acute leukemia and tumor lysis syndrome - accp

ACCP/ASHP Oncology Pharmacy Preparatory Review Course

Acute Leukemia and

Tumor Lysis Syndrome

Tippu Khan, Pharm.D., BCOP, CPP University of North Carolina Hospitals and Clinics

UNC Eshelman School of Pharmacy

Chapel Hill, North Carolina

Conflict of Interest

I have no real or perceived conflict of interest

related to the content of this presentation.

Learning Objectives

At the end of the presentation and after performing the

reading, the participant should be able to:

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

Identify laboratory and clinical tumor lysis syndrome as well as

proper management strategies

Patient Case

RO 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

Patient 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

Patient Case

After completing two week course of antibiotics, symptoms unresolved and fatigue worsening

Labs drawn with following results: WBC 42 x10 9th/L

HGB 9.5 G/DL

HCT 27 %

PLATELET COUNT 30,000

ABSOLUTE NEUTS 0.6 x10 9th/L

CREATININE 0.80 MG/DL

Bone marrow biopsy results 65% blasts

Consistent with AML

Acute Myeloid Leukemia (AML)

Approximately 13,780 new cases of AML were diagnosed in 2012 and 10,200 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-V2.2012.

Siegel R, et al. CA Cancer J Clin 2011;61:212-236.

Acute Myeloid Leukemia (AML)

AML rates rise exponentially after 50 y/o

AML NCCN Clinical Practice Guidelines in Oncology-V2.2012.

Siegel R, et al. CA Cancer J Clin 2011;61:212-236.

0

10

20

30

40

50

60

20 -34 35 - 44 45 - 54 55 - 64 65 - 74 75 - 84

% I

ncid

en

ce

Age Group

AML Incidence By Age

AML: 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.

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

I. AML with recurrent genetic abnormalities

II. AML with myelodysplasia-related changes

III. Therapy-related myeloid neoplasm

IV. AML not otherwise specified

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

Risk Grouping for AML

Byrd et al. Blood. 2002; 100:4325-36.

Slovak et al. Blood. 2000; 96:4075-83.

Grimwade et al. Blood. 1998; 92:2322-33.

Risk Cytogenetics 5 year Survival

Better Risk Inv(16)

t(16;16)

t(8;21)

t(15;17)

55-65%

Intermediate Risk Normal cytogenetics

+8 only

t(9;11)

24-40%

Poor Risk Complex (>3 abnormalities)

-5, -7, 5q-, 7q-

Abnormalities of 11q23, excluding

t(9;11)

Inversion 3

t(3;3), t(6;9), t(9;22)

5-14%

Risk Grouping for AML (continued)

NCCN Guidelines 2013.

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 only

t(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 3

t(3;3), t(6;9), t(9;22)

Normal cytogenetics with

FLT3-ITD mutation

Risk Stratification Based on Integrated Genetic Profiling.

Adapted from Patel et al. NEJM 2012; 366:1079-89

Cytogenetic Classification

Mutations Overall Risk Profile 3 yr Survival

Favorable Any

Favorable 64%

Normal karyotype or

Intermediate risk

cytogenetic lesions

FLT3 – ITD

neg

Mutant NMP1 and

IDH1 or IDH2

FLT3 – ITD

neg

Wild-type ASXL1,

MLL-PTD, PHF6, and

TET2

Intermediate 42% FLT3 – ITD

neg or pos

Mutant CEBPA

FLT3 – ITD

pos

Wild-type MLL-PTD,

TET2, and DNMT3A

and trisomy 8 negative

FLT3 – ITD

neg

Mutant TET2, MLL-

PTD, ASXL1, or PHF6

Unfavorable 12% FLT3 – ITD

pos

Mutant TET2, MLL-

PTD, DNMT3A, or

trisomy 8 without

mutant CEBPA

Unfavorable Any

Risk Grouping for AML (continued)

AML: Signs and Symptoms

Clinical manifestation of AML:

Bone marrow failure

Extramedullary tissue invasion

Leukostasis secondary to high WBC

Tumor cell break down (TLS)

Patient Case

Labs drawn with following results:

WBC 42 x10 9th/L

HGB 9.5 G/DL

HCT 27 %

PLATELET COUNT 30,000

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 Complete Remission

Post Remission Therapy Goal: Prevent/delay relapse

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 x 3

days

Cytarabine 100mg/m2 continuous infusion

for 7 days for all patients

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%

Cytarabine (AraC) Dosing

Comparison across 5 trials of different induction regimens

Standard Arm: (AraC 100mg/m2 x 7 days+ Dauno

60mg/m2 x 3 days. All patients received 2 course) 3

course high dose AraC 3gm/m2 q12 hours d1,3,5.

Study A: Two course of std dose AraC combination (VP16,

AraC, Ida) 3 course high dose AraC 3 gm/m2 q12 hours

d1,3,5.

Study B: Two course high dose AraC 2g/m2 d1,3,5,7

induction standard consolidation

Buchner T, et al. JCO 2012; 30:3604-10.

Cytarabine (AraC) Dosing, continued

Study C: standard AraC combination randomized to

early or late consolidation.

Early consolidation: AraC 1g/m2 q12h d1-4 + dauno.

Late consolidation: AraC 3gm/m2 q12hours d1-6 or Auto

HCT

Study D: (TAD-HAM) or (HAM-HAM) TAD base AraC

or HAM based AraC

Study E: Intensified therapy vs. std.

Intensified: Allo HCT for high risk, auto for int.

Consolidation random between Hidac x3 vs. AraC in combo with Amsacrine and

mitoxantrone



Std Arm A B C D E

N 290 815 368 209 741 572

CR/CRi 70% 75% 74% 82% 76% 74%

Death in aplasia 5% 6% 12% 10% 11% 1%

Resistant Dz 25% 20% 14% 9% 13% 26%

RFS 44.9% 34.9% 46.7% 47% 43.9% 47.3%

EFS 31.5% 27% 34.5% 38.5% 33.6% 34.8%

5yr OS 44.3% 41.4% 46.6% 47.5% 43.6% 46.4%

Cytarabine (AraC) Dosing, continued

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 not required for definition of complete remission

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

1. RO 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?

Audience Response Question #1

a. b. c. d.

2% 0%

98%

0%

a. Cytarabine and gemtuzumab

ozogamicin

b. Gemtuzumab ozogamicin

c. Cytarabine and daunorubicin

d. Idarubicin

Acute Leukemia: Complications

Cancer Related Problems

Anemia

Thrombocytopenia

Neutropenia

Tumor lysis syndrome (TLS)

Hyperleukocytosis

Treatment Related Problems

Bone marrow suppression

TLS

Nausea/vomiting

Organ toxicities

Mucositis/stomatitis

Nutrition

AML: Bone Marrow Suppression

Neutropenia 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

2. RO 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?

Audience Response Question #2

a. b. c. d.

7%

30%

21%

42%

a. Cytarabine + idarubicin (5 + 2)

b. High dose cytarabine

c. Mobilization of peripheral

stem cells to prepare for

subsequent stem cell transplant

d. Active Surveillance

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 cytarabine or standard dose cytarabine + anthracycline

Significant cytoreduction with residual 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

NCCN AML Practice Guidelines 2013

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

2. RO 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?

Audience Response Question #2 (Repeated)

a. Cytarabine + idarubicin (5 + 2)

b. High dose cytarabine

c. Mobilization of peripheral

stem cells to prepare for

subsequent stem cell transplant

d. Active surveillance

AML Special Populations

Relapsed/Refractory AML

Older patients (> 60 years)

Acute promyelocytic leukemia

Relapsed/Refractory AML

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

AML Median Survival

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

0

200

400

600

800

1000

1200

1400

0 - 10 yrs 11 - 20 yrs 21 - 40 yrs 41 - 60 yrs 61 - 80 yrs 81 + yrs

Med

ian

Su

rviv

al

(days)

Age

AML in Patients > 60 yo: Treatment Options

Supportive Care

• Hydroxyurea

• Transfusions

Chemotherapy

• Standard dose

• Low intensity

Acute Promyelocytic Leukemia

Patient Case

LJ is a 24 y/o male s/p gunshot wound. In the

ER a CBC with differential was obtained that

was suspicious for AML.

