Benign Hematology Update:
ASH, ISTH, and the Literature
2013
Craig M Kessler, MD, MACP
Professor of Medicine and Pathology
Lombardi Comprehensive Cancer Center
Georgetown University Medical Center
Washington, DC
Disclosures
• Research- Amgen, Baxter, Bayer, Biogen, Eisai,
Grifols, NovoNordisk, Octapharma
• Advisory Boards-Amgen, Baxter, Bayer, Biogen,
Eisai, Grifols, NovoNordisk, Octapharma
• Stock- Not applicable
• Employment – Not applicable
• Speakers’ Bureau – Not applicable
Topics
•
•
•
•
Autoimmune thrombocytopenia
Target specific oral anticoagulation
Duration of anticoagulation for VTE
New developments in von Willebrand
disease
• Advances in the treatment of sickle cell
anemia
• Miscellaneous
Pathophysiology of Immune
Thrombocytopenic Purpura
• Phagocyte-mediated accelerated clearance of
antiplatelet AB coated platelets in the RES
• Dysregulated T-cell function
• Direct cytotoxicity against megakaryocytes and
•
•
platelets
T-helper cell support for biosynthesis of Abs by Bcells
Abnormal number and function of T-regs
• Suboptimal platelet production
What is the best approach to corticosteroids for de novo ITP?
Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed
Dexamethasone In Treatment of Naïve Patients With Idiopathic
Thrombocytopenic Purpura
Matsche J et al
Week 1: All pts received prednisone (1 mg/kg/d) followed by a 1:1
randomization between daily prednisone and pulsed dexamethasone
Prednisone given at 1 mg/kg/d; after remission dose tapered 19 weeks to
maintenance dose ≤ 25 mg/d at wk 13 and < 7.5 mg/d at wk 19
If no remission at 2 wks, prednisone increased to 2 mg/kg/d for
another 2 weeks. If remission, tapered as above (≥ 50K platelets)
Dexamethasone given q 3 wks for 6 courses (0.6 mg/kg day 1 to 4)
Failure to achieve a remission: pts crossed over to the alternative treatment
Prednisone: no remission after 4 wks at 1-2 mg/kg/d
Dexamethasone: no remission after two cycles
Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed
Dexamethasone In Treatment of Naïve Patients With Idiopathic
Thrombocytopenic Purpura
Matsche J et al
No statistically significant difference in time
to remission (p=0.55)
Remission duration significantly longer
with dex vs prednisone (p=0.0139)
Median tx duration = 85 d (range: 28 – 153)
for pred;
Median tx cycles 5 (range: 3 – 7) for dex
Median cumulative cortisol equivalent dose
= 15.780 mg for pred; and 34.560 mg for
dex
Remission duration (platelets >50x109/l) in ITP pts
receiving daily prednisone versus pulsed
dexamethasone
No difference in Grade 3 or 4 bleeding
events
No difference in Grade 3 or 4 adverse
events: 1 pt on pred (hypertension) and 2
pts on dex (hyperglycemia, hypokalemia).
Suppression of Megakaryocyte
Maturation and Platelet
Production by ITP Plasma
% Control
Megakaryocytes
100
75
50
25
0
ITP-1 ITP-2 ITP-3 ITP-4
ITP-5 ITP-6 ITP-7 ITP-8 ITP-9 ITP-10 ITP-11 ITP-12
Heterogeneous responses in vitro: Anti-platelet ABs
affect megakaryocytes and circulating platelets
McMillan R, et al. Blood. 2004;103:1364-1369.
How Does Rituximab Affect ITP Outcome?
