acute leukemia and tumor lysis syndrome

ACCP/ASHP Oncology Pharmacy Preparatory Review Course

Acute Leukemia and Tumor Lysis Syndrome


Disclosure

Dr. John M. Valgus has nothing to disclose.


Learning Objectives

Describe the epidemiology, etiology, pathophysiology and prognostic factors of AML/ALL in adults

Identify and discuss the signs, symptoms and complications of AML/ ALL in adults

Outline appropriate patient-specific treatment for AML and ALL in adults including:

pharmacotherapy of leukemia

monitoring of drug-related toxicities

management of drug- and disease-related complications


Case KG is a 54 year old female who presents to her

primary care provider with signs of an upper respiratory tract infection

Patient also reports increased fatigue when shopping and playing with her grandchildren

The patient was given a course of azithromycin and asked to return to clinic if symptoms did not resolve


Case Past Medical History

Hypertension

Family History Mother and father alive with no history of

malignancy

Social History No history of tobacco use or recreational drug use Occasional alcohol use


Case After completing two week course of antibiotics,

symptoms unresolved and fatigue worsening Labs drawn with following results:

WBC 21.4 x10 9th/L

HGB 7.5 G/DL

HCT 22.3 %

PLATELET COUNT 150 x10 9th/L

ABSOLUTE NEUTS 0.6 x10 9th/L

CREATININE 0.80 MG/DL

Bone marrow biopsy results 69% blasts Consistent with AML


Acute Myeloid Leukemia (AML)

Approximately 12,950 new cases of AML were diagnosed in 2011 and 9,050 patients with die of AML

AML is the second most common form of leukemia in adults and the most common leukemic cause of death

Incidence of AML appears to be on the rise

AML NCCN Clinical Practice Guidelines in Oncology-V2.2011.Siegel R, et al. CA Cancer J Clin 2011;61:212-236.


Acute Myeloid Leukemia: WHO Definition

At least 20% of cells in peripheral blood or bone marrow are blasts that are myeloid in origin

Exceptions include: t(15;17), t(8;21), inv(16), or t(16;16) No blast limit

Vardiman JW, et al. Blood 2009;114:937-951.


Acute Myeloid Leukemia

Available at: http://www.healthsystem.virginia.edu/internet/hematology/hessidb/leukemias.cfm Accessed January 10, 2011.


Morphologic Classification French-American-British (FAB)

M0 undifferentiated ; blast cells express myeloid antigens

M1 acute myeloblastic leukemia with minimal differentiation

M2 acute myeloblastic leukemia with maturation

M3 acute promyelocytic leukemia

M4 acute myelomonocytic leukemia

M5a acute monoblastic leukemia without differentiation

M5b acute monoblastic leukemia with differentiation

M6 acute erythroleukemia

M7 megakaryocytic leukemia

Revised from DeVita VT. Cancer Principles and Practice of Oncology. 7th Edition. Philadelphia: Lippincott Williams & Wilkins,2005.


AML: WHO Classification

1. AML with recurrent genetic abnormalities

2. AML with myelodysplasia-related changes

3. Therapy-related myeloid neoplasm

4. AML not otherwise specified

Vardiman JW, et al. Blood 2009;114:937-51.


Risk Grouping for AML

Risk Cytogenetics Molecular Mutations

Better Risk Inv(16)t(16;16)t(8;21)t(15;17)

Normal cytogenetics with NPM1 mutation or isolated CEBPA mutation in absence of FLT3-ITD

Intermediate Risk Normal cytogenetics+8 onlyt(9;11)

t(8;21) , Inv(16), t(16;16) with c-KIT mutation

Poor Risk Complex (>3 abnormalities)-5, -7, 5q-, 7q-Abnormalities of 11q23,

excluding t(9;11)Inversion 3t(3;3), t(6;9), t(9;22)

Normal cytogenetics with FLT3-ITD mutation

Adapted from NCCN AML Practice Guidelines v.2.2011


AML: Signs and Symptoms

Clinical manifestation of AML: Bone marrow failure

Extramedullary tissue invasion

Leukostasis secondary to high WBC

Tumor cell break down (TLS)


Case Labs drawn with following results:

WBC 21.4 x10 9th/L HGB 7.5 G/DL HCT 22.3 % PLATELET COUNT 150 x10 9th/L ABSOLUTE NEUTS 0.6 x10 9th/L CREATININE 0.80 MG/DL


AML: Signs and Symptoms Abnormal WBC count:

WBC - stasis of blood flow

WBC - neutropenia

Bone marrow suppression Anemia - fatigue, malaise, weakness, CV effects

Thrombocytopenia - risk of bleeding

Neutropenia - risk of infection

Skin manifestations chloroma

Renal insufficiency tumor lysis syndrome


AML: Therapeutic Approaches

Induction Therapy

- Goal: Induce a CompleteRemission

Post Remission Therapy

- Goal: Prevent/delay relapse


AML: Treatment

Complete Remission Criteria: Peripheral neutrophil count >1.0 X 109

Platelet count > 100 X 109

Patient independent of transfusions Bone marrow < 5% blasts Absence of blasts with Auer rods Absence of extramedullary disease

The disappearance of a karyotype abnormality is notrequired for definition of complete remission

Döhner H, et al. Blood 2010;115:453-474.


Audience Response #1 Case : KG is a 54 year-old female admitted to the leukemia service

with newly diagnosed AML. What is the best treatment for remission induction for

KG?

A. Cytarabine and gemtuzumab ozogamicin

B. Gemtuzumab ozogamicin

C. Cytarabine and idarubicin

D. Idarubicin


AML: Induction Therapy

Cytarabine:100 - 200 mg /m2/day CI x 7 days

+

Anthracycline / anthracycline derivative:daunorubicin 60-90 mg/m2 x 3 days

- or -idarubicin 12 mg/m2 x 3 days

NCCN AML Practice Guidelines v.2.2011


Daunorubicin Dosing

Phase III, randomized trial

Daunorubicin 45mg/m2 vs 90mg/m2

Enrolled 675 young adults (< 60 years)

Cytarabine 100mg/m2 continuous infusion for 7 days for all patients

Primary endpoint of overall survival

Fernandez HF, et al. N Eng J Med 2009;361:1249-59.


Daunorubicin Dosing

Fernandez HF, et al. N Eng J Med 2009;361:1249-59.

Outcomes Daunorubicin 90mg/m2

Daunorubicin 45mg/m2

Complete Remission

70.6% 57.3%

Overall Survival

23.7 months 15.7 months

Induction Death

4.5% 5.5%


AML: Case

Case :

KG is a 54 year-old female admitted to the hospital with newly diagnosed AML

What is the best treatment for remission induction for KG?

a. Cytarabine and gemtuzumab ozogamicin

b. Gemtuzumab ozogamicin

c. Cytarabine and idarubicin

d. Idarubicin


Acute Leukemia: ComplicationsCancer Related Problems

Anemia

Thrombocytopenia

Neutropenia

Tumor lysis syndrome (TLS)

Hyperleukocytosis

Treatment Related Problems

Bone marrow suppressionTumor lysis syndrome

(TLS)Nausea/vomitingOrgan toxicitiesMucositis/stomatitisNutrition


AML: Bone Marrow SuppressionNeutropenia Extended period of

neutropenia associated with increased infection rates

The use of prophylactic antibiotics, antifungal, antivirals, and myeloid growth factors is debated

Empiric broad spectrum antibiotics for febrile neutropenia

Thrombocytopenia Menses suppression Gastric ulcer prophylaxis Management of acute

bleeding episodes


Audience Response #2

Audience Response #2

KG is a 54 year-old female admitted to the hospital with newly diagnosed AML. On day 14 a BM biopsy is hypocellular without any indication of residual leukemia. What is the treatment strategy at this time?

a. Cytarabine + idarubicin (5 + 2)

b. High dose cytarabine

c. Mobilization of peripheral stem cells to prepare for subsequent stem cell transplant

d. Watch and wait


Audience Response #2 KG is a 54 year-old female admitted to the hospital with newly

diagnosed AML. On day 14 a BM biopsy is hypocellular without any indication of residual leukemia. What is the treatment strategy at this

time?

