Chapter 20: Leukemia, Chronic Myelogenous

Michael W.N. Deininger; Brian J. Druker

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

5,980 (male: 3,130; female: 2,850.

Phase at presentation:

Estimated new cases for 2014 in the United States)

Chronic phase: 85–90%

Deaths:

Estimated 810 in 2014 (male: 550; female: 260)

Accelerated phase and blast crisis: 10–15%

Median age:

65 years

Male to female ratio:

1.7:1

Cervantes F et al. Haematologica 1999;84:324–327

O'Brien SG et al. N Engl J Med 2003;348:994–1004

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Pathology

Peripheral blood findings at diagnosis: median (range)

WBC: 174,000/mm³ (15–850/mm³)
Hemoglobin: 10.3 g/dL (4.9–16.6 g/dL)
Platelet count: 430,000/mm³ (17–3182/mm³)
Left-shifted white cell differential, basophilia, and eosinophilia
Blasts: <15%—chronic phase

Bone marrow findings at diagnosis

Increased cellularity
Increased myeloid-to-erythroid ratio with full myeloid maturation
Blasts <15%—chronic phase
Basophilia
Megakaryocyte hyperplasia
Reticulin fibrosis

Cytogenetics and molecular diagnostics

Philadelphia (Ph) chromosome including variant translocations (90%)
BCR-ABL translocation by FISH (95%)^✫
BCR-ABL transcripts by RT-PCR (95%)^✫
Chromosomal abnormalities in addition to the Ph chromosome (clonal evolution)^†:

(Associated with disease progression, usually absent in the chronic phase at diagnosis)

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Pathology

Trisomy 8

52.9%

Second Philadelphia chromosome

50.7%

Isochromosome 17

35.8%

Trisomy 19

24.3%

Deininger MWN. Semin Hematol 2003;40(2 Suppl 2):50–55

Johansson B et al. Acta Haematol 2002;107:76–94

Mitelman F. Leuk Lymphoma 1993;11(Suppl 1):11–15

Savage DG et al. Br J Haematol 1997;96:111–116

Thiele J et al. Leuk Lymphoma 2000;36:295–308

Work-up

History and physical examination

CBC and leukocyte differential counts, platelets, electrolytes, liver function tests
HLA typing for patients who are candidates for allogeneic hematopoietic cell transplantation
Bone marrow aspirate and biopsy (bone marrow cytogenetics can detect chromosomal abnormalities other than Ph chromosome that are not detectable using peripheral blood)
BCR-ABL1 transcript levels by quantitative reverse transcriptase polymerase reaction (QPCR) before initiation of treatment.
If collection of bone marrow is not feasible, fluorescence in situ hybridization (FISH) on a peripheral blood specimen with dual probes for BCR and ABL1 genes

Classification of Disease: Phases of Disease

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Classification of Disease: Phases of Disease

Chronic phase:

Bone marrow and peripheral blood blasts <15%
Peripheral blood promyelocytes and blasts combined <30%
Peripheral blood basophils <20%
Platelets >100,000/mm³

Accelerated phase:

Bone marrow and peripheral blood blasts 15–30%
Peripheral blood promyelocytes + blasts ≥30% (but blasts alone <30%)
Peripheral blood basophils ≥20%
Platelets ≤100,000/mm³ (unless related to therapy)

Blast crisis:

Bone marrow or peripheral blood blasts ≥30%
Myeloid immunophenotype: MPO-positive
Lymphoid immunophenotype: TdT-positive

Cytogenetic abnormalities in addition to the Philadelphia chromosome (typically, isochromosome 17, trisomy 8, trisomy 19, second Ph chromosome) are considered indicative of accelerated phase by some authors, even in the absence of other defining criteria. Adverse prognostic significance is best documented for isochromosome 17

Johansson B et al. Acta Haematol 2002;107:76–94

Talpaz M et al. Blood 2002;99:1928–1937

CML Extras

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CML Extras

Calculation of Relative Risk

Adapted from Hasford J et al. Blood 2011;118:686–692

Study

Calculation

Risk Definition by Calculation

Sokal et al. 1984^✫

Exp 0.0116 × (age − 43.4)

0.0345 × (spleen − 7.51)

0.188 × [(platelet count ÷ 700)² − 0.563]

0.0887 × (myeloblasts − 2.10)

Low risk: <0.8

Intermediate risk: 0.8–1.2

High risk: >1.2

Euro

Hasford et al. 1998^†

0.666 when age ≥50 y

(0.042 × spleen)

1.0956 when platelet count >1500 × 10⁹L

(0.0584 × myeloblast)

0.20399 when basophils >3%

(0.0413 × eosinophils) × 100

Low risk: ≤780

Intermediate risk: 781–1480

High risk: >1480

EUTOS

Hasford et al. 2011^‡

Spleen × 4

Basophils × 7

Low risk: ≤87

High risk: >87

Calculation of the risk requires use of clinical and hematologic data at diagnosis, prior to any treatment:

Age is given in years
Spleen is given in centimeters below the costal margin (maximum distance)
Myeloblasts, eosinophils, and basophils are given in percent of peripheral blood differential

Relative risk for the Sokal calculation is expressed as exponential of the total; that for the Hasford calculation is expressed as the total × 1000

To calculate Sokal and Euro risk score, go to:

http://www.leukemia-net.org/content/leukemias/cml/cml_score/index_eng.html

To calculate EUTOS risk score, go to:

http://www.leukemia-net.org/content/leukemias/cml/eutos_score/index_eng.html

^✫Sokal et al. Blood 1984;63:789–799. Risk according to Sokal et al. defined based on patients treated with conventional chemotherapy.

^†Hasford et al. J Natl Cancer Inst. 1998;90:850–858. Risk according to Hasford et al. defined based on patients treated with rIFNα-based regimens

^‡Hasford J et al. Blood 2011;118:686–692. Risk according to EUTOS score derived from patients treated with imatinib

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CML Extras

Response Definitions and Monitoring

Adapted from Baccarani et al. Blood 2013;122:872–884

Complete Hematologic Response (CHR)^✫

Cytogenetic Response (CyR)^†

Molecular Response (MolR)^‡

Definitions

Normalization of blood counts:
- Platelet count <450,000/mm³
- WBC <10,000/mm³;
- Differential without immature granulocytes and <5% basophils
Spleen not palpable
Disappearance of CML symptoms

Percent of 20 marrow metaphases with Philadelphia chromosome (Ph) detected by karyotyping:

Complete (CCyR)^✫ = 0%
Partial/Major (MCyR) = 1–35%
Minor CyR = 36%–65%
Minimal CyR = 66%–95%
None = >95%

“Complete (CMR, CMolR)” = Transcript not detectable^§ Major (MMolR)^✫ = ≥3 log₁₀ reduction in BCR-ABL1 transcripts (≤0.10% IS)

Monitoring

Check CBC every 2 weeks until CHR achieved and confirmed
Once CHR achieved check CBC every 3 months unless otherwise required

Check CyR at 3, 6, 12 months and then at least every 6 months until CCyR achieved and confirmed
Once CCyR achieved check every 12 months

Check every 3 months
Perform mutational analysis in case of failure, suboptimal response, or >5-fold increase in transcript level

^✫Complete HR, complete CCyR, and major MolR should be confirmed on at least 2 occasions

^†CyR is evaluated by morphologic cytogenetics of at least 20 marrow metaphases. FISH of peripheral blood cells should be used only if marrow metaphases cannot be obtained

^‡MolR is assessed on peripheral blood cells. Following quantitative real time PCR (qRT-PCR) analysis, the BCR-ABL1/control gene transcript ratio is determined using the International Scale (IS) standardized baseline. The international scale for measuring MolR is that proposed by Hughes et al. Blood 2006;108:28–37

^§There is no universal definition of complete molecular response (CMR, CMolR). Some of the studies used define CMR as a negative (undetectable) result on a nested PCR assay; however, this is problematic owing to test variability. Others suggest that CMR be defined as undetectable BCR-ABL1 mRNA in 2 consecutive samples with a 4.5-log detection limit. This definition may become inadequate once sensitivity increases beyond the 4.5-log levels. It may be best to indicate test sensitivity and avoid the term CMR

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CML Extras

Recommendations for Cytogenetic and Molecular Monitoring

Adapted from Baccarani et al. Blood 2013;122:872–884

At diagnosis

Chromosome banding analysis (CBA) of marrow cell metaphases

FISH in case of Ph negativity to identify variant, cryptic translocations

Qualitative PCR (identification of transcript type)

During treatment

Quantitative real-time PCR (RQ-PCR) for the determination of BCR-ABL1 transcripts level on the international scale, to be performed every 3 months until an MMR (BCR-ABL ≤0.1%, or MR^3.0) has been achieved, then every 3–6 months and/or

CBA of marrow cell metaphases (at least 20 banded metaphases), to be performed at 3, 6, and 12 months until a CCyR has been achieved, then every 12 months. Once a CCyR is achieved, FISH on blood cells can be done. If adequate molecular monitoring can be ensured, cytogenetics can be spared

Failure, progression

RQ-PCR, mutational analysis, and CBA of marrow cell metaphases. Immunophenotyping in BP

Warning

Molecular and cytogenetic tests to be performed more frequently. CBA of marrow cell metaphases recommended in case of myelodysplasia or CCA/Ph⁻ with chromosome 7 involvement

CCA/Ph⁻ clonal chromosome abnormalities in Ph⁻ cells; FISH, fluorescence in situ hybridization

Note: The responses can be assessed either with molecular tests alone or with cytogenetic tests alone, depending on the local laboratory facilities, but whenever possible, both cytogenetic and molecular tests are recommended until a CCyR and an MMR are achieved. Then RQ-PCR alone may be sufficient. Mutational analysis by conventional Sanger sequencing is recommended in case of progression, failure, and warning. In case of failure, warning, and development of myelodysplastic features (unexpected leucopenia, thrombocytopenia, or anemia), CBA of marrow cell metaphases is recommended