Abs 449: Rituximab As Second Line Treatment For Adult Immune
Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind,
Placebo-Controlled Study – The Ritp Study
Ghanima W et al
• First randomized placebo-controlled, double blind study
to assess both short and long-term efficacy and safety
of RTX in steroid-unresponsive ITP
• Pts randomized to 4 weekly infusions of 375mg/m2 RTX
or placebo
Steroids allowed throughout the study
• Main inclusion criteria:
1- unsplenectomized with primary ITP; platelets <30K
2- failure to achieve sustained response to 1-2 mg/kg prednisone
given > 2 wks or relapse during steroid-tapering/discontinuation
Per Cent of Patients NOT
Achieving Complete Response
Abs 449: Rituximab As Second Line TreatmentFor Adult Immune
Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, PlaceboControlled Study – The Ritp Study Ghanima W et al
• RTX did not reduce the rate of overall treatment failure
• Lower rate of splenectomy in the RTX-arm
• RTX induced significantly higher rate of CR at 24 wks
Time to Complete Response (days)
▬ Placebo
▬ Rituximab
Do TPO-RAs Enhance Rituximab Effectiveness?
Abs 329: Recombinant Human TPO and Rituximab vs Rituximab
Monotherapy in Corticosteroid-Resistant Primary ITP: a Multicenter
Randomized Controlled Study Xiu M et al
parameter
Age, median
(range)
RTX (n = 35)
P value
rhTPO + RTX
between
(n = 79)
groups
46 (14-68)
42 (13-82)
.664
Female / Male (n)
23/12
51/28
.905
Baseline platelet
count,
median(range)
13 (3-36)
8 (0-32)
.221
OR, %
71.4% (25/35) 78.5%( 62/79) .414
CR, %
NR, %
0.286
28.6%
0.43
21.5%
.143
.414
Time to Response, day(s)
28(4-90)
7(4-28)
.002*
Kaplan-Meier plot of time to relapse in patients
achieving response or complete response
•
•
RTX + rhTPO yields shorter
time to response vs RTX only
Combination extended time to
relapse
Thrombopoietin (TPO):
Properties and Pertinent Facts
• TPO = c-mpl ligand; c-mpl = TPO receptor
– c-mpl is the murine retroviral oncogene causing a
“myeloproliferative leukemia (mpl)” in mice
– c-mpl found in platelets and megakaryocytes
– TPO gene on human chromosome 3
• TPO is synthesized predominantly by
hepatocytes
– TPO mRNA also found in kidney, marrow, and
brain-? Hematopoietic importance
TPO affects viability of early progenitors of all lineages but
affects the late maturation only of megas: TPO only
stimulates production of platelets but not RBCs or WBCs
Increasing ploidy
The Oncologist January 1, 2009 vol. 14 no. 1 12-21
Normal
Levels
Increased
Levels
The Physiological regulation of TPO levels
Kuter DJ. The Oncologist 1996, 1:98-106.
Endogenous TPO Concentrations Are
Minimally Elevated in ITP Patients
Nichol J. In: Kuter DJ et al, eds. Thrombopoiesis and Thrombopoietins: Molecular, Cellular,
AA, aplastic anemia
Can Serum TPO Levels Predict Response
to TPO mimetics?
21 patients with ITP
(ELISA, R&D Systems, Minn, MN).
