Case discussion and topic review

Moderator Dr. Naveen Pandey

Presenter-Dr. Pradip katwal

• 35 years/ Female

• Siraha

• Housewife

• Vegetarian

– Presenting complains-

• Easy fatigability 5 months

• Fever 5 months

HOPI

• Fever, intermittent in nature, associated with chills no rigors, no diurnal variation of fever,no h/o rashes

• Easy fatigability which was progressive associated with shortness of breath, and now shortness of breath present on doing her daily activity.

Past history

• h/o total abdominal hysterectomy 1 years back for menorrhagia

• Tissue biopsy-showed granular tissue wih foreign body gaint cell

• Has received ATT for genitourinany tuberculosis.

Family history

• History of tuberculosis in family +

Examination

• General condition- thin built

• Pallor+ • nails-leukonychia • no petichea/purpura

• Pulse -88/min• Blood pressure -98/60 mmhg• Temperature -102 degree F• Respiratory rate -16/min

Systemic examination

Chest – B/L equal air entry B/L normal vesicular breath sounds

P/A-Soft, non tender -spleen not palpableCVS- S1 + S2 heard no murmurCNS- No neck rigidity WNL

12/24/2011

Differential diagnosis

• Megaloblastic anemia

• Aplastic anemia

• Acute leukemia

• Tuberculosis

• Systemic lupus erythematosus

• Myelodysplastic disorder

Lab investigations

• TLC- 2420 mm3• DLC-N 25% L45% M25% E 05%• HB- 2.74gm/dl• Platelates-2000 mm3• Urine RE/ME- WNL• Blood culture- sterile• Urine culture- sterile• Chest x-ray- wnl

12/24/2011

• RK 39 –ve

• HIV serology –ve

• Ps cytology

• ECG- sinus tachycardia

• Fundoscopy-no evidence of retinal hemorrhage

Ps cytology-

leukocytosis with presence of blast cells. Cells are large N:C ratio is high irregular nuclear membrane. Some of them showing lobulated nuclei prominent 2-3 nucleoli prominent 2-3 nuclei and moderate amount of cytoplasm.

DLC- blast 40% premylocytes-12 % metamylocytes 2%

Management

• Pt received three pints of fresh whole blood transfusion.

• Personal hygeine

• Dental hygeine

During her stay

• After the reports, the nature of illness and treatment options was explained. Patient party wanted to take to bharatpur cancer hospital for further management and was referred.

DIAGNOSIS

• ACUTE MYELOID LEUKEMIA

Epidemiology

• Incidence -3.5 per 100,000 people per year

• Median age at diagnosis- 67 years

• AML incidence increases with age

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytesB-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALLALL

AMLAML

Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATIONMATURATION

Adapted and modified from U Va website

Acute Leukemia

• Blasts in the marrow

differentiation block

enhancedproliferation

AcuteLeukemia+

Gain of function mutations of tyrosine kinases

eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFR

Loss of function of transcription factors needed for differentiation

eg. AML1-ETO CBF-SMMHC PML-RAR

Two-hit model of leukemogenesis

Etiology

• Heredity– Down syndrome– Fanconi anemia– Bloom syndrome– ataxia-telangiectasia– Congenital neutropenia (Kostmann syndrome)

• Radiation– High-dose radiation (atomic bombs survivors)

• chemical and occupational exposures– Benzene

– petroleum products

– Paint

– embalming fluids

– ethylene oxide

– Herbicides

– smoking

•

• Prospective data suggested an elevated risk of myeloid leukemia associated with cigarette smoking (relative risk, 1.4; 95% confidence interval, 1.2 to 1.6).

•  Population-attributable risk calculations suggested that approximately 14% of all US leukemia cases (including 17% of myeloid may be due to cigarette smoking.