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CML Extras

Definition of the Response to TKIs (Any TKI) as First-Line Treatment [Previously Untreated Patients in Early Chronic Phase (ECP) CML]

Adapted from Baccarani et al. Blood 2013;122:872–884

Time

Failure^✫

Warning^†

Optimal

Diagnosis/Baseline

High risk or

CCA/Ph⁺, major route^‡

3 months on TKI treatment

No CHR and/or

Ph⁺ >95%

BCR-ABL1 >10% and/or

Ph⁺ 36–95%

BCR-ABL1 ≤10% and/or

Ph⁺ ≤35%

6 months on TKI treatment

BCR-ABL1 >10% and/or

Ph⁺ >35%

BCR-ABL1 1–10% and/or

Ph⁺ 1–35%

BCR-ABL1 <1% and/or

Ph⁺ 0%

12 months on TKI treatment

BCR-ABL1 >1% and/or

Ph⁺ >0%

BCR-ABL1 >0.1–1%

BCR-ABL1 ≤0.1%

Then, and at any time

Loss of CHR

Loss of CCyR

Confirmed loss of MMR^§

New mutation

CCA/Ph⁺

CCA/Ph⁻ (−7 or 7q−)

BCR-ABL1 ≤0.1%

CCA, clonal chromosomal abnormalities; CCyR, complete cytogenetic response, Philadelphia chromosome (Ph) not detected by karyotyping in 20/20 marrow metaphases; CHR, complete hematologic response; CyR, cytogenetic response; NA, not applicable

^✫Failure implies patient should be moved to other treatments when available

^†Warning implies that the characteristics of the disease and the response to treatment require more frequent monitoring to permit timely changes in therapy in case of treatment failure. Such patients may become eligible for other treatments

^‡Major route abnormalities include trisomy 8, trisomy Ph (+der(22)t(9;22)(q34;q11)), isochromosome 17 (i(17)(q10)), trisomy 19 and ider(22)(q10)t(9;22)(q34;q11)

^§To be confirmed on 2 occasions, at least 1 of which with BCR-ABL ≥1%

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CML Extras

Definitions of the Response to Second-Line Therapy in Case of Failure of Imatinib

Adapted from Baccarani et al. Blood 2013;122:872–884

Failure

Warning

Optimal

Diagnosis/Baseline

No CHR or loss of CHR on imatinib or

Lack of CyR to first-line TKI or

High risk

3 months on TKI treatment

No CHR or

Ph⁺ >95% or

New mutations

BCR-ABL1 >10% and/or

Ph⁺ 65–95%

BCR-ABL1 ≤10% and/or

Ph⁺ <65%

6 months on TKI treatment

BCR-ABL1 >10% and/or

Ph⁺ >65% and/or

New mutations

Ph⁺ 35–65%

BCR-ABL1 ≤10% and/or

Ph⁺ <35%

12 months on TKI treatment

BCR-ABL1 >10% and/or

Ph⁺ >35% and/or

New mutations

BCR-ABL1 1–10% and/or

Ph⁺ 1–35%

BCR-ABL1 <1% and/or

Ph⁺ 0

Then, and at any time

Loss of CHR or

Loss of CCyR or PCyR

New mutations

Confirmed loss of MMR^✫

CCA/Ph⁺

CCA/Ph⁻ (−7 or 7q−) or

BCR-ABL1 >0.1%

BCR-ABL1 ≤0.1%

CCA/Ph⁺, clonal chromosome abnormalities in Ph⁺ cells; CCA/Ph⁻, clonal chromosome abnormalities in Ph⁻ cells; MMR, BCR-ABL1 ≥0.1% = MR3.0 or better; NA, not applicable

^✫In 2 consecutive tests, of which 1 with a BCR-ABL transcripts level ≥1%

Note: These definitions are mainly based on data reported for nilotinib and dasatinib, but can be used provisionally also for bosutinib and ponatinib, until more data are available. These definitions cannot apply to the evaluation of the response to third-line treatment.

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CML Extras

Rates of CCyR and MMR

Adapted from Mealing et al. Exp Hematol Oncol 2013;2:5

Study

Dasatinib

Nilotinib 600 mg

Nilotinib 800 mg

Imatinib 400 mg

Imatinib 800 mg

Percent with Complete Cytogenic Response (CCyR) at 6, 12, and 18 Months

Time (Months)

DASISION

85^✫

82^✫

ENESTnd

Baccarani et al.

German CML

Cortes et al.

ISTAHIT

SPIRIT

S0325 Intergroup^†

Percent with Major Molecular Response (MMR) at 12 Months

Baccarani et al.

DASISION

ENESTnd

German CML

Cortes et al.

SPIRIT

S0325 Intergroup^†

^✫24 months

^†Based on blood specimens collected 295–406 days after randomization (if a patient's molecular response was tested more than once during that interval, only the result obtained closest to day 365 was included in this analysis)

Baccarani et al: Baccarani et al. Blood 2009;113:4497–4504
Cortes et al: Cotes JE et al. J Clin Oncol 2010;28:424–430
DASISION: Kantarijan HM et al. N Engl J Med 2010;362:2260–2270; Kantarijan HM et al. Blood 2012;119:1123–1129
ENESTnd: Saglio G et al. N Engl J Med 2010;362:2251–2259; Larson RA et al. Leukemia, 2012;26:2197–2203; Hughes TP et al. Blood 2013 Dec 11

[Epub ahead of print]; Larson RA et al. Leukemia 2012;26:2197–2203

German CML: German CML-Study IV-Hehlmann R et al. J Clin Oncol 2013 Dec 2 [Epub ahead of print]
ISTAHIT: Petzer AL et al. Haematologica 2010;95:908–913
SPIRIT: Preudhomme C et al. N Engl J Med 2010;363:2511–2521
S0325 Intergroup: Deininger et al. Br J Hematol 2014;164:223–232

Expert Opinion

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FDA-Approved Indications and Usage

1. Imatinib is approved for:

Newly diagnosed adult and pediatric patients with CML^✫ in chronic phase
Patients with CML in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-α therapy
Adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL)
Pediatric patients with Ph⁺ ALL in combination with chemotherapy

2. Dasatinib is approved for:

Newly diagnosed adults with CML in chronic phase
Adults with chronic-, accelerated-, or myeloid or lymphoid blast-phase CML with resistance or intolerance to prior therapy that included imatinib
Adults with Ph⁺ ALL with resistance or intolerance to prior therapy

3. Nilotinib is approved for:

Newly diagnosed adults with CML in chronic phase
Adults with chronic- or accelerated-phase CML with resistance or intolerance to prior therapy that included imatinib

4. Bosutinib is approved for:

Adult patients with chronic-, accelerated-, or blast-phase CML with resistance or intolerance to prior therapy

5. Ponatinib is approved for:

T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph⁺ ALL
Chronic-phase, accelerated-phase, or blast-phase CML or Ph⁺ ALL for whom no other tyrosine-kinase inhibitor therapy is indicated

6. Omacetaxine Mepesuccinate is approved for:

Adult patients with chronic- or accelerated-phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs)

^✫According to the WHO, chronic myeloid leukemia (CML) is defined by the presence of the Ph chromosome or the BCR-ABL fusion gene in the context of a myeloproliferative neoplasm. Therefore the qualification “Ph chromosome-positive CML” is unnecessary

Treatment options:

In the opinion of some, imatinib remains the standard drug therapy regimen for the initial treatment of all phases of CML. Other agents are considered second-line and are reserved for patients who are intolerant of or whose disease is resistant to imatinib. In the opinion of others, nilotinib and dasatinib represent better first-line options than imatinib. But everyone agrees that the availability of 3 first-line therapies provides clinicians with a range of options for managing intolerance and resistance
Although imatinib is an excellent therapy, it is not perfect: with 8 years of follow-up, 16% of IRIS patients discontinued treatment for insufficient efficacy and 6% for adverse events. These outcomes led many to ask whether first-line use of more potent tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib, could reduce the rate of failures. Promising results in single-arm studies with both dasatinib and nilotinib led to randomized trials comparing dasatinib to imatinib (Dasatinib versus imatinib study in treatment naïve CML patients [DASISION] study) and nilotinib to imatinib (Evaluating nilotinib efficacy and safety in clinical trials of newly diagnosed Ph-positive CML patients [ENESTnd] study). Both studies found dasatinib and nilotinib superior to imatinib with respect to:
- Complete cytogenetic responses (CCyR)
- Major molecular responses (MMR), and
- Complete molecular responses (CMR)
These observations led to their approval for first-line therapy of CML-CP
Dasatinib and nilotinib provide several advantages
- Response milestones are achieved sooner and in a greater proportion of patients
- Progression to advanced disease is reduced (statistically significant for nilotinib)
However, the numerical advantages are slight, overall survival is not significantly different, and some late side effects have been observed for the second-generation inhibitors (nilotinib: peripheral occlusive arterial disease, POADs; dasatinib: pulmonary hypertension). Thus, longer follow-up will be necessary, before a general recommendation can be made
Dasatinib and nilotinib control the majority of BCR-ABL1 mutations that confer resistance to imatinib, with partially complementary exceptions. The choice between dasatinib and nilotinib can be partially rationalized based on BCR-ABL genotype (kinase domain mutation analysis) and patient history (side-effects profile). However, the 2 agents have not been compared in a prospective study. Patients with the T315I mutation of BCR-ABL do not respond to either agent
Bosutinib is active against several BCR-ABL1 mutants that confer resistance to nilotinib and dasatinib, and is approved for the treatment of adult patients with chronic-, accelerated-, or blast-phase CML with resistance or intolerance to prior therapy
The most problematic point mutation is the BCR-ABL^T315I “gatekeeper” mutation. BCR-ABL^T315I is insensitive to imatinib, dasatinib, nilotinib, and bosutinib
Ponatinib was demonstrated to have in vitro activity against BCR-ABL1^T315I and other resistant mutants. However, certain T315I-inclusive compound mutants exhibit high-level resistance. The extent to which T315I-inclusive compound mutations (eg, BCR-ABL1^E255V/T315I) reduce the effectiveness of ponatinib remains to be established. Ponatinib has demonstrated considerable clinical activity in patients with and without BCR-ABL^T315I, especially in the chronic phase of CML, but safety concerns prevents its use in second-line therapy, except in the case of BCR-ABL^T315I
Interferon-α may be considered in exceptional cases, but is generally ineffective in patients with disease resistant to tyrosine kinase inhibitors
Hydroxyurea is used for lowering excessively high white blood cell counts if the diagnosis is uncertain, and in the case of intolerance or resistance to tyrosine kinase inhibitors. Hydroxyurea is considered a palliative regimen, as it does not usually induce lasting responses
Although the Sokal score was developed in patients treated with chemotherapy, it also predicts the likelihood of achieving a complete cytogenetic response to imatinib (91% vs. 84% vs. 69% at 48 months for low-, intermediate-, and high-risk patients, respectively). Complete cytogenetic response is associated with a favorable outcome
The definitions of disease phases given above were used in the clinical trials of imatinib that led to regulatory approval. They are widely, but not universally, accepted
AML- or ALL-type chemotherapy is indicated for tyrosine kinase inhibitor-resistant CML in myeloid and lymphoid blast crisis, respectively. No data from controlled trials are available that demonstrate superiority of one regimen over another. All efforts should be made to proceed to allogeneic hematopoietic cell transplantation as soon as possible. Complete hematologic remission is achieved in 40–60% of patients

