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NCCN Clinical Practice Guidelines in Oncology

Chronic Myelogenous

LeukemiaV.2.2007

www.nccn.org


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Version 2.2007, 11/20/06 2006 National Comprehensive Cancer Network, Inc. All rights reserved.These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Guidelines Index

CML Table of Contents

MS, References

NCCN Practice Guidelines

in Oncology v.2.2007 Chronic Myelogenous Leukemia

NCCN Chronic Myelogenous Leukemia Panel Members

Susan OBrien, MD/Chair

University of Texas M. D. Anderson

Cancer Center

Ellin Berman, MD

Memorial Sloan-Kettering Cancer

Center

Kapil Bhalla, MD

H. Lee Moffitt Cancer Center and

Research Institute at the University of

South Florida

Edward A. Copelan, MD

Arthur G. James Cancer Hospital &Richard J. Solove Research Institute

at The Ohio State University

Marcel P. Devetten, MDUNMC Eppley Cancer Center at The

Nebraska Medical Center

Peter D. Emanuel, MDUniversity of Alabama at Birmingham

Comprehensive Cancer Center

B. Douglas Smith, MD

The Sidney Kimmel

Comprehensive Cancer Center at

Johns Hopkins

David S. Snyder, MD

City of Hope Cancer Center

Robert J. Soiffer, MD

Dana-Farber/Partners CancerCare

Martin S. Tallman, MD

Robert H. Lurie Comprehensive

Cancer Center of Northwestern

University

Moshe Talpaz, MD

University of Michigan

Comprehensive Cancer Center

Meir Wetzler, MD

Roswell Park Cancer Institute

Harry P. Erba, MD, PhD

University of Michigan Comprehensive

Cancer Center

Peter L. Greenberg, MD

Stanford Hospital and Clinics

Russell J. Schilder, MD

Fox Chase Cancer Center

Paul Shami, MD

Huntsman Cancer Institute at the

University of Utah

Joseph O. Moore, MDDuke Comprehensive Cancer Center

Donna Przepiorka, MD, PhDSt. Jude Children's Research

Hospital/University of Tennessee Cancer

Institute

Jerald P. Radich, MD

Fred Hutchinson Cancer Research

Center/Seattle Cancer Care Alliance

* Writing Committee Member

*

*

Hematology/Hematology oncology

Medical Oncology

Internal medicine

Bone Marrow Transplantation

Continue
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Guidelines Index


MS, References



These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patients care or treatment. The National Comprehensive Cancer Network makes no representations or warranties of any kind,regarding their content use or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrightedby National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any formwithout the express written permission of NCCN. 2006.

Table of Contents

NCCN Chronic Myelogenous Leukemia Panel Members

Workup (CML-1)

Primary Treatment (CML-1)

Imatinib (CML-1)

Hematopoietic stem cell transplantation (CML-1)Disease Progression (CML-5)

Monitoring For Patients Receiving Tyrosine Kinase Inhibitor Therapy (CML-A)

Management of Imatinib Toxicity (CML-C)

Management of Dasatinib Toxocity (CML-D)

Management of Interferon Toxicity (CML-F)

Definitions of Accelerated Phase (CML-G)

Definitions of Blast Crisis (CML-H)

Guidelines Index

Print the Chronic Myelogenous Leukemia Guideline

Supportive Care Strategies for Leukocytosis and Thrombocytosis (CML-B)

Criteria for Cytogenetic and Hematologic Response (CML-E)

For help using thesedocuments, please click here

Manuscript

References

Clinical Trials:

Categories of Consensus:NCCNAll recommendations are Category2A unless otherwise specified.

See

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

NCCN

To find clinical trials online at NCCNmember institutions,click here:nccn.org/clinical_trials/physician.html

NCCNCategories of Consensus

Summary of Guidelines Updates
http://contents.pdf/http://contents.pdf/http://print/http://help.pdf/http://help.pdf/http://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://contents.pdf/http://help.pdf/http://contents.pdf/http://print/


4/32Version 2.2007, 11/20/06 2006 National Comprehensive Cancer Network, Inc. All rights reserved.These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Guidelines Index


MS, ReferencesNCCN Practice Guidelines


Summary of the Guidelines updates

UPDATES

The changes in the 2.2007 version of the Chronic Myelogenous Leukemia guidelines from the 1.2006 version is the

addition of the updated manuscript representing the changes to the algorithm.

