Safety and effectiveness of granulocyte-colony stimulating factor in advanced chronic heart failure

1
Safety and effectiveness of granulocyte-colony
stimulating factor in advanced chronic heart
failure

• Jacob Joseph, MD
• Veterans Affairs Healthcare System- Boston and
  Boston University

Am J Cardiol 2006 97 681-684
2
Stem cell mobilization inAMI vs
CHF

• Weak homing signals
• Less mobilization
• Better myocardial milieu
• Significant electrical heterogeneity
• Safety (electrical heterogeneity, neutrophil
  mobilization)

• Activated homing signals
• Better mobilization
• Poor vascularity
• Less electrical heterogeneity if successful
  myocardial regeneration
• Safety (Collagenolysis due to neutrophil
  proteases)

3
Rationale for a phase I study of G-CSF in
advanced heart failure

• Stem cells may not be adequately mobilized in
  advanced heart failure
• Bone Marrow Hypoperfusion
• Cytokines
• Microscopic myocardial injury (ongoing myocyte
  necrosis with replacement fibrosis due to
  neurohormonal stimulation and ischemia) may
  produce homing of stem cells
• Safety issues unknown

4
Escalating Dose Protocol
5
Inclusion and Exclusion Criteria

• INCLUSION
• Age 18 years NYHA III or IV LVEF lt 35
• Background treatment with standard therapy for
  heart failure 3 months
• ICD in situ
• EXCLUSION
• Unstable ischemic syndrome
• Stroke or transient ischemic attacks within last
  3 months
• Severe organ dysfunction/illnesses limiting
  survival 6 months

6
Study Protocol
Measurement Base line Treatment Treatment Treatment Treatment Treatment Follow-up Follow-up Follow-up Follow-up Follow-up Follow-up
Day/Week/Mo Base line D1 D2 D3 D4 D5 D6 D8 D10 W6 M3 M9
G-CSF X X X X X
Chemistry X X X X X X X X X X X
CBC X X X X X X X X X X X
CD 34 X X X X X X X X X X X
Cytokines X X X X
Echo   X X X  
Optison Echo X X X
7
Endpoints

• Primary endpoint
• CD 34 cells above 10 cells/microliter
• Secondary endpoints
• Lack of significant changes (twice baseline
  measurements) in laboratory parameters during the
  entire study (safety endpoint)
• Increase in LVEF at 9 months
• Changes in cytokine levels

8
Baseline Characteristics
Patient 1 2 3 4 5 6
Age (years) 59 54 60 67 56 82
LVEF() 24 19 15 23 13 17
Etiology Ischemic Ischemic Ischemic Ischemic Non Ischemic Non Ischemic
Blood Pressure (mmHg) 131/77 122/69 139/98 113/64 91/64 140/83
Heart Rate (Beats per minute) 64 64 84 82 83 80
Serum creatinine (mg/dL) 0.9 1.2 1 1.2 1.1 1.6
White Blood Cell Count (x103/dL) 6.9 6.22 4.16 11.2 5.37 7.82
New York Heart Association Class III III IV III III III
Dose (mg/kg) 22.5 25 25 22.5 10 25
Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8 Mean age (SEM) was 63 4.2 years mean LVEF(SEM) was 18.51.8
9
Hematologic parameters
  Baseline Baseline Peak Peak
Patient WBC count (X103/ml) CD34ve cell count (cells/ml) WBC count (X103/ml) CD34ve cell count (cells/ml)
1 6.96 2.9 24.8 20.7
2 6.22 5.4 39.9 97.2
3 4.16 2.7 73.8 34.8
4 11.2 5 56.9 49.5
5 5.37 2.8 21.6 11.1
6 7.82 2.7 35.8 19
MeanSEM 6.91 3.60.5 42.18 38.713
p value lt 0.05 compared to corresponding baseline group p value lt 0.05 compared to corresponding baseline group p value lt 0.05 compared to corresponding baseline group p value lt 0.05 compared to corresponding baseline group p value lt 0.05 compared to corresponding baseline group
10
CD 34 cell mobilization
11
CD34 cell mobilization vs. WBC increase
12
Side Effects
Pt Side Effects
1 Increased AlkP
2 Increased AlkP, Calf cramping
3 Increased AlkP, Pain (calf, legs, back)
4 Increased AlkP
5 Increased AlkP, decreased UOP, increased Cr, shoulder back pain
6 Increased AlkP, Pain at the injection site
13
Effects on LV structure and function
Parameter Baseline 9 month p value (paired t-test)
Mean Left Ventricular Ejection Fraction (all patients) 18.51.8 24.83.5 0.069
Mean Left Ventricular Ejection Fraction (ischemic cardiomyopathy patients) 20.32.1 29.52.9 0.048
Left Ventricular End Diastolic Dimension (all patients) 6.80.4 6.6 0.4 0.517
Left Ventricular End Diastolic Dimension (ischemic cardiomyopathy patients) 6.50.5 6.10.4 0.543
Left Ventricular End Systolic Dimension (all patients) 6.30.3 5.90.4 0.347
Left Ventricular End Systolic Dimension (ischemic cardiomyopathy patients) 5.90.4 5.50.4 0.474
14
Cytokines in Heart failure

• Proinflammatory cytokine levels are increased in
  heart failure
• IL-6 and TNF alpha
• Anti-inflammatory cytokines are decreased in
  advanced chronic heart failure
• IL-10 and IL-10/TNF ratio
• IL-10/TNF alpha ratio correlates with response to
  treatment of CHF

• Clin Sci 2003 105 45-50 Eur Heart J 2003 24
  2186-2196

15
Mean cytokine levels in study patients
Cytokine Baseline level (pg/ml) Peak level (pg/ml) P value
Tumor Necrosis Factor-a? 2.8/-1.5 3.6/-1.0 NS
Interferon-g?? 14.4/-13.2 18.8/-10.3 NS
IL-2 1.4/-0.9 1.2/-0.7 NS
IL-4 4.8/-1.0 5.7/-1.1 NS
IL-5 2.7/-0.9 3.1/-1.0 NS
IL-10 4.2/-0.4 9.4/-1.1 0.003
16
Conclusions

• A low dose of GCSF (5 mg/kg/day) for 5 days can
  safely mobilize stem cells in advanced systolic
  heart failure
• WBC counts should be monitored for safety
• GCSF-induced stem cell mobilization may result in
  favorable long term effects on left ventricular
  function, especially in ischemic heart failure
• GCSF has a favorable effect on cytokine profile

17
Future directions

• Could there be differences in response of
  ischemic vs. non-ischemic cardiomyopathy?
• What is the optimal frequency of repeated cycles
  of GCSF?
• What is the role of cytokine modulation by GCSF
  mobilized cells?
• What is the mechanism of and clinical predictors
  of improvement in LV function?

18
Acknowledgements

• Asem Rimawi, MD
• Jawahar L .Mehta, MD, PhD
• Paulette Mehta, MD
• Michele Cottler-Fox, MD