Cortes J et al. Am J Hematol 2013;88:350–354

Cortes J et al. Blood 2012;120:2573–2580

Cortes JE et al. N Engl J Med 2012;367:2075–2088

Derderian PM et al. Am J Med 1993;94:69–74

Druker BJ et al. N Engl J Med 2006;355:2408–2417

Jabbour E et al. Blood 2011;117:1822–1827

Jabbour E et al. Blood 2011;118:4541–4546

Kantarjian H et al. N Engl J Med 2006;354:2542–2551

Kantarjian HM et al. Lancet Oncol 2011;12:841–851

Kantarjian HM et al. Am J Med 1987;83:445–454

Kantarjian HM et al. Blood 2012;119:1123–1129

Kantarjian HM et al. N Engl J Med 2010;362:2260–2270

Khoury HJ et al. Blood 2012;119:3403–3412

Saglio G et al. N Engl J Med 2010;362:2251–2259

Talpaz M et al. N Engl J Med 2006;354:2531–2541

CML REGIMEN: IMATINIB

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CML Regimen: Imatinib

Deininger MWN et al. J Clin Oncol 2003;21:1637–1647

Chronic phase CML:

Initial dose:

Imatinib 400 mg/day; administer orally, continually, with the largest meal of the day (total dose/week = 2800 mg)

Dose escalation:

Escalate to Imatinib 600 mg/day; administer orally, continually, with the largest meal of the day (total dose/week = 4200 mg), if patient has not reached:

Complete hematologic response at 3 months, or
<95% Ph-negative metaphases at 6 months, or
<35% Ph-negative metaphases at 12 months

Accelerated phase and blast crisis CML

Initial dose:

Imatinib 600 mg/day; administer orally, continually, with the largest meal of the day (total dose/week = 4200 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Efficacy (Chronic phase, N = 553)^✫

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Efficacy (Chronic phase, N = 553)^✫

Complete hematologic response

98%

Complete cytogenetic response

87%

Partial cytogenetic response (1–35% Ph⁺ metaphases)

Freedom from progression to accelerated phase or blast crisis

93%

^✫Projected rates at 60 months

Druker BJ et al. N Engl J Med 2006;355:2408–2417

Treatment Modifications

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Treatment Modifications

Hematologic Toxicity (No Modifications for Anemia)

G1/2

No dose modifications

Hold imatinib until toxicity resolves to grade 1^✫, then restart at 400 mg/day

Recurrent G3

Hold imatinib until toxicity resolves to grade 1, then restart at 300 mg/day

Withhold imatinib until toxicity resolves to grade 1, then restart at 300 mg/day

Recurrent G4

Hold imatinib until toxicity resolves to grade 1, then restart at 300 mg/day^†

Nonhematologic Toxicity

No dose modifications

G2/3

Hold imatinib until toxicity resolves to grade 1, then restart at 400 mg/day

Recurrent G2/3

Hold imatinib until toxicity resolves to grade 1, then restart at 300 mg/day

Recurrent G4

Discontinue imatinib

^✫Consider filgrastim for persistent neutropenia

^†No dose reduction to <300 mg/day

Deininger MWN et al. J Clin Oncol 2003;21: 1637–1647

Therapy Monitoring

CBC: Weekly; every 2 weeks after achievement of complete hematologic response; every 4–6 weeks after achievement of a complete cytogenetic response
Blood chemistry: Weekly; every 4–8 weeks after achievement of complete hematologic response
Bone marrow cytogenetics: Every 3 months until complete cytogenetic response, then at 12- to 24-month intervals
Quantitative RT-PCR for BCR-ABL from peripheral blood or bone marrow: Every 3–6 months after achievement of complete cytogenetic response

Patient Population Studied

Study of 553 patients with newly diagnosed CML in chronic phase

Toxicity (In >10% of patients, N = 553)

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Toxicity (In >10% of patients, N = 553)

Toxicity

% G1/2

% G3/4

Superficial edema

54.6

0.9

Thrombocytopenia

48.8

7.8

Neutropenia

46.5

14.3

Nausea

0.7

Anemia

41.5

3.1

Increased liver transaminases

38.1

5.1

Muscle cramps

1.3

Musculoskeletal pain

33.8

2.7

Rash

31.9

2.0

Fatigue

33.4

1.1

Diarrhea

1.8

Headache

30.8

0.4

Joint pain

25.9

2.4

Abdominal pain

24.6

2.4

Nasopharyngitis

22.0

—

Myalgia

19.9

1.5

Hemorrhage

20.2

0.7

Vomiting

15.4

1.5

Dyspepsia

16.2

—

Pharyngolaryngeal pain

15.8

0.2

Cough

14.3

0.2

Dizziness

13.6

0.9

Upper respiratory infection

14.3

0.2

Weight gain

12.5

0.9

Pyrexia

12.4

0.7

Insomnia

12.2

—

O'Brien SG et al. N Engl J Med 2003;348:994–1004

Notes

In patients who develop disease progression while receiving imatinib, the option of allogeneic stem cell transplantation should be reevaluated

CML REGIMEN: DASATINIB

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CML Regimen: Dasatinib

Shah NP et al. J Clin Oncol 2008;26:3204–3212

Chronic phase CML:

Initial dose:

Dasatinib 100 mg/day; administer orally, continually, with or without a meal (total dose/week = 700 mg)

Dose escalation:

Escalate to dasatinib 140 mg/day; administer orally, continually, with or without a meal in case of insufficient response (total dose/week = 980 mg)

Accelerated phase and blast crisis CML:

Initial dose:

Dasatinib 140 mg/day; administer orally, continually, with or without meal (total dose/week = 980 mg)

Dose escalation:

Escalate to dasatinib 180 mg/day; administer orally, continually, with or without a meal in case of insufficient response (total dose/week = 1260 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 166 patients with CML in chronic phase resistant to or intolerant of imatinib

Therapy Monitoring

CBC: Weekly; every 2 weeks after achievement of complete hematologic response; every 4–6 weeks after achievement of complete cytogenetic response
Blood chemistry: Weekly; every 4–8 weeks after achievement of complete hematologic response
Bone marrow cytogenetics: Every 3 months until complete cytogenetic response, then at 12–24 months intervals
Quantitative RT-PCR for BCR-ABL from peripheral blood or bone marrow: Every 3–6 months after achievement of complete cytogenetic response

Efficacy (Chronic phase, N = 166)

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Efficacy (Chronic phase, N = 166)

Complete hematologic response^✫

90%

Complete cytogenetic response^†

41%

Partial cytogenetic response^† (1–35% Ph⁺ metaphases)

18%

Freedom from progression to accelerated phase or blast crisis

93%

^✫51% of patients were in CHR at entry

^†20% of patients were in major cytogenetic response at entry

Shah NP et al. J Clin Oncol 2008;26:3204–3212

Toxicity (In >10% of patients, N = 166)

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Toxicity (In >10% of patients, N = 166)

Toxicity

% G1/2

% G3/4

Anemia

Leukocytopenia

Neutropenia

Thrombocytopenia

Fluid retention

Superficial edema

Pleural effusion

Headache

Diarrhea

Fatigue

Nausea

Rash

Myalgia

Dyspnea

Peripheral edema

Shah NP et al. J Clin Oncol 2008;26:3204–3212

Treatment Modifications

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Treatment Modifications

Hematologic Toxicity: Chronic Phase (No Modifications for Anemia)

G1/2

No dose modifications

ANC <500/mm³^✫

Hold dasatinib until ANC ≥1000/mm³

Recovery within 7 days: resume at 100 mg/day

Recovery within >7 days or first recurrence: resume at 80 mg/day

Second recurrence: discontinue

Platelet count <50,000/mm³

Hold dasatinib until platelet count is ≥50,000/mm³

Recovery within ≤7 days: resume at 100 mg/day

Recovery within >7 days or first recurrence: resume at 80 mg/day

Second recurrence: discontinue drug

Platelet count <25,000/mm³

Hold dasatinib until platelet count is ≥50,000/mm³ and resume at 80 mg/day

First recurrence: Hold dasatinib until platelet count is ≥50,000/mm³ and resume at 80 mg/day