Serum TPO levels >95 pg/mL predicts for reduced and less
durable responses to TPO receptor agonists in ITP patients
= inadequate megakaryopoiesis as basic pathology
Makar, R. S., et al. Am. J. Hematol.. doi: 10.1002/ajh.23562
AMG 531: Mechanism of Action
AMG 531
Thrombopoietin
Receptor
Active Receptor
Inactive Receptor
Cell Membrane
SHC GRB2
RAS/RAF
SOS
P
P
P
Cytoplasm
STAT
P
JAK
MAPK
Promotion of
cell growth
p42/44
Potentiate
maturation
Signal Transduction
Increased Platelet Production
Kuter DJ. Int J Hematol (2013) 98:10–23
Anti-apoptosis
Practical Considerations for Romiplostim
• T1/2 = 120 – 140 hours whether IV or SQ
– Not formulated for IV use
• T1/2 not affected by renal or hepatic function
• Not recommended during pregnancy since can
cross placental barrier via FcRn receptor
• Pregnancy registry- ? Safety with breastfeeding
• Start at 1 µg/Kg/wk; titrate up to 10 µg/Kg/wk
– Effective mean dose in most studies = 4-5 µg/Kg
• Do not withhold dose → precipitous nadirs
• Dose reduce 25-50% for >400K platelets
Eltrombopag (SB497115):
Mechanism of Action
Thrombopoietin
Receptor
Eltrombopag
Active Receptor
Inactive Receptor
Cell Membrane
SHC GRB2
SOS
P
P
RAS/RAF
P
Cytoplasm
STAT
Promotion of
cell growth
P
JAK
MAPK
p42/44
Potentiate
maturation
Signal Transduction
Increased Platelet Production
Kuter DJ. Int J Hematol (2013) 98:10–23
Antiapoptosis
Pharmacologic Considerations for Eltrombopag
• Activates signal
transduction pathways
differently than TPO or
romiplostim
• Weaker stimulator of JAK
and STAT phosphorylation
• Does not activate AKT
pathway at all, unlike TPO or
romiplostim
• Eltrombopag effect is
additive to TPO in vitro. ? In
vivo significance
Growth of TPO-dependent cell line
Kuter DJ. Internat J Hematology. 2013;98(1):10-23
Long-term safety and tolerability of romiplostim in ITP:
Pooled analysis of 13 clinical trials (653 patients)
All received ≥ 26 wks tx; all 8- 18
µg/kg/wk; 5/13 > 10µg/kg/wk
(Baseline cytogenetics consistent with MDS)
(PMF)
HM=hematological malignancies:
• Rom-CLL, AML, lymphoma (2), MPN
• SOC/placebo: lymphoma, MDS
HM = Hematologic malignancies
Rodeghiero F et al. Eur J Haematol 2013;91(5)
doi:10.1111/ejh.12181
Can Patients Eventually Discontinue TPO Agonists?
Abs 327: Prolonged Remission After TPO-Receptor Agonist Discontinuation In
Adults With Chronic ITP. Results Of a French Observational Study
Mahévas M et al.
•
Romiplostim & eltrombopag: 70-80% lasting response-rate in long-term studies
•
Platelets ↓ to baseline or lower within 10 d post TPO-RA withdrawal in majority of cases
•
54 pts (35 females) studied: 46 (85%) with chronic; 8 (15%) with newly-diagnosed ITP
Median of 4 treatment-lines (rituximab in 59%; splenectomy in 33%)
18 received eltrombopag; 22 romiplostim; 14 received both TPO-RAs sequentially
•
Overall response rate on TPO-RA: 81.5%; CR (51.8%); PR (29.6%)
•
In 20 out of 28 pts achieving a CR, TPO-RA was discontinued after median 10 mos (1-70)
Among the 14 evaluable pts: 6 (30%) relapsed within 10 d, requiring rescue therapy
8 pts (70%) with CR over median follow-up of 13.5 mos (range: 5-27)
•
No predictors of sustained response (age, gender, duration of ITP, previous types/number of
therapies before TPO-RA)
• Summary: 15 % pts treated with TPO-RA achieve a durable response
after treatment discontinuation. A prospective trial is needed
Thrombotic Events in Adult ITP:
Metaanalysis
• Estimated frequency of thromboembolism:
– 3.1% (95% CI, 1.8-4.4%) for TPOr agonists
– 1.7% (95% CI, 0.3-3.1%) for controls
• TPOr agonists show a numerically but nonstatistically significant trend to increase the
occurrence of thromboembolic events
• Underpowered
• Use of IVIg, ASA, splenectomy not accounted for
Catala-Lopez F et al. Med Clin (Barc). 2012 Oct 20;139(10):421-9.