A. Cytarabine + idarubicin (5 + 2)

B. High dose cytarabine

C. Mobilization of peripheral stem cells to prepare for subsequent stem cell transplant

D.Watch and wait


AML: Evaluation of Induction Therapy

If blasts remain in the bone marrow 7-10 days after induction completed:

• Significant residual blasts second course of induction with high or standard dose cytarabine + anthracycline

• in blasts second course of induction therapy with standard dose cytarabine plus anthracycline

• Bone marrow is hypoplastic second course is delayed until status of marrow is clear



AML: Hematopoietic Growth Factors

Have been given after induction chemotherapy to accelerate neutrophil recovery and reduce infectious mortality Consistently shorten period of neutropenia Decrease in infection rates (some studies) Decrease in infectious mortality (some studies) No consistent benefit on CR rate or OS No support of the fear of inducing leukemia

No proven benefits of growth factor priming

Smith TJ, et al. J Clin Oncol 2006;24:3187-3205.


AML: Post Remission Therapy

Consolidation with similar agents used in induction therapy Age > 60 yo

High-dose cytarabine (HiDAC) 1.5-3 gm/m2 q 12 hours x 6 doses (d 1,3,5)

Age < 60 yo and favorable risk

HD chemotherapy + allogeneic HSCT Not recommended if age > 60 or favorable risk

HD chemotherapy + autologous HSCT



AML: Post-Remission High Dose Cytarabine (HDAC)

Who should receive HD cytarabine? Pts that benefit most have favorable cytogenetics

Benefits for HiDAC in pts < 55-60 y/o Increases in disease-free and overall survival

Older pts receiving HiDAC- increased toxicity


AML: Case

KG is a 54 year-old female admitted to the hospital with newly diagnosed AML.

On day 14 a BM biopsy is hypocellular without any

indication of residual leukemia. What is the treatment

strategy at this time? a. Cytarabine + idarubicin (5 + 2)

b. High dose cytarabine

c. Mobilization of peripheral stem cells to prepare for subsequent stem cell transplant

d. Watch and wait


AML Special Populations

Relapsed/Refractory AML

Older patients (> 60 years)

Acute promyelocytic leukemia


Relapsed/Refractory AML


AML: Gemtuzumab ozogamicin

Description: Antibody-targeted chemotherapy Antibody to CD33+ antitumor antibiotic

Indicated for treatment of pts with CD33+ AML: In first relapse 60 y/o Not considered candidates for cytotoxic

chemotherapy

Mylotarg [package insert] Wyeth Pharmaceuticals Inc, Philadelphia, PA 2009


AML Relapse and Salvage Therapy

Clinical trials preferred

If late relapse (> 12 mo) then may repeat initial induction regimen

Salvage chemotherapy followed by stem cell transplant

Best supportive care



AML Older Patients


New Diagnosis AML (1950-1990)

Sorensen JT et al. Cancer 1993;72:1602-6.


AML Median Survival

Sorensen JT et al. Cancer 1993;72:1602-6.


AML in Patients > 60yo: Treatment Options

Supportive Care:

• Hydroxyurea

• Transfusions

Chemotherapy:

• Standard dose

• Low intensity


Acute Promyelocytic Leukemia


Case

• RW is a 35 year old male with a recent diagnosis of APL at an outside hospital

• He is admitted to the leukemia service for initiation of induction chemotherapy


Acute Promyelocytic Leukemia Accumulation of leukemic cells with t(15:17)

translocation t(15;17) translocation fuses the PML gene on

chromosome 15 to the RAR alpha on chromosome 17

PML-RAR fusion protein interferes with factors required for differentiation of myeloid precursors

Protein can be monitored by PCR to document disease burden and confirm “molecular remission”


Acute Promyelocytic Leukemia Complete remission (CR) in >90% of newly

diagnosed patients CR without bone marrow aplasia CR obtained at 25 - 70 days High risk: WBC > 10,000/mcL Coagulopathies can resolve within days

with treatment (Major cause of early death) ATRA Toxicities: Differentiation

syndrome, HA, mucosal dryness, hyperleukocytosis



APL Initial Management

Once diagnosis suspected, all-trans retinoic acid (ATRA) should be initiated

Prevent coagulopathy-related complications Maintain platelets above 30 X 109/L Maintain fibrinogen concentration above 100mg/dL

Manage hyperleukocytosis (>10X 109/L) through initiation of chemotherapy

Sanz MA, et al. Blood 2009;113:1875-91.