Second recurrence: discontinue drug

Hematologic Toxicity: Accelerated or Blastic Phase

G1–3

No dose modifications

G4–first occurrence

If cytopenia is unrelated to leukemia (bone marrow assessment), hold dasatinib until recovery to platelet count ≥20,000/mm³ and ANC ≥1000/mm³ and resume at 140 mg/day^†

G4–second occurrence

Hold dasatinib until recovery to platelet count ≥20,000/mm³ and ANC ≥1000/mm³, and resume at 100 mg/day

G4–third occurrence

Hold dasatinib until recovery to platelet count ≥20,000/mm³ and ANC ≥1000/mm³, and resume at 80 mg/day

Nonhematologic Toxicity

No dose modifications

G2/3

Hold dasatinib until toxicity resolves to grade 1, then restart at 100 mg/day

Recurrent G2/3

Hold dasatinib until toxicity resolves to grade 1, then restart at 80 mg/day

Recurrent G4

Discontinue dasatinib

^✫Consider filgrastim for persistent neutropenia

^†Consider dose escalation to 180 mg/day in case of leukemia-related cytopenia

http://packageinserts.bms.com/pi/pi_sprycel.pdf (last accessed Dec. 19, 2011)

CML REGIMEN: NILOTINIB

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CML Regimen: Nilotinib

le Coutre P et al. Blood 2008;111:1834–1839

Chronic phase CML:

Nilotinib 400 mg; administer orally twice daily, continually, at least 2 hours after the last and 1 hour before the next meal

Accelerated phase CML:

Nilotinib 400 mg; administer orally twice daily, continually, at least 2 hours after the last and 1 hour before the next meal

Note: Dose escalation is not indicated

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 280 patients with CML in chronic phase resistant to or intolerant of nilotinib

Toxicity (In >10% of patients, N = 280)

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Toxicity (In >10% of patients, N = 280)

Toxicity

% G1/2

% G3/4

Thrombocytopenia

Neutropenia

Rash

Pruritus

Headache

Fatigue

Constipation

Diarrhea

Vomiting

Nausea

LeCoutre P et al. Blood 2008;111:1834–1839

Treatment Modifications

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Treatment Modifications

Hematologic Toxicity (No Modifications for Anemia)

G1/2

No dose modifications

G3/4

Hold nilotinib until toxicity resolves to grade 2

Recovery within 2 weeks: restart at 400 mg twice daily

Recovery within >2 weeks: restart at 400 mg/day

Nonhematologic Toxicity (Noncardiac)

G1/2

No dose modifications

G3/4

Hold nilotinib until toxicity resolves to grade 1, then restart at 400 mg/day

If tolerated, consider re-escalation to 400 mg twice daily

QT Prolongation

QTcF >480 msec

Hold nilotinib and correct any hypokalemia and/or hypomagnesemia

QTcF <450 msec and within 20 msec of baseline within 2 weeks: resume at 400 mg twice daily

QTcF 450–480 msec: resume at 400 mg/day; if recurrence of QTcF >480 msec, discontinue nilotinib

http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf (last accessed, Dec. 19, 2011)

Therapy Monitoring

CBC: Weekly; every 2 weeks after achievement of complete hematologic response; every 4–6 weeks after achievement of complete cytogenetic response
Blood chemistry: Weekly; every 4–8 weeks after achievement of complete hematologic response
Bone marrow cytogenetics: Every 3 months until complete cytogenetic response, then at 12–24-month intervals
Quantitative RT-PCR for BCR-ABL from peripheral blood or bone marrow: Every 3–6 months after achievement of complete cytogenetic response

Efficacy (Chronic phase, N = 280)

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Efficacy (Chronic phase, N = 280)

Complete hematologic response^✫

74%

Complete cytogenetic response^✫

31%

Partial cytogenetic response^✫ (1–35% Ph⁺ metaphases)

16%

^✫Only patients without response at baseline

le Coutre P et al. Blood 2008;111:1834–1839

Notes

Hypokalemia and hypophosphatemia should be corrected before initiating nilotinib therapy and serum electrolyte levels monitored during nilotinib treatment
EKG monitoring for QT prolongation is indicated at baseline, within 7 days after initiating therapy or changing the dose, and periodically thereafter
The Fridericia correction of the QT interval (QTcF) should be used for all calculations

REFRACTORY PHILADELPHIA CHROMOSOME-POSITIVE CML REGIMEN: PONATINIB (ICLUSIG)

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Refractory Philadelphia Chromosome-Positive CML Regimen: Ponatinib (ICLUSIG)

Cortes JE et al. N Engl J Med 2012;367:2075–2088

Ponatinib hydrochloride 45 mg/day; administer orally with or without food, continually for 28 consecutive days, on days 1–28, every 4 weeks (total dose/28-day cycle = 1260 mg)

Notes:

On the basis of safety, pharmacokinetic, and pharmacodynamic data, 45 mg of ponatinib was determined to be the maximum tolerated dose
The optimal dose of ponatinib has not been identified. In clinical trials, the starting dose of ponatinib was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy
More safety information will become available with additional analysis and follow-up
Start dosing with 45 mg once daily. Consider reducing the dose of ponatinib for CP CML and AP CML patients who have achieved a major cytogenetic response
The recommended dose should be reduced to 30 mg once daily when administering ponatinib with strong CYP3A subfamily inhibitors

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

United States Food and Drug Administration (US FDA): Safety Announcement, 12-20-2013

The U.S. Food and Drug Administration (FDA) is requiring several new safety measures for the leukemia drug Iclusig (ponatinib) to address the risk of life-threatening blood clots and severe narrowing of blood vessels. Once these new safety measures are in place, the manufacturer of Iclusig is expected to resume marketing to appropriate patients. Healthcare professionals should review these additional safety measures and carefully consider them when evaluating the risks and benefits of Iclusig for each patient

The required safety measures involve label changes to narrow the indication, provide additional warnings and precautions about the risk of blood clots and severe narrowing of blood vessels, revise recommendations about dosage and administration of Iclusig, and update the patient Medication Guide. We are also requiring a risk evaluation and mitigation strategy (REMS). In addition, the manufacturer of Iclusig, ARIAD Pharmaceuticals, must conduct postmarket investigations to further characterize the drug's safety and dosing

On October 31, 2013, FDA requested and ARIAD agreed to voluntarily suspend marketing of Iclusig. FDA's request resulted from FDA's investigation, which revealed a steady increase in the number of serious vascular occlusion events identified through continued safety monitoring of the drug. This observation represented a significant change in the safety profile of Iclusig as the proportion of patients on the drug experiencing vascular occlusion events such as blood clots and severe narrowing of blood vessels was significantly greater than the proportion reported at the time of its approval in December 2012

During the marketing suspension, Iclusig treatment has been available through single patient or emergency investigational new drug applications (INDs). Patients should continue to receive Iclusig under their authorized IND until marketing of Iclusig is resumed. FDA is working closely with ARIAD on the new safety measures and anticipates these will be in place by the end of January 2014. Once that process is complete, patients being treated under these INDs can be transitioned back to receiving the marketed Iclusig product. In more detail, the new safety measures for Iclusig include the following:

The indications for use are limited to:
- Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL)
- Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph⁺ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated
The Warnings and Precautions in the label are revised to describe the vascular occlusion events. This includes a description of the observed arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with Iclusig
The Dosage and Administration recommendations are revised to state that the optimal dose of Iclusig has not been identified. The recommended starting dose remains 45 mg administered orally once daily with or without food; however, additional information is included regarding dose decreases and discontinuations
The patient Medication Guide is revised to include additional safety information consistent with the safety information in the revised drug label
The Iclusig REMS will inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug
We urge healthcare professionals and patients to report side effects involving Iclusig to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page

European Medicines Agency Recommendations: November 22, 2013

Following a review of the data on the risk of occlusive vascular events with Iclusig, the European Medicines Agency has concluded that healthcare professionals may continue to use ponatinib in its authorized indication with increased caution. The Agency has made the following recommendations:

Iclusig should not be used in patients with a history of heart attack or stroke, unless the potential benefits of treatment outweigh the risks
The cardiovascular status of patients should be assessed and cardiovascular risk factors actively managed before starting treatment with Iclusig. Cardiovascular status should continue to be monitored and optimized during treatment
Hypertension should be controlled during treatment with Iclusig and healthcare professionals should consider interrupting treatment if hypertension is not controlled
Patients should be monitored for evidence of vascular occlusion or thromboembolism, and treatment should be interrupted immediately if this occurs

The recommendations are based on a review of data from clinical studies, including 2 ongoing studies (a phase I dose-finding study and a pivotal phase II study), which showed a higher incidence of arterial and venous thrombotic events in patients treated with Iclusig than was observed at the time of marketing authorization. In the phase I study, preliminary analysis of follow-up data from September 2013 showed a rate of serious occlusive vascular events of 22% (18 out of 81 patients) while in a preliminary analysis of data from the phase II study the rate was 13.8% (62 out of 449 patients). Median treatment duration was 2.7 years in the phase I study and 1.3 years in the phase II study

In addition, in a recently discontinued phase III study that compared Iclusig with imatinib with a median treatment duration of 3 months, there was a higher number of occlusive vascular events reported in the Iclusig arm, although the data from this study are still preliminary

The reported events from the studies include cardiovascular, cerebrovascular, peripheral vascular and venous thrombotic events. These events were seen in patients with and without risk factors but were seen more frequently in older patients and patients with a history of ischaemia (such as heart attacks) and strokes, high blood pressure, diabetes or blood fat disorders

Changes in Prescribing Information for Iclusig (Ponatinib) as of 12/2013 in Accordance with Fda Guidelines:

Boxed Warning

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

Vascular Occlusion:

Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events
Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit–risk consideration should guide a decision to restart Iclusig therapy

Heart Failure:

Heart failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure

Hepatotoxicity:

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected

Indications and Usage

Iclusig (ponatinib) is a kinase inhibitor indicated for the:
- Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) and T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL)
- Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph⁺ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig
Dosage and Administration
- 2.1. Recommended Dosing
  - The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy
  - Start dosing with 45 mg once daily. Consider reducing the dose of Iclusig for CP CML and AP CML patients who have achieved a major cytogenetic response
  - Consider discontinuing Iclusig if response has not occurred by 3 months (90 days)
  - Iclusig may be taken with or without food. Tablets should be swallowed whole

Warnings and Precautions

3.1. Vascular Occlusion

Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. Iclusig can also cause recurrent or multisite vascular occlusion

In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph⁺ ALL developed vascular occlusive events. The median time to onset of the first vascular occlusion event was 5 months. Iclusig can cause fatal and life-threatening vascular occlusion in patients treated at dose levels as low as 15 mg per day

Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table)

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Vascular Occlusion Incidence in Iclusig-Treated Patients in Phase II Trial According to Risk Categories

Prior History of Ischemia, Hypertension, Diabetes, or Hyperlipidemia

No History of Ischemia, Hypertension, Diabetes, or Hyperlipidemia

Age: 49 or younger

18% (6/33)

12% (13/112)

Age: 50 to 74 years

33% (50/152)

18% (20/114)

Age: 75 and older

56% (14/25)

46% (6/13)

All age groups

33% (70/210)

16% (39/239)

Total

24% (109/449)

Arterial Occlusion and Thrombosis

Arterial occlusion and thrombosis occurred in at least 20% (91/449) of Iclusig-treated patients with some patients experiencing events of more than 1 type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) because of vascular occlusion from Iclusig

Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 12% (55/449) of Iclusig-treated patients, Patients have developed heart failure concurrent or subsequent to themyocardial ischemic event

Cerebrovascular occlusion, including fatal stroke has occurred in 6% (27/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (eg, carotid, vertebral, middle cerebralartery)

Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease have occurred in 8% (36/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations

Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial thrombotic events, interrupt or stop Iclusig. A benefit–risk consideration should guide a decision to restart Iclusig therapy

Venous Thromboembolism

Venous thromboembolic events occurred in 5% (23/449) of Iclusig-treated patients, including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism

3.2. Heart Failure
- Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (N = 22). Eight percent of patients (N = 35) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure
3.3. Hypertension
- Treatment-emergent hypertension occurred in 67% of patients (300/449). Eight patients (2%) treated with Iclusig in clinical trials experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensivecrisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP <140 mm Hg and baseline diastolic BP <90 mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled
3.4. Neuropathy
- Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4)
- Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected
3.5. Ocular Toxicity
- Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients
- Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

1st arterial thrombotic event

Interrupt and consider discontinuation of ponatinib

2nd arterial thrombotic event

Discontinue ponatinib

1st episode of G3/4 hepatotoxicity

Interrupt and then reduce or discontinue ponatinib

2nd episode of G3/4 hepatotoxicity

Discontinue ponatinib

First occurrence of ANC <1 × 10⁹/L or platelet <50 × 10⁹/L

Interrupt ponatinib and resume initial 45 mg dose after recovery to ANC ≥1.5 × 10⁹/L and platelet ≥75 × 10⁹/L

Second occurrence of ANC <1 × 10⁹/L or platelet <50 × 10⁹/L

Interrupt ponatinib and resume at 30 mg after recovery to ANC ≥1.5 × 10⁹/L and platelet ≥75 × 10⁹/L

Third occurrence of ANC <1 × 10⁹/L or platelet <50 × 10⁹/L

Interrupt ponatinib and resume at 15 mg after recovery to ANC ≥1.5 × 10⁹/L and platelet ≥75 × 10⁹/L

Elevation of liver transaminase >3 × ULN (G ≥2) at a ponatinib dose of 45 mg

Discontinue ponatinib and monitor hepatic function. Resume ponatinib at 30 mg after recovery to G ≤1 (<3 × ULN)

Elevation of liver transaminase >3 × ULN (G ≥2) at a ponatinib dose of 30 mg

Discontinue ponatinib and monitor hepatic function. Resume ponatinib at 15 mg after recovery to G ≤1 (<3 × ULN)

Elevation of liver transaminase >3 × ULN (G ≥2) at a ponatinib dose of 15 mg

Discontinue ponatinib

Elevation of liver transaminase >3 × ULN (G ≥2) concurrent with an elevation of bilirubin >2 × ULN and alkaline phosphatase <2 × ULN

Discontinue ponatinib

Asymptomatic G1/2 elevation of serum lipase

Consider interruption or dose reduction of ponatinib

Asymptomatic G3/4 elevation of lipase (>2 × ULN) or asymptomatic radiologic pancreatitis (G2 pancreatitis) at a ponatinib dose of 45 mg

Interrupt ponatinib and resume at 30 mg after recovery to G ≤1 (<1.5 × ULN)

Asymptomatic G3/4 elevation of lipase (>2 × ULN) or asymptomatic radiologic pancreatitis (G2 pancreatitis) at a ponatinib dose of 30 mg

Interrupt ponatinib and resume at 15 mg after recovery to G ≤1 (<1.5 × ULN)

Asymptomatic G3/4 elevation of lipase (>2 × ULN) or asymptomatic radiologic pancreatitis (G2 pancreatitis) at a ponatinib dose of 15 mg

Discontinue ponatinib

Symptomatic G3 pancreatitis at a ponatinib dose of 45 mg

Interrupt ponatinib and resume at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to G ≤1

Symptomatic G3 pancreatitis at a ponatinib dose of 30 mg

Interrupt ponatinib and resume at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to G ≤1

Symptomatic G3 pancreatitis at a ponatinib dose of 15 mg

Discontinue ponatinib

G4 pancreatitis

Discontinue ponatinib

Notes:

Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in ponatinib-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of ponatinib-treated patients. Interrupt and consider discontinuation of ponatinib in patients who develop arterial thrombotic events

Hepatic Toxicity: Hepatotoxicity, liver failure and death have occurred in ponatinib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ponatinib for hepatotoxicity

Efficacy

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Efficacy

Philadelphia Chromosome–Positive CML

Chronic Phase (N = 43)

Accelerated Phase (N = 9)

Blast Phase (N = 8)

Received treatment

43 (100)

9 (100)

8 (100)

Continuing treatment at time of analysis

33 (77)

2 (22)

Median follow up (range, weeks)

73 (7–140)

13 (2–121)

Discontinued treatment

10 (23)

7 (78)

8 (100)

Documented progressive disease

3 (7)

1 (11)

5 (62)

Adverse event

5 (12)

3 (33)

Death

1 (11)

1 (12)

Withdrawal of consent

1 (2)

1 (11)

Administrative decision

1 (2)

1 (11)

2 (25)

Variable

Chronic-Phase CML

Accelerated-Phase CML, Blast-Phase CML, and PH-Positive ALL (N = 22)

Mutation (Number of Patients)

All (43)^✫

T315I (12)

Other (15)

None (13)

All (22)^†

T315I (7)

Other (8)

None (5)

Complete hematologic response

42 (98)^‡

12 (100)

14 (93)

13 (100)

Major hematologic response

8 (36)

2 (29)

2 (25)

3 (60)

Major cytogenetic response

31 (72)^§

11 (92)

10 (67)

8 (62)

7 (32)

2 (29)

3 (38)

2 (40)

Complete cytogenetic response

27 (63)

9 (75)

10 (67)

6 (46)

3 (14)

1 (14)

2 (40)

Partial cytogenetic response

4 (9)

2 (17)

2 (15)

4 (18)

1 (14)

3 (38)

Major molecular response

19 (44)

8 (67)

8 (53)

2 (15)

2 (9)

2 (29)

Molecular response 4

9 (21)

3 (25)

6 (40)

Molecular response 4.5

3 (7)

3 (20)

NA denotes not applicable

^✫Sequencing data were not available for 3 patients with chronic-phase CML; all 3 had a complete hematologic response, 2 had a major cytogenetic response (both complete), and 1 had a major molecular response

^†Sequencing data were not available for 1 patient with accelerated-phase CML and 1 patient with blast-phase CML; the former patient had a major hematologic response

^‡Of these patients, 26 had a complete hematologic response at baseline, and all 26 remained in complete hematologic response during the study

^§At baseline, 1 patient had a complete hematologic response and a molecular relapse. This patient had a major molecular response during the study. Eight patients had a partial cytogenetic response at entry; of these patients, 7 had a complete cytogenetic response during the study, and 1 maintained a partial cytogenetic response

Molecular response 4 was defined as at least a 4-log reduction, or a transcript ratio of BCR-ABL to ABL ≤0.01% (expressed as a percentage on the International Scale) in peripheral blood, as measured on quantitative reverse-transcriptase–polymerase-chain-reaction assay. Molecular response 4.5 indicates that the ratio is <0.0032%

Toxicity

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Toxicity

Most Frequent Treatment-Related Adverse Events (AEs)^✫ Treatment-Related Adverse Events Total Study Population (N = 81)

Any Grade

G ≥3

Serious

Number of Patients (Percent)

Nonhematologic Event

Rash^†

26 (32)

1 (1)

Arthralgia

14 (17)

1 (1)

Increased lipase

12 (15)^‡

6 (7)

Fatigue

11 (14)

1 (1)

Acneiform dermatitis

11 (14)

1 (1)

Dry skin

11 (14)

Nausea

11 (14)

Headache

10 (12)

Hypertriglyceridemia

10 (12)

Myalgia

10 (12)

Pancreatitis^§

11 (14)

4 (5)

8 (10)

Abdominal pain

8 (10)

1 (1)

Increased alanine aminotransferase

8 (10)

1 (1)

Increased aspartate aminotransferase

7 (9)

1 (1)

Abdominal distention

3 (4)

1 (1)

Increased amylase

3 (4)

2 (2)

Chills

3 (4)

1 (1)

Dyspnea

3 (4)

1 (1)

Prolonged QT interval

3 (4)