Summary of the changes in the 1.2007 version of the Chronic Myelogenous Leukemia guidelines from the 1.2006 version

include:

In the Primary Treatment of CML, higher doses of imatinib may be considered in some patients. This was added as footnote f

with a supporting reference ( ).Footnote h was modified to include the consideration of IFN for rare patients not able to tolerate dasatinib( ).

After the 3-month evaluation, the recommendations for patients not in hematologic remission, or in hematologic relapse were

changed to "Dasatinib and reconsider HSCT or clinical trial" ( ).

After the 6-month evaluation, the recommendations for patients with no cytogenetic response or cytogenetic relapse were

modified to include Dasatinib. IFN was removed as a treatment option ( ).

After the 12-month evaluation, the recommendations for patients with a partial cytogenetic response were modified with the

removal of HSCT and clinical trial as treatment option s ( ).After the 12-month evaluation, the recommendations for patients with a minor or no cytogenetic response or cytogenetic

relapse were modified to include Dasatinib. IFN was removed as a treatment option ( ).

The 18-month evaluation and treatment options are new recommendations( ).

Patients treated with HSCT as primary therapy, not in remission, or in relapse, and a complete cytogenetic response after

monitored withdrawal of immune suppression in the setting of No GVHD; the treatment recommendations are now based on

the PCR result. PCR negative patients, the recommendation is observation. PCR positive patients, the recommendation is for

imatinib and DLI for progression.( ).Patients treated with HSCT as primary therapy, not in remission, or in relapse, and GVHD; IFN was removed as a treatment

recommendation( ).

For patients with disease progression on imatinib therapy, Dasatinib followed by HSCT was added as a treatment

recommendation for patients in accelerated phase or blast crisis. ( ).

Monitoring for Patients Receiving Tyrosine Kinase Inhibitor Therapy is a new attachment ( ) and replaces the previous

Monitoring During Therapy attachment.

Management of Dasatinib Toxicity is a new attachment ( ).

CML-1CML-1

CML-2

CML-2

CML-3

CML-3

CML-3

CML-4

CML-4

CML-5

CML-A

CML-D


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Donor

available and

prefers HSCT

No donor

available or

declined HSCT

SeeFollow-upTherapy(CML-4)

See

Treatment for

Not HSCT

candidate,

below

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

WORKUP a

Chronic

phaseadult CML

Ph negative

and

1

BCR-

ABL negative

Ph positive

or

1

BCR-ABL

positive

H&P

CBC, platelets

Chemistry profile

Bone marrow

aspirate and biopsy

Morphologicreview

Percent

basophilsCytogenetics,

FISH, PCR

Percent blasts

Evaluate for other

diseases (not CML)

CML-1

a .

b

g

HSCT has definite survival benefits whereas, despite very promising earlyresponses, the survival benefit, long term toxicities, and durability of response ofimatinib are unknown. Interferon has been shown to produce inferior short termresponses compared to imatinib, although long term comparisons of effect arestill not available. The majority of NCCN institutions recommend imatinib as theprimary treatment option in patients who do not undergo HSCT.

For patients with symptomatic leukocytosis or thrombocytosis,.

HSCT = hematopoietic stem cell transplantation. Refers to a matched related andunrelated allogeneic transplant.

Indications and outcomes of related and unrelated transplant are age, donor type

and transplant center dependent. Nonmyeloablative transplant is underinvestigation and should be performed only in the context of a clinical trial.

Consider higher doses in some patients. Kantarjian H, Talpaz M, Garcia-Manero G,et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphiachromosome-positive chronic phase chronic myeloid leukemia. Blood2004:103(8):2873-2878.

Rare patients unable to tolerate imatinib mesylate or dasatinib, then consider IFN.

For monitoring at 12 mo and thereafter.

c

d

e

f

h

i

See Monitoring for Patients Receiving Tyrosine Kinase Inhibitor therapy (CML-A)

see Supportive Care Strategies (CML-B)See Management of Imatinib Toxicity (CML-C).

Discussion of

treatment options

including:

HSCT

Imatinib

Clinical trial

b,c

d

HSCT

candidated,e

Not HSCT

candidate

HLA

testing

Imatinib 400 mg

(category 1) or

higher po daily

Peripheral blood

or bone marrow:

FISH QPCR as a

baseline sample

f

i

g,h

PRIMARY TREATMENT

See 3-MonthFollow-upTherapy(CML-2)


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a

d

h

j

.

