La Neutropenia

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La Neutropenia
Marco Danova Oncologia Medica Universita e IRCCS
San Matteo Pavia
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Grading of Chemotherapy-Induced Neutropenia
ANC x 109/L

• LLN
• Grade 1

? 1.5 Grade 2
? 1.0 Grade 3
? 0.5 Grade 4
Absolute neutrophil count Lower limit of
normal
Common Toxicity Criteria for Adverse Effects
Version 3.0 electronic document. Bethesda, Md
National Cancer Institute 1999 Available at
http//ctep.info.nih.gov/reporting/ctc.html.
Accessed January 4 2005
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Neutropenia A Devastating Side Effect of
Chemotherapy

• Neutropenia Deficiency of neutrophils
• A common side effect in patients receiving
  chemotherapy treatment
• Predisposes to life-threatening infections
• Neutropenic complications after myelosuppressive
  chemotherapy can lead to
• Morbidity
• Mortality

Boxer L, et al. Semin Hematol 20023975-81.
Crawford J, et al. Cancer. 2004100228-237
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Risk Factors for Neutropenia
Prior therapy-related risk factors
Independent and disease-related risk factors
High-dose chemotherapy

• Advanced age gt 65 years
• Advanced cancer
• Performance status (ECOG II-IV)
• Bone marrow involvement
• Infection, open wounds
• Renal disease Above normal LDH Serum
  albumin gt 3.5 g/dL

• Low cycle 1 nadir ANC
• History of recurrent
• chemotherapy-induced
• neutropenia
• Pre-existing neutropenia due to
• Extensive myelosuppressive
• therapy
• Radiation therapy to pelvis or
• other large regions of bone
• marrow

Neutropenia
Febrile Neutropenia
Non-Hodgkin's lymphoma Breast cancer Silber
JH, et al. J Clin Oncol 1998162392-400 Scott S,
Am. J Health Syst Pharm 2002 59 (15 suppl
4)S16-S19 Ozer H, et al. J. Clin. Oncol.
2000183558-3585 Crivellari D, et al. J Clin
Oncol 2000181412-1422
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Why Guidelines?

• To assist clinicians in evidence-based treatment
  decisions
• To ensure optimal resource allocation
• To standardise high quality of care
• Guidelines are created and updated when
• Issues of significant clinical or economic
  importance arise
• There are variations in treatment/access to care
• There are new data
• There are ethical considerations

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Why Guidelines to Prevent Neutropenia?

• Neutropenia is a common side effect in patients
  receiving chemotherapy treatment and predisposes
  patients to life-threatening infections
• Neutropenic complications after myelosuppressive
  chemotherapy can lead to morbidity and mortality
• Neutropenic events often result in
  dose-reductions or treatment delays and therefore
  may compromise clinical outcome
• Neutropenia is the major dose-limiting toxicity
  of conventional chemotherapy

Crawford J, et al. Cancer 2004100228-237 Johnsto
n EM and Crawford J. Semin Oncol 199825552-561
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What are the Potential Short- and Long-Term
Consequences of neutropenia?

Short-term impact1
Long-term impact2
CT dose delay/reduction
Infections
Reduced efficacy of treatment3
Hospitalisation
1Kuderer NM, et al. Proc Am Soc Clin Oncol
200422 Abstract 6049 2Leonard RCF, et al. Br J
Cancer 2003892062-2068 3Bonadonna G, et al. N
Engl J Med 1995332901-906
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G-CSF Decreases the Depth and Duration of
Neutropenia
Median ANC during cycle 1,CAE chemotherapy in
small-cell lung cancer
Placebo (n 110) G-CSF (n 101)
Start G-CSF/placebo
100.0
10.0
ANC (? 109/L)
1.0
0.5
0.1
Severe neutropenia (ANC ? 500)
0.01
0
4
8
12
16
20
24
Study day
Crawford J, et al. N Engl J Med 1991325164-170
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A History of Growth Factor Guidelines ASCO
1994-2000

• CSFs are recommended as primary preventive care
  for patients
• At gt 40 risk of FN
• At high risk of CT-induced infectious
  complications
• Intervention for subsequent cycles
• Physicians should consider dose reduction as a
  primary therapeutic option
• List of FN risk factors
• Pre-existing neutropenia due to disease
• Extensive prior chemotherapy
• Previous radiation to the pelvis or other areas
  with large amounts of bone-marrow
• A history of recurrent FN while receiving earlier
  chemotherapy of similar or lesser dose intensity
• Conditions potentially enhancing the risk of
  serious infection(e.g. poor performance status,
  more advanced cancer, decreased immune function,
  open wounds, already-active tissue infections)

American Society of Clinical Oncology. J Clin
Oncol 1994122471-2508 Ozer H, et al. J Clin
Oncol 2000183558-3585
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Implementation of CSF Guidelines can reduce the
impact of neutropenia
Data from the West Michigan Cancer Centre White N
et al. Cancer Nurs 20052862-69
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G-CSF Therapy at gt 20 FN Risk Provides Clinical
Benefits