2 (2)

1 (1)

Erythema nodosum

2 (2)

1 (1)

Increased creatine kinase

1 (1)

Congestive cardiac failure

1 (1)

Decreased ejection fraction

1 (1)

Fluid retention

1 (1)

Interstitial lung disease

1 (1)

Melanoma

1 (1)

Migraine

1 (1)

Pain

1 (1)

Accidental overdose

1 (1)

Cardiomyopathy

1 (1)

Hematologic Event

Thrombocytopenia

22 (27)

16 (20)

1 (1)

Neutropenia

10 (12)

8 (10)

Anemia

8 (10)

2 (2)

Lymphopenia

3 (4)

1 (1)

Decreased white-cell count

3 (4)

1 (1)

^✫Treatment-related AEs were graded by the NCI Common Terminology Criteria for Adverse Events (v.3) and defined as events investigators deemed to have a possible, probable, or definite relationship to ponatinib. Listed are treatment-related AEs reported in ≥10% of patients, along with any G ≥3 or serious events

^†Rash includes erythematous and papular rash

^‡A G1 increase in the lipase level deemed probably not related to ponatinib occurred in 1 patient

^§Included in this category is 1 patient who had 3 events of pancreatitis (all G2; all serious) that were deemed to either not related or probably not related to ponatinib. One event was changed to G3 and possibly related to ponatinib after the database cutoff

Patient Population Studied

Patients with a diagnosis of CML whose disease had relapsed or was resistant to standard care, or for which no standard care was available or acceptable. Ph-positive disease was classified and characterized as relapsed or refractory disease on the basis of standard criteria. In addition, patients were required to have an Eastern Cooperative Oncology Group performance status of 2 or lower

Treatment Monitoring

Complete blood counts (CBCs) and leukocyte differential counts should be performed weekly during the first 3 cycles, then every second week during subsequent cycles
Serum ALT, AST, alkaline phosphatase, lipase, and (pancreatic) amylase at baseline and weekly during the first 2 cycles, then every second week during subsequent cycles

REFRACTORY PHILADELPHIA CHROMOSOME–POSITIVE CML REGIMEN: BOSUTINIB

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Refractory Philadelphia Chromosome–Positive CML Regimen: Bosutinib

Khoury HJ et al. Blood 2012;119:3403–3412

Bosutinib 500 mg/day; administer orally with food, continually (total dose/week = 3500 mg)

Notes:

If a dose is missed by more than 12 hours, the patient should skip the dose and resume taking the usual prescribed dose on the following day
Consider dose escalation from 500 mg daily to 600 mg once daily with food in patients who do not reach complete hematologic response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, and who did not have G ≥3 adverse reactions
Use in Hepatic Impairment: In patients with pre-existing mild, moderate, and severe hepatic impairment (Child-Pugh classes A, B, and C, respectively), the recommended dose of bosutinib is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in systemic exposure (area under the concentration curve; AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML
Concomitant Use With CYP3A Inhibitors: Avoid the concomitant use of strong or moderate CYP3A subfamily and/or P-glycoprotein (P-gp, ABCB1, MDR1) inhibitors with bosutinib as an increase in bosutinib plasma concentration is expected
1. Strong CYP3A inhibitors include: boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, and telithromycin
2. Moderate CYP3A inhibitors include: amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit products, imatinib, and verapamil
Concomitant Use With CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers with bosutinib as a large reduction in exposure is expected
1. Strong CYP3A inducers include: carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort
2. Moderate CYP3A inducers include: bosentan, efavirenz, etravirine, modafinil, and nafcillin

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Treatment Modification

AST/ALT >5 × ULN

Withhold bosutinib until AST/ALT ≤2.5 × ULN, then resume use at 400 mg once daily

AST/ALT >5 × ULN >4 weeks

Discontinue bosutinib

AST/ALT ≤3 × ULN concurrently with bilirubin elevations >2 × ULN and alkaline phosphatase <2 × ULN (Hy's law case definition)

Discontinue bosutinib

G3/4 diarrhea (≥7 stools/day over baseline/pretreatment)

Withhold bosutinib until recovery to G ≤1 and resume at 400 mg once daily

Other G3/4 nonhematologic toxicity

Withhold bosutinib until recovery to G ≤1, then resume use at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of bosutinib to 500 mg once daily

1st episode of ANC <1000 × 10⁶/L or platelets <50,000 × 10⁶/L with recovery in <2 weeks

Withhold bosutinib until ANC ≥1000 × 10⁶/L and platelets ≥50,000 × 10⁶/L Resume treatment with bosutinib at the same dose

2nd episode of ANC <1000 × 10⁶/L or platelets <50,000 × 10⁶/L with recovery in <2 weeks

Withhold bosutinib until ANC ≥1000 × 10⁶/L and platelets ≥50,000 × 10⁶/L then resume bosutinib at a dose 100 mg less than the dose previously administered

ANC <1000 × 10⁶/L or platelets <50,000 × 10⁶/L with recovery in <2 weeks

Withhold bosutinib until ANC ≥1000 × 10⁶/L and platelets ≥50,000 × 10⁶/L, then resume bosutinib use at a dose 100 mg less than the dose previously administered

Fluid retention (pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema)

Monitor and manage patients using standards of care. Interrupt, decrease the dose, or discontinue bosutinib as necessary

Efficacy

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Efficacy

Response, n (%)

IM + DAS Resistant (n = 37)

IM + DAS Intolerant (n = 50)

IM + NI Resistant (n = 27)

IM + DAS + NI (n = 4)^✫

Total (n = 118)

Median follow-up, mo

Median follow-up, (range)

(2.7–51.3)

34.5

(0.3–56.2)

(7.1–54)

34.5

(22.8–40)

28.5

(0.3–56.2)

Hematologic Response^†

Evaluable patients

116

Complete response

23 (62)

39 (80)

20 (77)

3 (75)

85 (73)

Hematologic Response Among Patients with no Baseline CHR

Evaluable patients

Complete response

11 (50)

16 (67)

15 (75)

2 (100)

44 (65)

Cytogenetic Response^‡

Evaluable patients

108

Major response

11 (31)

13 (30)

9 (35)

2 (50)

35 (32)

Complete response

5 (14)

12 (28)

7 (27)

2 (50)

26 (24)

Partial response

6 (17)

1 (2)

2 (8)

9 (8)

Minor response

4 (9)

2 (8)

6 (6)

Molecular response^§

Evaluable patients

105

Major response

1 (3)

12 (25)

2 (11)

1 (33)

16 (15)

Complete response

9 (19)

2 (11)

1 (33)

12 (11)

DAS, dasatinib; IM, imatinib; NI, nilotinib; CHR, complete hematologic response

^✫Includes 3 patients who previously received all 3 inhibitors and 1 patient with NI intolerance

^†Evaluable patients had a baseline disease assessment. Patients with CHR at baseline were evaluable for hematologic response and were considered responders if they maintained their response at 2 consecutive postbaseline assessments ≥4 weeks apart

^‡Evaluable patients had a baseline disease assessment. Patients with CCyR at baseline were considered nonresponders for assessment of cytogenetic response

^§Because of logistical constraints, patients from sites in China, India, Russia, and South Africa were not assessed for molecular response. MMR indicates ≥3 log reduction from standardized baseline Bcr-Abl: Abl ratio, and CMR, undetectable Bcr-Abl, with a sensitivity of ≥5 log. Molecular response was not assessed according to the International Scale

Response by Baseline Mutation Status

Cumulative Response, n/n Evaluable (%)

Mutation Status

CHR

MCyR

No mutation

34/44 (77)

15/43 (35)

Any mutation

26/39 (67)

11/35 (31)

>1 mutation

3/9 (33)

2/9 (22)

Mutation type^✫

P-loop^†

9/14 (64)

4/13 (31)

G250E

3/6

0/5

Y253H

5/6

4/6

E255K

0/1

E255V

1/1

0/1

Non–P-loop^‡

18/29 (62)

9/26 (35)

M244V

3/3

2/3

V299L

1/2

0/2

Q300R

1/1

T315I

2/7

0/6

F317L

4/8

1/7

N336S

1/1

0/1

M351T

1/1

0/1

F359C

2/2



F359I

2/2

F359V

0/2



L387F

1/1

0/1

H396R

0/1

E453A

1/1

0/0

C475V

1/1

F486S

0/1

^✫Patients with >1 mutation may be counted in both the P-loop and non–P-loop categories

^†P-loop mutations include those from positions 248 to 255

^‡Non–P-loop mutations include those from positions 244 to 247 and >255

Patient Population Studied

Study patients represented a subpopulation of adults with a confirmed diagnosis of Ph⁺ chronic-phase CML who previously received treatment with imatinib followed by dasatinib and/or nilotinib. All had an Eastern Cooperative Oncology Group performance status of 0 or 1, and no allogeneic hematopoietic stem cell transplantation within 3 months before starting study treatment. All patients had previously received imatinib and developed primary or acquired resistance or intolerance to imatinib, and had also received and developed resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as failure to achieve or maintain any of the following with previously administered treatments: hematologic improvement within 4 weeks, CHR after 12 weeks, any cytogenetic response by 24 weeks, or MCyR by 12 months. Acquired resistance was defined as loss of a MCyR or any hematologic response. Patients could also have resistance related to Bcr-Abl mutations. Intolerance was defined as an inability to take a protein kinase inhibitor because of drug-related G4 hematologic toxicity lasting more than 7 days, drug-related G3/4 nonhematologic toxicity, persistent G2 toxicity that did not respond to dose reduction and medical management, or loss of previously attained response on lower doses of protein kinase inhibitor therapy with an inability to receive a higher dose because of drug-related toxicity at higher doses