HSCT = hematopoietic stem cell transplantation. Refers to a matched related and unrelated allogeneic transplant.

Rare patients unable to tolerate imatinib mesylate or dasatinib, then consider IFN.

.

.

g .

k


See Management of Dasatinib Toxicity (CML-D)

See Criteria for Cytogenetic and Hematologic Response (CML-E)

See Management of Imatinib Toxicity (CML-C)

CML-2

3-moevaluation

Hematologic

remission

Not in

hematologic

remission, or

in hematologic

relapse

Continue

same dose

of imatinibg

Dasatinib and

reconsider HSCTorClinical trial

h,j

3 MONTH FOLLOW-UP THERAPYa

6-mo evaluation

including

karyotypic bone

marrow

cytogenetics

Complete

cytogenetic

response k

Partial or

minor

cytogenetic

response k

Continue same dose of

imatinib or increase dose of

imatinib to a maximum of

600-800 mg, as tolerated g

No

cytogenetic

response k or

cytogenetic

relapse

Dasatinibor

j

Increase dose of imatinib

(600-800 mg, as tolerated)orClinical trialorHSCT

g

d

6 MONTH FOLLOW-UP THERAPY a

Continue same

dose of imatinibg




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a

d

j

.


.

.

g .

k




See Management of Imatinib Toxicity (CML-C)



12 MONTH FOLLOW-UP THERAPY a

CML-3

12-mo evaluation

including bone

marrow

cytogenetics

Complete

cytogenetic

response k

Partial

cytogenetic

response k

Minor or no

or

cytogenetic

relapse

cytogenetic

response k

Continue same

dose of imatinibg

Continue samedose of imatiniborIncrease dose of

imatinib to a

maximum of

600-800 mg, as

tolerated

g

g

DasatiniborClinical trialorHSCT

j

d

18-mo evaluation

including bonemarrow

cytogenetics

Complete

cytogenetic

response k

Partial, minor or

no

or

cytogenetic

relapse

cytogenetic

response k

Continue same

dose of imatinibg

Increase dose of

imatinib to a

maximum of

600-800 mg, as

tolerated

orDasatiniborHSCTorClinical trial

g

j

See DiseaseProgression(CML-5)


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d

g


.

e

l

Indications and outcomes of related and unrelated transplant are age, donor type and transplant center dependent.Nonmyeloablative transplant is under investigation and should be performed only in the context of a clinical trial.

.

.

kSee Management of Imatinib Toxicity (CML-B)


See Management of IFN Toxicity (CML-F)

PRIMARY TREATMENT

GVHD

No GVHD

Positive

Negative

Marrow

cytogenetics

Positive

Negative

Imatinib

orClinical trial

g

Complete

cytogeneticresponse k

No completecytogenetic

response k

Imatinib

or

IFNorDLI

orClinical trial

g

l

Cytogenetic

remission

Not in

remission,or in relapse

FOLLOW-UP THERAPY

Monitored

withdrawal of

immune

suppression

HSCT

(myelo-

ablative)

d,e

PCR monitoring

(peripheral blood

or bone marrow)

every 6 mo for 2

years, thenyearly

Treat according to

Not in remission,

or in relapse, below

ObservationorClinical trial

CML-4

PCR

negative

PCR

positive Imatinibg

Observe

DLI
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Blast crisisn

Accelerated phasem

d

jHSCT = hematopoietic stem cell transplantation. Refers to a matched related and unrelated allogeneic transplant.

.m

n.

.


See Definitions of Accelerated Phase (CML-G)

See Definitions of Blast Crisis (CML-H)

WORKUP TREATMENT

Disease

progression

on imatinib

Bone marrow

Flow cytometry

CytochemistryPeroxidaseTdT

Cytogenetics

Dasatinib followed

by HSCT, if

feasibleorClinical trial

j

d

Clinical trialorAML-type induction

chemotherapy,

Dasatinib followed

by HSCT , if feasibleor

followed by HSCT,

if feasible

j

d

d

See NCCN AML

Guidelines

Myeloid

Lymphoid

Dasatinib followed

by HSCT , if feasibleorALL-type induction

chemotherapy,

orClinical trial

j

d

d

followed by HSCT,

if feasible

CML-5

Clinical trial

Clinical trial

Clinical trial

Clinical trial

Clinical trial
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CML-A



MONITORING FOR PATIENTS RECEIVING TYROSINE KINASE INHIBITOR THERAPY 1

Indications for cytogenetics and PCR for BCR-ABL mRNA

Indications for ABL kinase domain (KD) mutation analysis

At diagnosis of CML

Bone marrow cytogenetics and measurement of BCR-ABL transcript numbers by PCR before initiation of treatment.