Subsequent evaluation revealed AML (M3) and

LJ was admitted to for further work-up and

treatment.

His WBC today is 1.5 x 103/cu mm (nml 4.3 –

10.8 x 103/cu mm) with a platelet count of

10K (nml range 200 – 400 K).

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 (continued)

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)


APL Initial Management

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

ATRA Toxicities: Differentiation syndrome, HA, mucosal dryness, hyperleukocytosis

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 (may also occur from use of chemotherapy agents)

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

years

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

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

APL: Arsenic Trioxide (continued)

Differentiation syndrome

Management same as ATRA

QT/QTc Prolongation

Careful monitoring of QT/QTc

Maintenance of electrolytes within the normal range

(ie magnesium > 1.8 mg/dL and potassium >

4.0 mEq/L)

Patient Case

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

CBC reveals a WBC of 25K.

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 Syndrome

Presentation 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.

Acute Lymphoblastic Leukemia (ALL)

DH is a 19 yo male admitted to the hospital with uncustomary fatigue and bruising without trauma.

Physical exam revealed splenomegaly, slight hepatomegaly, and lymphadenopathy.

A recent CBC reveals the following:

WBC 20.4 x 103/cu mm

Hgb 10 g/dL

Plt 50K

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

Bone pain

Dizziness

Infections

CNS involvement (mature B-cell ALL)

Mediastinal involvement (T-lineage)

Classification of Adult ALL

> 20% blasts in BMbx

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) MLL translocation, hypodiploidy-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 debated 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/intrathecal chemotherapy + 6MP + MTX

Late intensification:

doxo + VCR + dex + CTX + 6TG + cytarabine

Prolonged Maintenance:

VCR + pred + MTX + 6MP

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

ALL: Treatment Strategies in Adults

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.

Patient 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


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 Δ from Baseline

Uric Acid > 8mg/dL 25% increase

Potassium > 6mmol/L 25% increase

Phosphorus > 1.45mmol/L 25% increase

Calcium < 1.75mmol/L 25% decrease

Note: 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


High Intermediate Low

NHL Burkitt's,

lymphoblastic, B-ALL

DLBCL Indolent NHL

ALL WBC ≥ 100,000 WBC 50,000-100,000 WBC ≤ 50,000

AML WBC ≥ 50,000,

monoblastic

WBC 10,000-50,000 WBC ≤ 10,000

CLL WBC 10,000-100,000

Tx w/fludarabine

WBC ≤ 10,000

Other hematologic

malignancies

(including CML and

multiple myeloma)

and solid tumors

Rapid proliferation

with expected rapid

response to therapy

Remainder of patients

adapted from Coiffier B, et al. JCO 2008;26:2766-78


Prevention of TLS

Low Risk

Clinical judgment 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)

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

Imatinib mesylate + HyperCVAD produced

> 90% CR rates

Dasatinib can be used 1st-line therapy in

combination with Hyper-CVAD

Initial data with ponatinib seems to indicate

efficacy in the setting of refractory ph+ ALL

Role of allogeneic SCT debated but only

chance of cure

Thomas DA, et al. Blood 2004;103:4396-407. Foa R, et al. Blood 2011; 118:6521-8.

Cortes JE, et al NEJM 2012; 367:2075-88.

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

ACCP/ASHP Oncology Pharmacy Preparatory Review Course

Acute Leukemia and


Tippu Khan, Pharm.D., BCOP, CPP

University of North Carolina Hospitals and Clinics

UNC Eshelman School of Pharmacy

acute leukemia and tumor lysis syndrome - accp

Documents