Phase 1/2, open-label, multicenter, 2-part study. The phase 1 (part 1) dose-escalation study enrolled patients with chronic phase CML previously treated with only imatinib. It determined the part 2 starting dose of bosutinib 500 mg/day, despite not reaching a study-defined maximum tolerated dose. Part 2 of the study evaluated the efficacy and safety of bosutinib across multiple patient subpopulations, including those with chronic-phase CML who had been previously treated with imatinib and dasatinib and/or nilotinib. The primary analysis in the subpopulation of patients with chronic-phase CML previously treated with multiple protein kinase inhibitors was MCyR by 24 weeks

Treatment Monitoring

Complete blood counts (CBCs) and leukocyte differential counts should be performed weekly during the first month after starting bosutinib, and at least monthly thereafter
Serum hepatic enzymes monthly during the first 3 months after starting bosutinib, and as clinically indicated thereafter. Increase the frequency of monitoring if hepatic transaminases increase after starting treatment

Toxicity

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Toxicity

Dose interruptions and reductions resulting from AEs were required for 63% and 48% of patients, respectively. Twenty-four (20%) patients discontinued bosutinib because of AEs as shown in Table

IM + DAS Resistant (n = 37)

IM + DAS Intolerant (n = 50)

IM + NI Resistant (n = 27)

IM + DAS + NI (n = 4)^✫

Total (n = 118)

Reason, n (%)

Discontinued treatment

31 (84)

34 (68)

16 (59)

3 (75)

84 (71)

Unsatisfactory response

12 (32)

7 (14)

5 (19)

1 (25)

25 (21)

Adverse event^†

6 (16)

15 (30)

3 (11)

24 (20)

Disease progression

8 (22)

4 (8)

6 (22)

2 (50)

20 (17)

Death

2 (5)

2 (4)

4 (3)

Patient request

2 (4)

1 (4)

3 (3)

Lost to follow-up

2 (5)

2 (2)

Investigator request

1 (4)

1 (1)

Protocol violation

1 (2)

1 (1)

Other^‡

1 (3)

3 (6)

4 (3)

DAS, dasatinib; IM, imatinib; NI, nilotinib

^✫Includes 3 patients who previously received all 3 inhibitors and 1 patient with NI intolerance

^†AEs most frequently leading to discontinuation included thrombocytopenia (4%), neutropenia (3%), and elevated ALT (3%). Of note, 6 patients were in MCyR at the time that they discontinued treatment because of an AE

^‡Includes patient noncompliance (n = 2), lack of finances (n = 1), and started chemotherapy for gastric adenocarcinoma (n = 1)

Treatment-Related AEs Occurring in >10% of Patients

All Grades, n (%)

Grade 3/4, n (%)

Diarrhea

96 (81)

10 (8)

Nausea

51 (43)

Vomiting

38 (32)

1 (1)

Rash

26 (22)

5 (4)

Fatigue

21 (18)

1 (1)

Abdominal pain

18 (15)

Headache

16 (14)

1 (1)

Upper abdominal pain

15 (13)

Pruritus

12 (10)

1 (1)

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Toxicity

Laboratory Abnormalities Reported by >20% of Patients on Therapy

At Baseline

On Therapy

All G, n (%)

G3/4, n (%)

All G, n (%)

G3/4, n (%)

Laboratory Abnormality

Anemia

66 (56)

1 (1)

99 (84)

10 (8)

Thrombocytopenia^✫

20 (17)

1 (1)

69 (58)

30 (25)

Elevated ALT^✫

12 (10)

58 (49)

8 (7)

Neutropenia^✫

23 (19)

4 (3)

54 (46)

23 (19)

↑Creatinine

13 (11)

50 (42)

1 (1)

↑ AST

15 (13)

48 (41)

4 (3)

Hypocalcemia

8 (7)

1 (1)

44 (37)

6 (5)

↑ Alkaline phosphatase

12 (10)

41 (35)

Hypophosphatemia

8 (7)

37 (31)

3 (2)

Hyperglycemia

15 (13)

36 (31)

1 (1)

Low bicarbonate

4 (3)

36 (31)

Hypermagnesemia

11 (9)

9 (8)

34 (29)

14 (12)

↑ PTT

16 (14)

30 (25)

1 (1)

↑ Lipase

7 (6)

28 (24)

8 (7)

Hyperkalemia

3 (3)

1 (1)

27 (23)

^✫Dose interruptions and reductions resulting from AEs were required for 63% and 48% of patients, respectively. AEs most frequently leading to discontinuation included thrombocytopenia (4%), neutropenia (3%), and elevated ALT (3%)

Reason Dasatinib Intolerant

Number Dasatinib Intolerant

Same G3/4 AE with Bosutinib as with Dasatinib

Discontinued Bosutinib Because of Same AE with Bosutinib as with Dasatinib

Any AE^✫

11 (22)

4 (8)

Hematologic events

8 (40)

2 (10)

Thrombocytopenia

6 (75)

1 (13)

Pancytopenia

Neutropenia

4 (100)

1 (25)

Cardiovascular events

0^‡

1 (33)

Gastrointestinal events

0^‡

Diarrhea

0^‡

Musculoskeletal events

0^‡

Respiratory events

3 (13)

1 (4)

Pleural effusion

2 (11)^†

0 ^†

Dyspnea

1 (33)

Skin disorders

0^‡

^✫Includes all AEs with ≥3 patients categorized as intolerant on prior dasatinib

^†Two patients had G3/4 pleural effusions on bosutinib (at days 597 and 967 of treatment), but neither discontinued bosutinib because of a pleural effusion

^‡No patient with dasatinib intolerance related to cardiovascular events, gastrointestinal events, musculoskeletal events, or skin disorders experienced the same toxicity as a G3/4 AE on bosutinib

REFRACTORY PHILADELPHIA CHROMOSOME–POSITIVE CML REGIMEN: CHRONIC OR ACCELERATED PHASE CHRONIC CML WITH RESISTANCE AND/OR INTOLERANCE TO 2 OR MORE TYROSINE KINASE INHIBITORS (TKIs): OMACETAXINE MEPESUCCINATE

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Refractory Philadelphia Chromosome–Positive CML Regimen: Chronic or Accelerated Phase Chronic CML with Resistance and/or Intolerance to 2 or More Tyrosine Kinase Inhibitors (TKIS): Omacetaxine Mepesuccinate

Cortes J et al. Am J Hematol 2013;88:350–354

Cortes J et al. Blood 2012;120:2573–2580

Omacetaxine mepesuccinate 1.25 mg/m² per dose by subcutaneous injection:

Induction regimen schedule

Doses are given twice daily for 14 consecutive days, on days 1–14, every 28 days until patients achieve a hematologic response (total dosage/28-day cycle = 35 mg/m²)

Maintenance regimen schedule

Doses are given twice daily for 7 consecutive days, on days 1–7, every 28 days for as long as patients experience clinical benefit from treatment (total dosage/28-day cycle = 17.5 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

The efficacy of omacetaxine mepesuccinate was evaluated using a combined cohort of adult patients with CML from 2 trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as 1 of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (ie, 100% Ph-positive [Ph⁺]) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (ie, ≥35% Ph⁺) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as 1 of the following: (a) G3/4 nonhematologic toxicity that did not resolve with adequate intervention; (b) G4 hematologic toxicity lasting more than 7 days; or (c) any G ≥2 toxicity unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia, or other uncontrolled cardiac conditions were excluded

A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 30% were 65 years of age or older. All had previously received 2 or more TKIs, including imatinib. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%)

Treatment Modifications

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Treatment Modifications

G4 neutropenia (ANC <0.5 × 10⁹/L) or G3 thrombocytopenia (<50 × 10⁹/L) during a cycle

Delay start of next cycle until ANC ≥1 × 10⁹/L and platelet count ≥50 × 10⁹/L. Also, for the next cycle, reduce the number of dosing days by 2 days (eg, to 12 or 5 days)

G3/4 non-hematologic toxicity

Interrupt and/or delay omacetaxine mepesuccinate until toxicity is G ≤1. Also, for the next cycle, reduce the number of dosing days by 2 days (eg, to 12 or 5 days)

G2 AE unresponsive to supportive care

Interrupt treatment until G ≤1 then resume omacetaxine mepesuccinate at full dose

G ≥3 AE unresponsive to supportive care

Interrupt treatment until G ≤1 then resume omacetaxine mepesuccinate reducing the number of treatment days by 2 in subsequent cycles

Toxicity

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Toxicity

Adverse Reactions Occurring in at Least 10% of Patients (Chronic Myeloid Leukemia–Chronic Phase)

Adverse Reaction

Number (%) of Patients (N = 108)

All Reactions

G3/4 Reactions

Patients with ≥1 commonly occurring adverse reaction

107 (99)

94 (87)

Blood and Lymphatic System Disorders

Thrombocytopenia

80 (74)

72 (67)

Anemia

66 (61)

39 (36)

Neutropenia

54 (50)

49 (45)

Lymphopenia

18 (17)

17 (16)

Bone marrow failure

11 (10)

Febrile neutropenia

11 (10)

Gastrointestinal Disorders

Diarrhea

45 (42)

1 (1)

Nausea

35 (32)

1 (1)

Constipation

16 (15)

Abdominal pain, upper

15 (14)

Vomiting

13 (12)

General Disorders and Administration Site Conditions

Fatigue

28 (26)

5 (5)

Pyrexia

26 (24)

1 (1)

Asthenia

25 (23)

1 (1)

Edema peripheral

14 (13)

Infusion and injection site–related reactions

37 (34)

Infections and Infestations

Bacterial, viral, fungal, and nonspecified infections

50 (46)

12 (11)

Musculoskeletal and Connective Tissue Disorders

Arthralgia

20 (19)

1 (1)

Pain in Extremity

14 (13)

1 (1)

Back pain

12 (11)

2 (2)

Nervous System Disorders

Headache

20 (19)

1 (1)

Psychiatric Disorders

Insomnia

11 (10)

Respiratory, Thoracic and Mediastinal Disorders

Cough

17 (16)

1 (1)

Epistaxis

16 (15)