• Drugs– Alkylating agent– Topoisomerase II inhibitor– Chloramphenicol– Phenylbutazone– Chloroquine– methoxypsoralen

ClassificationWorld Health Organization ClassificationAML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22);RUNX1-RUNX1T1b

AML with inv(16)(pl3.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11b

Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARAb

AML with t(9;11)(p22;q23); MLLT3-MLL

AML with t(6;9)(p23;q34); DEK-NUP214

AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1

AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1Provisional entity: AML with mutated NPM1Provisional entity: AML with mutated CEBPA

AML with myelodysplasia-related changes

Therapy-related myeloid neoplasms

AML not otherwise specified

AML with minimal differentiation

AML without maturation

AML with maturation

Acute myelomonocytic leukemia

Acute monoblastic and monocytic leukemia

Acute erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis

Myeloid leukemia associated with Down syndrome

Blastic plasmacytoid dendritic cell neoplasm

Acute leukemia of ambiguous lineage

Acute undifferentiated leukemia

Mixed phenotype acute leukemia with t(9;22)(q34;q11,20); BCR-ABL11

Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged

Mixed phenotype acute leukemia, B/myeloid, NOS

Mixed phenotype acute leukemia, T/myeloid, NOS

Provisional entity: Natural killer (NK)-cell lymphoblastic leukemia/lymphoma

Clinical Presentation

• Nonspecific symptoms

• Fatigue

• Anorexia

• Weight loss

• Fever

• Bleeding, easy bruising

• Bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis

Physical Findings

• Fever

• Splenomegaly

• Hepatomegaly

• Lymphadenopathy

• Sternal tenderness

• Evidence of infection and hemorrhage

Gum hypertrophy

myeloid sarcoma

• Myeloid sarcoma is a tumor mass consisting of myeloid blasts in which the tissue architecture is effaced, occurring at an anatomical site other than the bone marrow

Leukemia cutis

Hematologic Findings

• Anemia =normocytic normochromic

• The median presenting leukocyte count is about 15,000/L

25 and 40% of patients <5000/L

20% >100,000/L

Fewer than 5% no detectable leukemic cells in the blood

Diagnostic procedure

• Morphology

• cytochemistry

• Immunophenotyping

• Cytogenetics

• Molecular cytogenetics

• Molecular genetics

• The morphology of the malignant cell varies in different subsets– the cytoplasm often contains primary

(nonspecific) granules– the nucleus shows fine, lacy chromatin with one

or more nucleoli– Abnormal rod-shaped granules called Auer rods

are present– neutrophil -abnormal lobulation and deficient

granulation.

Bone marrow in acute leukemia

• Necessary for diagnosis

• Useful for determining type

• Useful for prognosis

• Acute leukemias are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells)

AML

AML

Auer rods in AML

Pretreatment Evaluation Initial Diagnostic Evaluation and Management of Adult Patients with AML

History

Increasing fatigue or decreased exercise tolerance (anemia)

Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)

Fevers or recurrent infections (granulocytopenia)

Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)

Early satiety (splenomegaly)

Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia)

History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors)

Occupational exposures (radiation, benzene, petroleum products, paint, smoking, pesticides

Physical Examination

Performance status (prognostic factor)

Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)

Fever and tachycardia (signs of infection)

Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)

Poor dentition, dental abscesses

Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)

Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia)

Lymphadenopathy, splenomegaly, hepatomegaly

Back pain, lower extremity weakness [spinal granulocytic sarcoma, most likely in t(8;21) patients]

Initial Diagnostic Evaluation and Management of Adult Patients with AML

Laboratory and Radiologic Studies

CBC with manual differential cell count

Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepatic enzymes, bilirubin, LDH, amylase, lipase)

Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer)

Viral serologies (CMV, HSV-1, varicella-zoster)

RBC type and screen

HLA typing for potential allogeneic HSCT

Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry, molecular studies for NPM1 and CEBPA mutations and FLT3-ITD)

Cryopreservation of viable leukemia cells

Echocardiogram or heart scan

PA and lateral chest radiograph

Placement of central venous access device

Initial Diagnostic Evaluation and Management of Adult Patients with AML

Interventions for Specific Patients

Dental evaluation (for those with poor dentition)

Lumbar puncture (for those with symptoms of CNS involvement)

Screening spine MRI (for patients with back pain, lower extremity weakness, paresthesias)

Social work referral for patient and family psychosocial support

Counseling for All Patients

Provide patient with information regarding their disease, financial counseling, and support group contacts.

Prognostic Factors

• Age at diagnosis

• Chronic and intercurrent diseases

• Performance status

• A prolonged symptomatic interval with cytopenias preceding diagnosis

• A high presenting leukocyte count

• Chromosome findings at diagnosis*

• Achievement of CR

• Secondary AML

Principles of treatment

• Combination chemotherapy– First goal is complete remission– Further rx to prevent relapse

• Supportive medical care– Transfusions, antibiotics, nutrition

• Psychosocial support– Patient and family

Complete remission

CR is defined-

•Blood neutrophil count -1000/L

•Platelet count 100,000/L.