APL Therapy Induction

ATRA + idarubicin or daunorubicin

Consolidation Ida or dauno x 2 cycles + ATRA

Addition of cytarabine for high risk (WBC > 10 x 109/L)

Maintenance ATRA + weekly methotrexate + 6-

mercaptopurine x 1-2 yearsSanz MA, et al. Blood 2009;113:1875-91.


Case

Three days after initiation of ATRA, RW develops progressive shortness of breath

He also is febrile and has gained 5kg over the past 72 hours

RW is transferred to the step-down unit and is started on dexamethasone 10mg IV BID

ATRA and chemotherapy are continued


Differentiation SyndromePresentation: Respiratory distress Fever Pulmonary infiltrates Weight gain Renal failure Hypotension Management: Dexamethasone 10 mg IV q 12 x 3 days (minimum) Continue ATRA unless severe symptoms

Montesinos P, et al. Blood 2009;113:775-83.


APL: Arsenic Trioxide

Early studies of arsenic trioxide (ATO) demonstrated excellent outcomes in refractory patients

More recent data suggests a role in the consolidation phase of therapy

May be used in induction for patients unable to tolerate an anthracycline-based induction regimen


Estey E et al. Blood 2006;107:3469.

ATRA + ATO Initial Induction

Evaluated in low risk patients Plt > 40, WBC < 10

ATO started day 10 ATRA

CR in 24/25 patients

Median follow-up 16 months

Alternative in low risk patient unable to tolerate chemotherapy


APL: Arsenic Trioxide

Differentiation syndrome Management same as ATRA

QT/QTc Prolongation Careful monitoring of QT/QTc

Maintenance of electrolytes within the normal range (ie magnesium > 1.8mg/dL and potassium > 4.0mEq/L)


Acute Lymphoblastic Leukemia (ALL)

SE is a 42 year old female who presents with symptoms of extreme fatigue, easy bruising and night sweats

A recent CBC reveals the following: WBC 11.0x109/L Hgb 9.0g/dL Plt 23x109/L Note: Increase lymphoblasts

Bone marrow biopsy results in new diagnosis of pre-B ALL


ALL: Signs and Symptoms

Clinical manifestations of ALL: Constitutional symptoms: Fever, night sweats,

weight loss) Easy bruising/bleeding Dyspnea Dizziness Infections CNS involvement (mature B-cell ALL) Mediastinal involvement (T-lineage)


Classification of Adult ALL

Immunophenotyping: B-lineage more common in adult ALL 25% of adult patients are T-cell lineage

Cytogenetics: Most common cytogenetic abnormality is t(9;22)

translocation (20-30% of adult ALL) Philadelphia chromosome is poor prognostic indicator

t(4;11)-poor prognostic factor


Unfavorable Prognostic Factors

Age > 55 years

WBC > 30X109/L (> 100 in T-lineage)

t(9;22)

Delayed time to induction of CR

CNS involvement

Minimal residual disease

Bassan R et al. J Clin Oncol 2011;29:532-43.


Acute Leukemia: Phases of Therapy

Induction Therapy Goal: Induce a CR Prephase, induction I, induction II

Post Remission Therapy Goal: Prevent/delay relapse Intensification Consolidation

Maintenance Therapy In select patients (B-cell precursor ALL)

Allogeneic Transplant Role debaed based on risk stratification and MRD


ALL: Induction

Induction therapy should be built around vincristine + an anthracycline + corticosteroids

Most modern regimens have intensified the regimen based on poor prognostic factors in adult patients Asparaginase Cyclophosphamide Cytarabine Methotrexate

Role of CNS prophylaxis


ALL: Treatment Strategies in Adults

Induction with 5 drugs:CTX +VCR +Pred +l-aspar +dauno

Early intensification (course II):CTX + SQ araC + 6MP+ VCR + sq l-aspar

CNS Prophylaxis + Maintenance:cranial XRT + 6MP + MTX

Late intensification:doxo + VRC + dex + CTX + 6TG + cytarabine

Prolonged Maintenance:VCR + pred + MTX + 6MP

Larson RA, et al. Blood 1995;85:2025-37.