1 (1)

Skin and Subcutaneous Tissue Disorders

Alopecia

16 (15)

Rash

11 (10)

Notes:

Safety data were evaluated in 163 patients, including 108 patients with CML-CP and 55 patients with CML-AP who received at least 1 dose of omacetaxine mepesuccinate and an additional 4 patients with CML-CP from another open-label, single-arm trial. Ten deaths were reported within 30 days after the last omacetaxine mepesuccinate dose. Four of these were attributed to progressive disease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and 1 to unknown causes

Efficacy

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Efficacy

The accelerated FDA approval was based on combined data from 2 open-label single-arm trials enrolling patients with CML in chronic phase (CML-CP) or in accelerated phase (CML-AP). The efficacy population included 76 patients with CML-CP who had received 2 or more prior TKIs, including imatinib

Efficacy Results for Patients with CP CML

The efficacy end point was based on MCyR

Patients (N = 76)

Primary Response–MCyR

Total with MCyR, n (%)

14 (18.4)

95% confidence interval

(10.5%–29%)

Cytogenetic Response, n (%)

Confirmed complete

6 (7.9)

Confirmed partial

3 (3.9)

Mean time to MCyR onset (N = 14)

3.5 months

Median duration of MCyR (N = 14)

12.5 months (Kaplan-Meier estimate)

Cytogenetic response evaluation is based on standard cytogenetic analysis (at least 20 metaphases)

Complete: no Ph⁺ cells; Partial: >0 to 35% Ph⁺ cells

Treatment Monitoring

Complete blood counts (CBCs) should be performed weekly during induction and initial maintenance cycles
After initial maintenance cycles, monitor CBCs every 2 weeks, or as clinically indicated
Monitor blood glucose concentrations frequently, especially in patients with diabetes or risk factors for diabetes

CML REGIMEN: HYDROXYUREA

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CML Regimen: Hydroxyurea

Hehlmann R et al. Blood 1994;84:4064–4077

Starting dose: Hydroxyurea 40 mg/kg; administer orally after meals, continually, as a single daily dose or divided into 2 doses (total dosage/week [initially] = 280 mg/kg)

Optimal dose is determined empirically, with very frequent monitoring of CBC (eg, every 3 days)
A dose of 1000–2000 mg/day is frequently sufficient for patients with WBC <100,000/mm³. With higher WBCs and a need to rapidly lower WBC, hydroxyurea 6000–8000 mg/day may be required initially
Total daily dose depends on disease activity and is extremely variable (range: hydroxyurea 500–15,000 mg/day)
Therapeutic goal is normalization of the WBC (target: 5000–10,000/mm³). This may require significantly higher or lower doses than the initial dose. If response is insufficient, aggressiveness of dose escalation must match aggressiveness of the disease. Frequent monitoring of WBC is mandatory during changes to the regimen
1. Slowly rising WBC or failure to achieve therapeutic target: increase total daily hydroxyurea dose 25–50%, assess effect after 5–7 days before further escalation
2. Rapidly rising WBC: increase total daily hydroxyurea dose by 50–100%, assess effect of dose increase for 3 days before further dose escalation
Very high doses carry a risk of prolonged aplasia

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Study of 194 patients with newly diagnosed CML in chronic phase

Efficacy (N = 194)

5-year survival: 45%

Toxicity

Hematologic side effects

Neutropenia and anemia are common, whereas thrombocytopenia is rare^✫
Cytopenias are usually rapidly reversible (within 3–4 days)
High doses and/or failure to interrupt treatment despite cytopenia may result in prolonged aplasia

Relatively common nonhematologic side effects

Gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea)
Acute skin reactions (rash, ulceration, dermatomyositis-like changes, erythema)

Rare, nonhematologic side effects

Chronic skin reactions (hyperpigmentation, atrophy of skin and nails, skin cancer, alopecia)
Headache, drowsiness, convulsions
Fever, chills, asthenia
Renal and hepatic impairment

Therapy Monitoring

CBC: At least weekly at first, then every 2–4 weeks after achieving stable blood counts
Blood chemistry profile: Every 6 months
Bone marrow morphology and cytogenetics: Every 6 months

Treatment Modifications

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Treatment Modifications

Hematological Toxicity

No dose modifications. G1 WBC or ANC are acceptable or even desirable

G2 or G3

Hold hydroxyurea until toxicity resolves to G1, then restart at 75% of initial dose

Recurrent G2/3

Hold hydroxyurea until toxicity resolves to G1, then restart at 50% of initial dose

Hold hydroxyurea until toxicity resolves to G1, then restart at 25% of initial dose

Recurrent G4

Hold hydroxyurea until toxicity resolves to G1, then restart at 50% of the previous dose

Nonhematologic Toxicity

No dose modifications

G2/3

Hold hydroxyurea until toxicity resolves to G1, then restart at initial dose

Recurrent G2/3

Hold hydroxyurea until toxicity resolves to G1, then restart at 75% of initial dose

Hold hydroxyurea until toxicity resolves to G1, then restart at 50% of dose previously administered

Recurrent G4

Discontinue hydroxyurea

Notes

Hydroxyurea is the drug of choice when a rapid reduction of the white cell count is clinically mandated, but the diagnosis of BCR-ABL-positive CML has not been established
Hydroxyurea may be indicated in cases of imatinib intolerance or resistance

CML REGIMEN: INTERFERON ALFA

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CML Regimen: Interferon Alfa

Baccarani M et al. Blood 2002;99:1527–1535

Hehlmann R et al. Blood 1994;84:4064–4077

Premedication:

Acetaminophen 500–650 mg/dose; administer orally, every 4 to 6 hours as needed

Target dose of Interferon alfa:

Interferon alfa-2a 5 million IU/m² per day; administer subcutaneously, continually (preferably at bedtime) (total dosage/week = 35 million IU/m²)

Interferon alfa-2b 5 million IU/m² per day; administer subcutaneously, continually (preferably at bedtime) (total dosage/week = 35 million IU/m²)

Typical dose of Interferon alfa:

5 million IU/m² per day. To increase tolerability, interferon alfa should be started at low doses (eg, 1.5 million IU/m² per day), with gradual increases over several weeks until the target dose is achieved

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Notes

Interferon alfa is reserved for patients who are intolerant of imatinib, nilotinib, and dasatinib. Patients whose disease is resistant to these drugs usually do not respond to interferon alfa

On October 1, 2007, Hoffmann-La Roche, Inc. (Nutley, NJ) announced interferon alfa-2a (Roferon-A^®) would be discontinued from the U.S. market

In 1989, interferon alfa-2a received orphan drug designation from the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia and other oncological diseases

Patient Population Studied

Patients with newly diagnosed CML in chronic phase:

n = 263

(Baccarani M et al. Blood 2002;99:1527–1535)

n = 194

(Hehlmann R et al. Blood 1994;84:4064–4077)

Efficacy (N = 263)

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Efficacy (N = 263)

Complete or partial hematologic response

74%

Complete cytogenetic response

7.6%

Partial cytogenetic response

10.3%

5-year survival

65%

Baccarani M et al. Blood 2002;99:1527–1535

Treatment Modifications

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Treatment Modifications

The practical management of patients receiving interferon alfa is complex. The simplified dose modification schema shown below is only a minimal guideline

Nonhematologic Toxicity

No dose reduction

Reduce interferon alfa dosage by 25%

G3/4

Stop interferon alfa. Restart at 50% of the previously administered dose after toxicity resolves. If resumption is tolerated, increase to 75% of the dose that produced G3/4 toxicity

Hematologic Toxicity

G1/2

No dose reduction

Reduce interferon alfa dosage in 25% decrements until abates to grade <3

Stop interferon alfa. Restart at a dosage decreased by 50% when toxicity resolves; increase dosage to 75% of the dose that produced G4 toxicity if tolerated

Modified from: O'Brien S et al. Leuk Lymphoma 1996;23:247–252

Toxicity

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Toxicity

% (All Grades)

Fever

Asthenia or fatigue

Myalgia

Chills

Anorexia

Arthralgia/bone pain

Headache

Nausea, vomiting

Diarrhea

Depression

Cough

Hair changes

Skin rashes

Decreased mental status

Sweating

Dizziness

Sleep disturbances

Paresthesia

Dyspnea

Cardiac dysrhythmia

Involuntary movements

Dry skin

Pruritus

Visual disturbances

Roferon-A (interferon alfa-2a, recombinant) product label, October 2004. Hoffmann-La Roche Inc., Nutley, NJ

Therapy Monitoring

CBC: Weekly; every 3–4 weeks after achievement of complete hematologic response, if counts are stable; every 4–6 weeks after achievement of complete cytogenetic response
Blood chemistry: Twice weekly; every 4–6 weeks after achievement of complete hematologic response
Bone marrow cytogenetics: Every 6 months; every 6–12 months after achievement of complete cytogenetic response
Quantitative RT-PCR for BCR-ABL from peripheral blood or bone marrow: Every 3 months

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Chapter 20: Leukemia, Chronic Myelogenous

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INTRODUCTION

Expert Opinion

CML REGIMEN: IMATINIB

CML REGIMEN: DASATINIB

CML REGIMEN: NILOTINIB

REFRACTORY PHILADELPHIA CHROMOSOME-POSITIVE CML REGIMEN: PONATINIB (ICLUSIG)

REFRACTORY PHILADELPHIA CHROMOSOME–POSITIVE CML REGIMEN: BOSUTINIB

REFRACTORY PHILADELPHIA CHROMOSOME–POSITIVE CML REGIMEN: CHRONIC OR ACCELERATED PHASE CHRONIC CML WITH RESISTANCE AND/OR INTOLERANCE TO 2 OR MORE TYROSINE KINASE INHIBITORS (TKIs): OMACETAXINE MEPESUCCINATE

CML REGIMEN: HYDROXYUREA

CML REGIMEN: INTERFERON ALFA

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