If collection of BM is not feasible, fluorescence in situ hybridization (FISH) on a PB specimen using dual probes for the BCR

and ABL genes is an acceptable method of confirming the diagnosis of CML.

While a patient appears to be responding to treatment

BCR-ABL transcript levels should be measured every 3 months.

Bone marrow cytogenetics at 6 and 12 months from initiation of therapy.

Bone marrow cytogenetics at 18 months if patient not in a complete cytogenetic remission (CCR) at 12 months.

When a patient reaches complete cytogenetic remission (CCR)

BCR-ABL transcript levels should be measured every 3 months.

Bone marrow cytogenetics every 12 months.

When a patient appears to have rising level of BCR-ABL transcripts

Rising levels should be confirmed by two measurements not more than a month apart.

If a rising level of BCR-ABL transcripts is confirmed, the frequency of measurement should be increased to once a month.Mutation testing should be performed (see below).

Chronic phase CML

ABL KD mutation screening is indicated if there is inadequate initial response (failure to achieve complete hematologic

response at 3 months, minimal cytogenetic response at 6 months or major cytogenetic response at 12 months) or any sign of

loss of response (defined as hematologic relapse, relapse to Ph-positivity or an increase in BCR-ABL transcript ratio).

Accelerated and blast phase CML

Testing for KD mutations should be carried out routinely at 3 month intervals in high-risk patients, regardless of level of

response to TK inhibitors.

1Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations forharmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108(1):28-37.

G id li I d
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SUPPORTIVE CARE STRATEGIES FOR LEUKOCYTOSIS AND THROMBOCYTOSIS

Factors to consider when choosing treatment include: patient's age, risk factors for thromboembolic disease, and degree of

thrombocytosis.

Symptomatic leukocytosis:

Treatment options include hydroxyurea, apheresis, imatinib or clinical trial

Treatment options include hydroxyurea, antiaggregants, anagrelide or apheresis

Symptomatic thrombocytosis:

CML-B



Guidelines Index


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1

2

3

Many toxicities are self-limiting, consider re-escalating dose at a later time.

If patient remains nonresponsive with erythroid or myeloid therapy, consider obtaining bone marrow.

Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib

mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652.

CML-C(1 of 3)

MANAGEMENT OF IMATINIB TOXICITY (PAGE 1 of 3) 1

Hematologic

Nonhematologic

2

Grade 3-4 neutropenia (neutrophil count < 1000/mm ):Add growth factor, titrate to maintain neutrophil count above 1000.

orHold drug until grade 2 or better, resume at the same dose if grade 2 reached within 2 wks or at 25-33% dose reduction (not less

than 300 mg) if grade 3-4 persisted more than 2 wks.

Grade 3-4 thrombocytopenia (platelet count < 50,000/mm ):Hold drug until grade 2 or better, resume at the same dose if grade 2 reached within 2 wks or at 25-33% dose reduction (not less

than 300 mg) if grade 3-4 persisted more than 2 wks.

Diarrhea: supportive care

Edema: diuretics, supportive care

Fluid retention: diuretics, supportive care, dose reduction, interruption or discontinuation

GI upset: take medication with a meal and large glass of waterMuscle cramps: calcium supplement, tonic water

Rash: topical or systemic steroids, dose reduction, interruption or discontinuation

Grade 2, hold drug until grade 1. Resume at 25-33% dose reduction (not less than 300 mg). Evaluate for other hepatotoxic drugs

that may be contributing to toxicity, including acetaminophen.

3

3

3

3

Grade 3-4 anemia: Erythropoietin( )

In accelerated phase, patients may have cytopenias related to disease, it is not necessary to discontinue or hold imatinib

Grade 3:Use specific interventions, listed aboveIf not responsive to symptomatic measures, treat as Grade 4

Grade 4:

Hold drug until grade 1 or better, then consider resuming dose at 25-33% dose reduction (not less than 300 mg).

Specific Interventions

Nonhematologic - Liver

See the NCCN Cancer and Treatment-Related Anemia Guidelines

Potential Drug Interactions (see CML-C 2 of 3)

Guidelines Index
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CML-C(2 of 3)

CYP450 = cytochrome P450; LFT = liver function test.

