical Guidelines in Oncology: Acute Myeloid Leukdemia. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]: Title Page- MS-73. Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdfKantarjan HM, Thomas XG, Dmoszynska A, Wierbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J, Kuo C-Y, Oriol A, Ravandi F, Faderl S, Delauny J, Lysak D, Minden M, Arthur A. Multicenter, Randomized, Open-Label, Phase III trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology [Internet]. 2012 July 20 [cited 2016 September 13]; 30(21): 2670-2677. Available from: http://jco.ascopubs.org/content/30/21/2670.long Baden LR, Sankar S, Angarone M, Blouin G, Camins B, Casper C, Cooper B, Dubberke ER, Morris A, Freifeld AG, Greene JN, Ito JI, Kaul DR, Lustberg ME, Montoya JG, Rolston K, Satyanarayana G, Segal B, Seo S, Shoham S, Taplitz R, Topal J, Wilson JW. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prevention and Treatment of Cancer-Related Infections. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]. Title page- MS 114. Available from: https://www.nccn.org/professionals/physician_gls/pdf/infections.pdfLevy M, Smith T, Alvarez-Perez A, Back A, Baker JN, Beck AC, Block S, Dalai S, Bergman MA, Scavone J, Dans M, Fitch TR, Kapo J, Kutner JS, Kvale E, Misra S, Mitchell W, Portman DG, Sauer TM, Spiegel D, Sutton L, Szmullowicz E, Taylor RM, Temel J, Tickoo R, Urba SG, Weinstein E, Zachariah F. NCCN Clinical Practical Guidelines in Oncology: Palliative Care. NCCN Guidelines [Internet]. 2016. [cited 2016 September 13]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf

Others:Marcucci G, Bloomfield CD. Acute Myeloid Leukemia. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine [Internet]. 19 e New York (NY): McGraw-Hill; c2015. Chapter 132. [cited 2016 September 13]. [Chapter 132]; AccessMedicine. Available from: http://accessmedicine.mhmedical.com/content.aspx?sectionid=79731765&bookid=1130&Resultclick=2Mayoclinic Staff. Mayoclinic.org [Internet]. Rochester, Minnesota: Mayo Clinic; c1998-2016. Disease and Conditions: Acute Myelogenous Leukemia (AML); 2015 September 12 [cited 2016 September 13]; [Defintion, Symptoms, Causes, Risk Factors, Preparing for Your Appointment, Test and diagnosis, Treatments and drugs, Alternative Medicine, Coping Skills]. Available from: http://www.mayoclinic.org/diseases-conditions/acute-myelogenous-leukemia/basics/risk-factors/con-20043431 National Cancer Institute. Cancer.gov [Internet]. National Cancer Institute (NIH); c.2015. Cancer Types: Acute Myeloid Leukemia Treatment-Patient Version; 2016 [cited 2016 September 13]; [Acute Myeloid Leukemia Treatment-Patient Version]. Available from: https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdqNational Cancer Institute. Cancer.gov [Internet]. National Cancer Institute (NIH); c.2015. Cancer Types: Acute Myeloid Leukemia Treatment-Patient Version; 2016 [cited 2016 September 13]; [Leukemia May Affect Red Blood Cells, White Blood Cells and Platelets]. Available from: https://www.cancer.gov/images/cdr/live/CDR526219.jpg UpToDate [Internet]. UpToDate. c.2016. Patient Education: Acute Myeloid Leukemia in adults (Beyond the Basics); 2016 [cited 2016 September 13]; Acute Myeloid Leukemia in adults (Beyond the Basics). Available from: http://www.uptodate.com/contents/acute-myeloid-leukemia-aml-treatment-in-adults-beyond-the-basics American Cancer Society [Internet]. Atlanta Georgia: American Cancer Society/Cancer.org. c. 2016. How is Acute Myeloid Leukemia Diagnosed?; 2016 February 22 [cited 2016 September 13]; [Complete Blood Cell Count and Peripheral Blood Smear; Cytochemistry]. Available from: http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute-myeloid-myelogenous-diagnosedLexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs; [cited 2016 September 13]. Available from: https://online.lexi.com/lco/action/home

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