doi: 10.1016/j.medcli.2011.11.023. Epub 2012 Jan 23
Novel Approaches to the Treatment of ITP
• Oral Syk inhibitor R788
– Syk is downstream signal transduction regulator of
monocyte and macrophage phagocytosis
– Blockage of Syk pathway hypothetically should inhibit
platelet destruction
– Pilot study (N=16), 50% ITP pats demonstrated sustained
platelet counts >50K 1
• Anti-CD40 ligand
– CD40L is critical for T-cell-dependent B-cell expansion;
autoreactive CD4+ T-cells increased in ITP
– IDEC-131 and hu5c8 (anti-CD40L monoclonal AB) had
overall response rate of 13-16% 2
1. Podolanczuk A et al. Blood.2009;113:3154; 2. Patel VL et al. Br J Haematol.2008;141:545
Clinical Comparisons of the Novel Oral
Anti-Xa Anticoagulants
Dabigatran Rivaroxaban
Apixaban
Edoxaban
tmax
1.5 - 3 hrs
2 - 4 hrs
1 - 3 hrs
1-2 hrs
Half life
12 - 14hrs
9 - 13 hrs
8 - 15hrs
9-11 hrs
Renal
excretion
80%
66 %
ca. 25 %
35%
FDA
approval
• A. fib
• A. fib
• VTE
prevention
• VTE
treatment
• A. fib
• N/A
In clinical development: Betrixaban (not FDA approved)
Edoxaban
• Oral direct factor Xa inhibitor with a rapid onset of action
and half-life of 10–14 hours
• 60 mg once daily dose was selected based on phase II
data
• Dose of 30 mg in case of
• moderate renal impairment (CrCl 30 - 50mL/min)
• low body weight, i.e., ≤ 60 Kg
• concomitant use of P-gp inhibitors
Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial
(LMW)heparin overlapping with warfarin, followed by warfarin only in the treatment of subjects
with acute symptomatic venous thromboembolism for the prevention of symptomatic recurrent
venous thromboembolism during a 12-month study period
edoxaban
Sham INR
Symptomatic
confirmed
VTE event
R
INR
warfarin
Day 1- 5
Day 6- 12
initial (LMW)Heparin
placebo warfarin
placebo edoxaban
3M
6M
12 M
Efficacy outcomes
Edoxaban
(N=4118)
Warfarin
(N=4122)
Hazard ratio
(95% CI)
P Value
130 (3.2)
146 (3.5)
0.89
(0.70-1.13)
<0.001
First recurrent VTE - no. (%)
Overall study period
Patients with index DVT*
83 (3.4)
81 (3.3)
Patients with index PE**
47 (2.8)
65 (3.9)
66 (1.6)
80 (1.9)
On-treatment period
Subgroup severe PE
(RV dysfunction ProBNP)
n/N (%)
*
**
15/454 (3.3)
30/485 ( 6.2)
Noninferiority
1.02
(0.75-1.38)
0.73
(0.50-1.06)
0.82
(0.60-1.14)
0.52
(0.28 to 0.98)
Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively
Denominator is number of patients with index PE : 1650 and 1669 in edoxaban and warfarin group respectively
<0.001
noninferiority)
Safety outcomes
Edoxaban
(N=4118)
Warfarin
(N=4122)
Hazard ratio
(95% CI)
P Value
First major or clinically relevant
non major – no. (%)
349 (8.5)
423 (10.3)
0.81
(0.71-0.94)
0.004
Major – no. (%)
56 (1.4)
66 (1.6)
2 (<0.1)
10 (0.2)
Fatal
Intracranial
Non-Fatal in Critical Sites
Intracranial
Non-Fatal in Non-Critical Sites
Clinically Relevant Non-Major–
no. (%)
0
13 (0.3)
5 (0.1)
41 (1.0)
298 (7.2)
0.84
(0.59-1.21)
superiority
0.35
superiority
6 (0.1)
25 (0.6)
12 (0.3)
33 (0.8) †
368 (8.9)
0.80
(0.68-0.93)
0.004
superiority
† some patients have more than 1 bleeding
Principal Safety Outcome
hep /
edoxaban
hep / warfarin