• Recent publications have demonstrated efficacy of
  G-CSF for patients at a moderate risk of FN
• Use of G-CSF significantly reduced the incidence
  of
• FN1,2
• FN-related hospitalisation2
• use of IV anti-infectives2

1Timmer-Bonte J, et al. Proc Am Soc Clin Oncol
200422726. Abstract 8002 2Vogel CL, et al. J
Clin Oncol 2005231178-1184
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Patient-Related FN Risk Factors

• Advanced age
• Female gender
• Poor nutrition
• Low PS
• Low pre-treatment blood count
• Low lymphocyte count

• Low haemoglobin
• High LDH
• Bone marrow involvement
• Patient comorbidities
• Chronic lung disease
• Diabetes

Komrokji RS and Lyman GH. Expert Opin Biol Ther
200441897-1910
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NCCN 2005 Guidelines

• The NCCN guidelines take into account new data
  that was not available to ASCO in 2000
• NCCN 2005 G-CSF guidelines focus on risk
  assessment of chemotherapy regimen and patients
• Taking new data into account, NCCN recommend
  routine use of G-CSF for patients at gt 20 risk
  of FN

NCCN Clinical Practice Guidelines in Oncology
Myeloid Growth Factors in Cancer Treatment.
Available at http//www.nccn.org. Accessed July
2005.
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Comparison of NCCN 2005 ASCO 2000 Guidelines
for G-CSF
Filgrastim (daily dose 5 mcg/kg s.c.
administered from 1-3 days after chemotherapy
until neutrophils reach normal level) Pegfilgrasti
m (single dose per chemotherapy cycle starting 24
hr after initiation of chemotherapy)
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Implementing New Guidelines in Clinical Practice

• Case-Study Examples

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Algorithm for Primary Preventive Growth Factor
Support
1. Patient
2. Risk
3. Protect
High gt 20 FN Risk
Disease
Chemotherapy Regimen
Intermediate 10 20 FN Risk
Patient Risk Factors
Low lt 10 FN Risk
Treatment Intent
Adapted from Lyman GH. JNCCN 20053557-571
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Case 1

• 37-year-old female with relapsed high grade NHL
• First-line treatment was R-CHOP 21
• Did not experience neutropenic complications with
  first-line chemotherapy
• Now receives ESHAP second-line chemotherapy
• Average risk of FN for relapsed patients with
  this treatment is over 301-3
• Q Is G-CSF support appropriate for primary
  preventive care in this case?

1Velasquez WS, et al. J Clin Oncol
1994121169-1176 2Johnson PW, et al. Ann Oncol
1993463-67 3Ozturk MA, et al. Chemotherapy
200248252-258
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Case 1 Additional Patient Notes
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Case 1 Algorithm for Primary Preventive Growth
Factor Support
1. Patient
2. Risk
3. Protect
High gt 20FN Risk
Disease
Lymphoma
Use G-CSF
Chemotherapy Regimen
ESHAP 30
Intermediate 1020 FN Risk
Consider G-CSF
Patient Risk Factors
Female gender Prior chemotherapy
Low lt 10 FN Risk
No G-CSF
Treatment Intent
Curative
Adapted from Lyman GH. JNCCN 20053557-571
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Examples of NHL Regimens with High (gt 20) FN Risk

• ESHAP1
• DHAP2
• VAPEC-B3
• A(N)CVB4
• Note that these regimens carry a gt 20 risk of
  FN, independent of other risk factors

1Velasquez WS, et al. J Clin Oncol
1994121169-1176 2Velasquez WS, et al. Blood
198871117-122 3Pettengell R, et al. Blood
1992801430-1436 4Gisselbrecht C, et al. Leuk
Lymphoma 199725289-300
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Case 2

• 50-year-old male
• Newly diagnosed with small cell lung cancer
  (SCLC)
• Naive to chemotherapy
• Prescribed etoposide and carboplatin (EP)
  chemotherapy and concomitant radiotherapy
• The treatment carries an average FN risk of 10
  to 201
• Q Is G-CSF support appropriate for primary
  preventive care in this case?

1NCCN Clinical Practice Guidelines in Oncology
Myeloid Growth Factors in Cancer Treatment.
Accessed from the following website
07/2005 http//www.nccn.org/professionals/physici
an_gls/PDF/myeloid_growth.pdf
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Case 2 Additional Patient Notes
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Case 2 Algorithm for Primary Preventive Growth
Factor Support
1. Patient
2. Risk
3. Protect
High gt 20 FN Risk
SCLC (limited stage)
Disease
Use G-CSF
?
Chemotherapy Regimen
EP
Intermediate 1020 FN Risk
Consider G-CSF
ECOG 2CAD obese
Patient Risk Factors
Low lt 10 FN Risk
No G-CSF
Treatment Intent
Palliative
Adapted from Lyman GH. JNCCN 20053557-571
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Examples of SCLC Regimens