POTENTIAL DRUG INTERACTIONS WITH IMATINIB (2 of 3) 4

DRUG INTERACTION

acetaminophenImatinib can cause LFT abnormalities. Liver failure and death occurred in one patient taking largedoses of both acetaminophen and imatinib. The use of acetaminophen should be limited in patientstaking imatinib. For most patients, this means taking 1300 mg acetaminophen/day or less.

aprepitant Aprepitant inhibits CYP450 3A4, increasing the imatinib plasma concentration.

carbamazepine Carbamazepine induces CYP450 3A4 and decreases the plasma concentration of imatinib. Increase

in imatinib dose is usually necessary.

clarithromycin Clarithromycin inhibits CYP450 3A4, increasing the imatinib plasma concentration

cyclosporine Imatinib inhibits CYP450 3A4, increasing the cyclosporine plasma concentration; this is a concern

given the narrow therapeutic window of cyclosporine.

dexamethasone Dexamethasone induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in

imatinib dose is usually necessary.

erythromycin Erythromycin inhibits CYP450 3A4, increasing the imatinib plasma concentration

hypericum perforatum St. John's Wort induces CYP450 3A4 and may decrease the imatinib plasma concentration. Increase

in imatinib dose may be necessary in patients receiving St. John's Wort.

itraconazole Itraconazole inhibits CYP450 3A4, increasing the imatinib plasma concentration.

Potential Drug Interactions continued(see CML-C 3 of 3)

4Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task Force Report : Optimal management of patients withgastrointestinal stromal tumor (GIST)---Expansion and Update of NCCN Clinical Practice Guidelines. JNCCN2004;2(suppl1):S1-S26.

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POTENTIAL DRUG INTERACTIONS WITH IMATINIB (3 of 3) 4



CML-C(3 of 3)

DRUG INTERACTION

phenobarbital Phenobarbital induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in


phenytoin Phenytoin induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in


pimozide Imatinib inhibits CYP450 3A4, increasing pimozide plasma concentration. This is a concern given

the narrow therapeutic window of pimozide.

rifabutin Rifabutin induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in imatinib

dose is usually necessary.

rifampin Rifampin induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in imatinib

dose is usually necessary.

rifapentine Rifapentine induces CYP450 3A4, decreasing the imatinib plasma concentration. Increase in


simvastatin

Imatinib inhibits CYP450 3A4, increasing the simvastatin plasma concentration. A dose

adjustment of simvastatin may be necessary.

warfarinWarfarinis metabolized by the CYP450 isoenzymes CYP 2C9 and CYP 3A4. Use of warfarin withimatinib could cause an increase in the availability of warfarin. Patients requiring anticoagulationshould be given heparin or low-molecular-weight heparin instead of warfarin.

ketoconazole Ketoconazole inhibits CYP450 3A4, increasing the imatinib plasma concentration.

CYP450 = cytochrome P450; LFT = liver function test.4Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task Force Report : Optimal management of patients with

gastrointestinal stromal tumor (GIST)---Expansion and Update of NCCN Clinical Practice Guidelines. JNCCN2004;2(suppl1):S1-S26.

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CML-D1 of 2



MANAGEMENT OF DASATINIB TOXICITY (1 of 2)

Potential Drug Interactions (see CML-D 2 of 2)

Hematologic

Specific Interventions

Nonhematologic

Grade 3-4 neutropenia (neutrophil count < 1000/mm ):Add growth factor, titrate to maintain neutrophil count above 1000.

orHold drug until grade 2 or better, resume at the same dose if grade 2 reached within 7 days or reduce one dose level if

grade 3-4 persisted more than 7 days.

Grade 3-4 thrombocytopenia (platelet count < 50,000/mm ):Hold drug until grade 2 or better, resume at the same dose if grade 2 reached within 7 days or reduce one dose level if

grade 3-4 persisted more than 7 days.Grade 3-4 anemia: Erythropoietin( )

In accelerated phase, patients may have cytopenias related to disease, it is not necessary to discontinue or hold

dasatinib

Edema: diuretics, supportive care

Pleural/pericardial effusion: diuretics, dose interruption. If pt has significant symptoms, consider short course of

steroids (prednisone 20 mg/day x 3); when resolved, reduce one dose level.

