Mohamad A. Hussein
H. Lee Moffitt Cancer & Research Institute
Tampa, Florida
MANA
M
G
ANA EMENT
G
OF
TOXICITIES
Novel Agents
Side Effect Profiles
Hypercoa
yp
gulable
g
States
Venous
Arterial
Neurologic
Motor
Sensory
Hematologic
Skin reactions
Non symptomatic
Symptomatic
Hypercoa
yp
gulable
g
States in PCD
Pts
DVT
%
MGUS
174
10
7.5%
Amyloid
56
6
10 7%
.
MM
407
40
9.8%
PCD
671
59
8.8%
Srkalovic G, et al. Cancer 101 (3):558-566, 2004
Hypercoagulable States with Novel Agents
Risk Va
V ries
a
by
b
Newly diagnosed or Relapsed/Refractory
Time in course of therap
ther y
ap
The compound
Combination agents
g
Supportive care therapy applied
Incidence varies from 20-75%
7% and is dependant
p
on
risks noted above in addition to degree of
vigilance!
Hypercoagulable States with Novel Agents
Specific risk factors studies
The combination of thalidomide with anthracyclines was
associated with the highest odds ratio (OR, 4.3;
P0.001)
Newly diagnosed disease (OR, 2.5; P=0.001)
Chromosome 11 abnormality (OR, 1.8; P=0.048)
Zangari M, et al. Clin Lymphoma 2003;4(1):32
Hypercoagulable States in MM
Pat
Pa ho-physiolog
ph
y
ysiolog of backgro
kgr und VTE
High IL-6 levels
Manage
Manag ment
Preventive
Aspirin
p
LMWH
Coumadin
Therapeutic
Same as above (except for ASA), however in therapeutic
dosage
dosag s
Hypercoa
yp
gulable
g
States; Management
g
Ra
R tionale fo
f r Aspirin
Platelet endothelial interaction1
Pre and post therapy platelet aggregation to Ristocetin and von
Willebrand levels were significantly increased
Suggesting a platelet-endothelial pathophysiology
Rationale for Low dose vs. high dose2
Rationale for Low dose vs. high dose
Higher doses inhibit both thromboxane and prostacyclin
Lower aspirin doses inhibit thromboxane gener
pg
ation
The improved ratio of prostaglandins obtained with lower doses is
less thrombogenic
1.
Baz R et al, Mayo Clin.Proc. 80 (12):15681574, 2005.
2.
Patrono C, et al. N Engl J Med 2005;353(22):23732383.
Hypercoagulable States; Management
Evidence for Aspirin (DVd-T1)2
Evidence for Aspirin (DVd T )
Two endpoints in this study:
The time to first VTE
The time to the composite endpoint of death or first VTE
Multivariate time to event analysis, aspirin use
continued to be associated with
A lower relative risk of VTE (HR=0.215, C.I=0.098-0.472,
p=0.0001)
0001)
A composite endpoint (HR=0.28, C.I=0.153-0.513,
p<0.0001)
1.
Hussein MA, et al. Mayo Clin.Proc. 81 (7):889895, 2006.
2.
Baz R et al, Mayo Clin.Proc. 80 (12):15681574, 2005.
Hypercoagulable States; Management
Fo
F llow
llo up evidence fo
f r low
lo dose ASA
DVd-R (pegylated doxorubicin, vincristine, reduced-
frequency dexamethasone, and Revlimid®
[lenalidomide]) 1
BiRD (Biaxin [clarithromycin], Revlimid® [lenalidomide],
2
and dexamethasone)
MPR (melphalan, prednisone, and Revlimid®
[lenalidomide]) 3
[lenalidomide]) .
1. Baz R, et al. Ann Oncol 2006; ASCO 2007, Abst# 3576
2. Niesvizky, R., et al. [abstract 3454]. Blood 106(11), 964a. 2005.
3. Palumbo, A., et l. Blood 106 (Part 1 of 2 Parts)(11), 231a232a. 2005.
Hypercoagulable States Role of LMWH
Author
Regimen
MM
# of Patients
Prophylaxis
% DVT
Minnema et al Leukemia VAD
ND
201
None
5
2004;18(12):2044-
TAD
ND
211
LMWH
9
Zangari et al Br J
Chemotherapy
ND
134
None
8.6
Haematol
Chemotherapy + T
ND
87
None
34.5
2004;126(5):715-
Chemotherapy + T
ND
35
Warfarin
31.4
(1 mg/day)
Chemotherapy
ND
68
None
14.5
Chemotherapy + T
ND
62
LMWH
14.7
Zangari et al Blood
DTPA
DTP CE
A
RR
98
LMWH
LMW
10
2004;104(11):4914
VDTPACE
RR
69
LMWH
0
Hypercoa
yp
gulable
g
States: Summary
Incidence without active therapy is ~ 10%
Incidence with Dex as single agents is low
Anti-Inflammatory characteristics
Low Dose Aspirin (81-100mg/d) is effective
If used consistently
LMWH (prophylactic dose) is as active as Aspirin
Velcade seems to eliminate the risk?
Further studying to compare LD ASA to LMWH are
required
Neurological
g
events
Related to steroids
Newly diagnosed less tolerant to Steroids1
Active PT during intense dosing and chronic therapy
Related to Bortezomib2
Peripheral
Dose reduction and or frequency
Symptomatic treatment
Autonomic
In the form of bloating, nausea, vomiting or orthostasis
Reducing dose and or frequency
1.
Hussein MA, et al. Mayo Clin.Proc. 81 (7):889895, 2006.
2.
Richardson PG, et al. N.Engl.J.Med. 348 (26):26092617, 2003.
Neurological
g
events
Re
R lated to IMiD's
Moderate to severe lower and upper extremity
cramps1,2
Occurs early in the course of therapy (<5%)
During chronic therapy occurs in 20% of the patients
Therapy with L-Glutamine at 2gms BID.
80 % of patients will respond
1.
Hussein MA, et al. Mayo Clin.Proc. 81 (7):889895, 2006.
2.
Baz R, et al. Ann Oncol 2006.
Hematologic
g
Av
A ailable
v
preliminary data
Suggest that dose and schedule correlate with
Overall response
p
rate
Quality of response
Manageable cytopenias should not result in reduction of
Dose
Schedule
Skin Reactions
Review concomitant medications
Avoid Sulfa containing anti-biotics
Allopurinol
Manage
Manag ment
e
based on symptoms
Non symptomatic
Continue therapy without any modifications
Close
i
mon toring
Symptomatic
Depends on the severity and symptoms
f
I moderate to severe discontinue therapy
Steroids
Anti-histaminics
Summary
Objectives of Therapy
jpy will determine
Intensity of therapy
Extent of toxicity, i.e., side effects vs. benefit
Careful strategic blending of agents
New agents with better safety margin
When a critical mass of agents
ag
is available
av
we
w could
possibly have agents approved based on safety
Management of patient as a whole
Avoid ignoring side effects for efficacy especially if
quality of life is compromized