• High (gt 20) FN risk
• CAE1-3
• Topotecan1,4
• Topotecan/paclitaxel1
• Intermediate (10 20) FN risk
• Etoposide/carboplatin1
• Topotecan/cisplatin1,5

1NCCN Clinical Practice Guidelines in Oncology
Myeloid Growth Factors in Cancer Treatment.
Accessed from the following website
07/2005 http//www.nccn.org/professionals/physici
an_gls/PDF/myeloid_growth.pdf 2Crawford J, et al.
Ann Oncol 199781117-1124 3Crawford J, et al. N
Engl J Med 1991325164-170 4Von Pawel J, et al.
J Clin Oncol 199917658-667 5Ardizzoni A, et al.
Clin Cancer Res 20039143-150
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Case 3

• 55-year-old male
• Presents with localised lymphadenopathy
• Diagnosed with NHL
• Receives R-CHOP 21 chemotherapy
• The average FN risk with this regimen is
  approximately 201
• Q Is G-CSF support appropriate for primary
  preventive care in this case?

1Calculated from data in Lyman GH and Delgado DJ.
Cancer 2003982402-2409
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Case 3 Additional Patient Notes
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Case 3 Algorithm for Primary Preventive Growth
Factor Support
1. Patient
2. Risk
3. Protect
High gt 20 FN Risk
Low grade NHLElevated LDH
Disease
Use G-CSF
?
Chemotherapy Regimen
R-CHOP 21
Intermediate 1020 FN Risk
Consider G-CSF
Planned RDI gt 80 Anthracycline chemotherapy
Patient Risk Factors
Low lt 10 FN Risk
No G-CSF
Treatment Intent
Curative
Adapted from Lyman GH. JNCCN 20053557-571
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Examples of NHL Regimens with Intermediate (10 -
20) FN risk

• R-CHOP1,2
• Fludarabine/mitoxantrone1,3
• ACOD1,4
• Note that these regimens carry an FN risk of
  10-20, independent of other risk factors

1NCCN Clinical Practice Guidelines in Oncology
Myeloid Growth Factors in Cancer Treatment.
Accessed from the following website
07/2005 http//www.nccn.org/professionals/physici
an_gls/PDF/myeloid_growth.pdf 2Lyman GH and
Delgado DJ. Cancer 2003982402-2409 3Dimopoulos
MA, et al. Leuk Lymphoma 200243111-114 4Martinel
li G, et al. Leuk Lymphoma 200344801-806
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Case 3 Continued

• This patient did not receive G-CSF primary
  prophylaxis and experienced FN during cycle 1,
  starting day 10
• This patient required hospitalisation and i.v.
  antibiotics
• This patient has now recovered and has returned
  for his second cycle of chemotherapy
• Q Is G-CSF support appropriate for intervention
  for subsequent cycles in this case?

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Case 4

• 32-year-old female presents with lymphadenopathy
• Diagnosed with Hodgkins lymphoma
• Patient is chemotherapy-naive
• AVBD given as first-line chemotherapy
• The risk of neutropenia for this treatment is
  less than 101
• Q Is G-CSF support appropriate for primary
  preventive care in this case?

1Silvestri F, et al. Tumori 199480453-458
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Case 4 Additional Patient Notes
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Case 4 Algorithm for Primary Preventive Growth
Factor Support
1. Patient
2. Risk
3. Protect
High gt 20 FN Risk
Hodgkins lymphoma
Disease
Use G-CSF
Chemotherapy Regimen
AVBD
Intermediate 1020 FN Risk
Consider G-CSF
Planned RDI gt 80 Anthracycline chemotherapy
Patient Risk Factors
Low lt 10 FN Risk
No G-CSF
Treatment Intent
Curative
Adapted from Lyman GH. JNCCN 20053557-571
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Case 5

• 34-year-old woman, newly diagnosed with breast
  cancer
• 6 positive axillary lymph nodes
• She is prescribed 6 cycles of adjuvant TAC
  chemotherapy as first-line treatment
• This regimen carries an FN risk of approximately
  241
• Q Is G-CSF support appropriate for primary
  preventive care in this case?

1Martin M, et al. Proc Am Soc Clin Oncol
200422Abstract 620
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Case 5 Additional Patient Notes
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Case 5 Algorithm for Primary Preventive Growth
Factor Support
1. Patient
2. Risk
3. Protect
High gt 20 FN Risk
Breast cancer
Disease
Use G-CSF
Chemotherapy Regimen
TAC
Intermediate 1020 FN Risk
Consider G-CSF
Patient Risk Factors
Female gender Planned RDI gt 80
Low lt 10 FN Risk
No G-CSF
Treatment Intent
Curative
Adapted from Lyman GH. JNCCN 20053557-571
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Examples of Breast Cancer Regimens

• High (gt 20) FN risk
• AC?T1
• Doxorubicin/paclitaxel2,3
• Doxorubicin/docetaxel4,5
• TAC6
• Intermediate (10 20) FN risk
• Docetaxel7,8
• Doxorubicin/vinorelbine9
• AC10
• 5-FU/docetaxel7