•Circulating blasts - absent.

•The bone marrow <5% blasts

•Auer rods -absent.

•Extramedullary leukemia -absent

Management: Acute Myeloid Leukemia

Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal Medicine 18th Ed. 2011

Induction Chemotherapy

• Cytarabine is usually administered as a continuous intravenous infusion for 7 days

• Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen).

• Etoposide

Postremission Therapy

• Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival

• Intensive chemotherapy– High-dose cytarabine 4 cycles of HiDAC

(3 g/m2 per q12h on days 1, 3, and 5)

• Allogeneic or autologous HSCT

• Patients who fail to attain CR after two induction courses should be treated with an allogeneic hematopoietic stem cell transplant (HSCT)

Hematopoietic stem cell transplantation

• Permits “rescue” from otherwise excessively toxic treatment

• Additional advantage of graft-vs-leukemia effect in allogeneic transplants

• Trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxic

Molecularly targeted therapy

• Gemtuzumab ozogamicin

• Anti-cd33 antibody

• Chemically linked to the cytotoxic agent calicheamicin

• Inhibits DNA synthesis andinduces apoptosis

Zein N, Sinha AM, McGahren WJ, Ellestad GA. Calicheamicin gamma 1l: an antitumor antibiotic that cleaves double-stranded DNA site specifi-cally.Science.1988;240(4856):1198-1201.

Treatment of Promyelocytic Leukemia

• Tretinoin– APL differentiation syndrome

• anthracycline-based chemotherapy

• Arsenic trioxide

• Gemtuzumab ozogamicin

Management of special situations

Hyperleukocytosis

• Hyperleukocytosis with leukostasis immediate medical treatment.

• Leukapheresis • Hydroxyurea, given at dosages up

– 50 to 60 mg/kg per day.– Until the wbc has been reduced.

• Prevention of tumor lysis syndrome– Hydration,

– Control of uric acid production using allopurinol or rasburicase

– Control of urine ph

Cns involvement

• Less than 5% of patient

• Intrathecal cytarabine

• Dexamethasone to prevent arachnoiditis

Supportive Care

Prophylactic anti-infectious treatment

• Personal hygiene

• Dental hygiene

• Vigorous hand washing

• Anti-fungal prophylaxis

• Antibiotic prophylaxis

Leibovici L, Paul M, Cullen M, et al. prophylaxis in neutropenic patients. New evidence, practical decisions.Cancer.2006;107(8):1743-1751.

Growth factors

• GM-CSF or G-CSF*– Accelerate neutrophil recovery by 2 to 5 days– Reduce antibiotic use– Reduce duration of fever– Number of days spent in hospital– Do not retard platelet recovery– Do not have a detrimental effect by

stimulation of leukemic cell growth*Estey EH. Growth factors in acute myeloid leukaemia.Best Pract Res Clin Haematol. 2001;14(1):175-187

Transfusion support

• Prophylactic platelet transfusions-• hemoglobin level above 8 g/dL

• Prevent alloimmunization• Gamma irradiation (at least 25 Gy)

Schiffer CA, Anderson KC, Bennett CL, et al. transfusion for patients with cancer: clini-cal practice guidelines of the American Clinical Oncology.J Clin Oncol.2001;19(5):1519-1538.

Selected New Agents under Study for the Treatment of Adults with AMLClass of Drugs Examples of Agents in Class

Tyrosine kinase inhibitors PKC412, MLN518, SU11248, CHIR-258, imatinib (STI571, Gleevec), dasatinib, AMN107

Demethylating agents Decitabine, 5-azacytidine

Histone deacetylase inhibitors Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid

Heavy metals Arsenic trioxide

Farnesyl transferase inhibitors R115777, SCH66336

HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG), DMAG, or derivatives

Cell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032

Toxin-conjugated antibodies Gemtuzumab ozogamicin

Proteasome inhibitors Bortezomib

Aurora inhibitors AZD1152, MLN-8237, AT9283

Immunomodulatory Lenalidomide, IL-2, histamine dihydrochloride

Refrences

• Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal Medicine 18th Ed. 2011

• Current Medical Diagnosis and Treatment 2012

• Boblöwenberg et al, acute myeloid leukemia, review article, www.nejm.org

• Hartmut Döhner et. Al, recommendations from an international expert panel, on behalf of the Diagnosis and management of acute myeloid leukemia in adults:European LeukemiaNet