Headache: Supportive careGI upset: take medication with a meal and large glass of water

Diarrhea: supportive care

Rash: topical or systemic steroids, dose reduction, interruption or discontinuation

Grade 3:Use specific interventions, listed aboveIf not responsive to symptomatic measures, treat as Grade 4

Grade 4:Hold drug until grade 1 or better, then consider resuming at decreased dose level

3

3

See the NCCN Cancer and Treatment-Related Anemia Guidelines

Dose Levels

0 70 mg ID-1 50 mg BID-2 40 mg BID

B

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CML-D2 of 2

Caution is warranted when administering dasatinib to subjects taking drugs that are highly

dependent on CYP3A4 for metabolism and have a narrow therapeutic index. Systemic

exposures to these medications could be increased while receiving dasatinib. In in vitro

studies, dasatinib is a strong inhibitor of the human CYP3A4 enzyme and a weak inhibitor of

CYP1A2, CYP2D6 and CYP2C19.

Until information regarding exposure-toxicity and exposure-response relationships is available

with dasatinib, concomitant CYP3A4 inhibitors and inducers should be avoided, if possible,

since they could alter the systemic exposure to dasatinib.

Medications associated with QT prolongation that should be avoided include:

quinidine, procainamide, disopyramide

amiodarone, sotalol, ibutilide, dofetilide

erythromycins, clarithromycinchlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine,

levomethadyl, pentamidine, sparfloxacin, lidoflazine

In vitro solubility data indicate that dasatinib may have decreased solubility and absorption at

pH > 4. Until further data are available, patients should try to avoid taking proton pump

inhibitors and H antagonists. Short-acting antacid agents may be taken, but is recommended

that these not be taken from 4 hours before to 4 hours after dosing of dasatinib.

2

POTENTIAL DRUG INTERACTIONS WITH DASATINIB (2 of 2)

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1

2

Adapted, with permission, from Faderl S et al: Chronic myelogenous leukemia: Biology and therapy. Ann Intern Med 1999;131:207-219.The American College of Physicians-American Society of Internal Medicine is not responsible for the accuracy of the translation.

A minimum of 20 metaphases should be examined.

Back to CML Tableof Contents

Complete hematologic response

Cytogenetic response

Partial hematologic response

Complete normalization of peripheral blood counts with leukocyte

count < 10 x 10 /L

Platelet count < 450 x 10 /L

No immature cells, such as myelocytes, promyelocytes, or blasts

in peripheral blood

No signs and symptoms of disease with disappearance ofpalpable splenomegaly

Complete- No Ph -positive metaphases

Partial- 1%-34% Ph-positive metaphases

Minor- 35%-90% Ph-positive metaphases

Same as complete hematologic response, except for:

Presence of immature cells

Platelet count < 50% of the pretreatment count, but > 450 x 10 /L

Persistent splenomegaly, but < 50% of the pretreatment extent

9

2

9

1

9

CRITERIA FOR CYTOGENETIC AND HEMATOLOGIC RESPONSE 1

CML-E

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CML-F



MANAGEMENT OF INTERFERON TOXICITY

Management:

Dose modification:

Discontinue IFN if patient has:

Depression: antidepressants (eg, fluoxetine, paroxetine)

Thyroid function: monitor every 6 mo if marked fatigue

Pulmonary function tests if respiratory distress

CNS toxicityMemory changesConcentration problemsFatigue grade 2-3

Suicidal tendencies

ParkinsonismAutoimmune hemolytic anemia

Pulmonary, cardiac toxicity (rare)

Any grade 3 toxicity not responsive to dose reduction
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DEFINITIONS OF BLAST CRISIS



World Health Organization

(WHO) Criteria1

Blasts 20% of peripheral

blood white cells or of

nucleated bone marrow cells

Extramedullary blastproliferation

Large foci or clusters of

blasts in the bone marrow

biopsy

1

2

Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumoursof Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001

DeVita VT, Hellman S et al: Cancer: Principles and Practice of Oncology, 6 Edition. Vol 2., pgs 2433-2447, 2001, Lippincott, Williams &Wilkins

th

30% blasts in the blood,

marrow, or both

Extramedullary infiltrates

of leukemic cells

International Bone Marrow

Transplant Registry2

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CML-H


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http://www.clinicaltrials.gov/ct/show/NCT00124748?order=3http://contents.pdf/


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http://www.clinicaltrials.gov/ct/show/NCT00070499?order=1http://contents.pdf/


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[ghiduri][cancer]chronic myelogenous leukemia

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