Dose Intensive Phase 8 cycles of chemotherapy alternating between

HyperCVAD and high-dose mtx/cytarabine HyperCVAD-cyclophosphamide, vincristine,

doxorubicin, dexamethasone CNS prophylaxis

Maintenance Phase Risk stratified 6MP, vincristine, mtx, prednisone

Kantarjian HM, et al. J Clin Oncol 2000;18:547-61.



Asparaginase: MOA: enzyme that catalyzes the hydrolysis of asparagine

(nonessential amino acid) to aspartic acid and ammonia Toxicities

Hypersensitivity reaction Anorexia Neurologic: HA, lethargy, depression, confusion, obtundation,

coma, seizures (rare)

Decreased fibrinogen (recommend keep > 100) Decrease vitamin K dependent clotting factors Decreased antithrombin III Pancreatitis (5%)


Case

The morning following the start of induction therapy for SE, the following labs are reported: SCr 2.0mg/dL

Potassium 6.0mmol/L

Calcium 7.5mg/dL

Phosphorus 5.5mg/dL

Uric acid 10.5mg/dL

The covering MD orders a stat dose of rasburicase 0.2mg/kg


Tumor Lysis Syndrome

A group of metabolic derrangements caused by the abrupt and massive release of cellular components into the blood after the rapid lysis of malignant cells

Most commonly seen in ALL and Burkitt’s lymphoma (high proliferative rate, large tumor burden, highly chemosensitive)



Cairo-Bishop Definition of Laboratory TLS

Element Value ∆ from Baseline

Uric Acid > 8mg/dL 25% increase

Potassium > 6mmol/L 25% increase

Phosphorus > 1.45mmol/L 25% increase

Calcium < 1.75mmol/L 25% decreaseNote: Two or more laboratory changes within 3 days before or 7 days after cytotoxic chemotherapy

Adapted from: Coiffier B, et al. J Clin Oncol 2008;26:2766-78.



Clinical tumor lysis syndrome defined by level of SCr elevation, presence and severity of cardiac arrhythmia, and presence and severity of seizures

Non-tumor risk factors include baseline renal dysfunction and high baseline serum uric acid



Prevention of TLS Low Risk

Clinical judgement and monitoring

Moderate Risk Hydration + allopurinol

Rasburicase can be considered in pediatric population

High Risk Hydration + rasburicase

Coiffier B, et al. J Clin Oncol 2008;26:2766-78.



Allopurinol: Initiate with diagnosis Loading dose may be needed if treatment to start

immediately Decrease dose for renal dysfunction

Hydration: Choice and rate of hydration should be based on

patient factors No proven benefit of alkalinization of urine


TLS: Rasburicase (Elitek)Recombinant form of urate oxidase acts as a catalyst in enzymatic oxidation of uric acid to allantoin (> solubility than uric acid)

Purine

hypoxanthine

Uric acid

allantoinRasburicase


TLS: Rasburicase (Elitek)

Dose: based on pediatric – 0.15-0.2 mg/kg IV over 30 minutes per day (up to 7 days)

Pros: Rapid onset of action ( uric acid within 2 - 4 hrs) Does not increase xanthine or hypoxantine

Cons: Cost Derived from protein from Aspergillus flavus Hypersensitivity: quick onset, with subsequent use

Note: Immediately place uric acid samples on ice


ALL Special Populations


Ph+ ALL

Addition of imatinib to standard ALL induction therapy (Hyper-CVAD)

All 15 patients achieved CR At median follow-up of 20 months, 15 patients

alive with no signs of ALL 50% able to undergo allo-transplant

14/15 alive without evidence of ALL at 1 year

60% of non-transplant patients w/o ALL at 1 year

Thomas DA, et al. Blood 2004;103:4396-407.


ALL: Relapsed/Refractory

Clofarabine Second generation purine nucleoside analog Approved for refractory (>2 prior chemo regimens) ALL in

pediatric patients Growing evidence in adult ALL and AML alone or in

combination

Nelarabine Pro-drug of Ara-G Approved for refractory (>2 prior chemo regimens) T-Cell

ALL in adults and pediatrics CR Rate 18%; Median OS 20.6 weeks


acute leukemia and tumor lysis syndrome

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