HR
(n / N)
(95% CI)
349 / 4,118
423 / 4,122
0.81
8.5%
10.3%
(0.71–0.94)
(n / N)
Number of patients at risk
warfarin
4122
3757
3627
3522
3313
3218
2979
2165
2007
1883
1754
1613
1212
edoxaban
4118
3840
3695
3587
3382
3308
3038
2192
2043
1904
1767
1650
1241
Baseline characteristics
Mean age, years (SD)
Edoxaban
(N=4118)
56 (16)
Warfarin
(N=4122)
56 (16)
Male gender, n (%)
2360 (57)
2356 (57)
Qualifying diagnosis, n (%)
DVT
PE
2468 (60)
1650 (40)
2453 (60)
1669 (40)
2713 (66)
378 (9)
784 (19)
2697 (65)
393 (10)
736 (18)
733 (18)
719 (17)
Clinical presentation and risk factors, n
(%)
Unprovoked
Cancer
Previous VTE
Dose of 30 mg ( e.g ≤ 60 kg, CrCl≥30
≤50 ml/min), n (%)
Abs 211: Edoxaban For Long-Term Treatment Of
Venous Thromboembolism In Cancer Patients
• 771 CA pts enrolled (208 with active cancer/563 with CA history)
• Median duration of tx for edox = 267 d vs 266 d for warf (180 to 360 d in
both groups)
• Recurrent VTE in active CA pts: 3.7% in edox; 7.1% in warf (HR 0.55)
• Clinically relevant bleeding in 18.3% on edox (major= 4.6%) vs 25.3% on
warf (major = 3.0%) (HR = for clinically relevant bleeding 0.72)
• For non-CA pts: recurrent VTE = 2.8% for edox; 2.7% for warf (HR = 1.03)
• For non-CA pts: relevant bleeding = 7.7% on edox; (1% major); 9.1% on
warf (1.3% major) (HR = 0.83)
• Edoxaban is as effective, and possibly more effective, than warfarin in CA
pts with VTE
– Bleeding is appreciable during anticoagulant therapy, but may be less
with edox than warf in CA pts
– Need additional studies of edox for longer duration and vs LMWH
alone rather than warf
Venous Thromboembolism Prevention in High Risk
Cancer Outpatients
% VTE in the anticoagulant & placebo arms of SAVE-ONCO and PROTECHT:
Full population versus high-risk subgroups (risk score ≥3)
J Natl Compr Canc Network. 2013;11:1435
Predictive Scoring Identifies High Risk CA
Patients Who May Benefit from VTE Prophylaxis
Abs 580: Randomized Controlled Trial Of Dalteparin For Primary
Thromboprophylaxis For Venous Thromboembolism (VTE) In
Patients With Advanced Pancreatic Cancer (APC): Risk Factors
Predictive Of VTE Vadhan-Raj S et al
Predictors of VTE (multivariate logistic regression)
Variables
Odds Ratio
(95% confidence
interval)
P value
Elevated baseline Ddimer level*
1.00 (1.000-1.001)
0.01
ECOG performance
status ( ≥ 1)
20.60 (1.13-376.53)
0.04
Presence of CVC
16.91 (1.55-184.98)
0.02
Prophylaxis with
dalteparin
0.014 (0.00-0.62)
0.03
OR = 1.40, for every 500 unit increase from baseline Ddimer level
85 ambulatory pts with locally
advanced or metastatic CA
and active chemotx
N=38 (dalteparin 5000 U sq/d
for 16 wks during chemotx)
N=37 (placebo)
VTE: 22% placebo vs 5%
dalteparin p=0.02
(75% reduction in VTE)
No major bleeds w/dalteparin
D-dimer >5000 ng/ml predicts
baseline incidental VTE
Abs 458: Genome-Wide Association Study (GWAS) Of Venous
Thromboembolism (VTE) In African-Americans From The Electronic
Medical Records & Genomics (eMERGE) Network Heit JA et al
• Background: Incidence of VTE in AAs ≥ Caucasians of European ancestry
– Carrier frequencies of inherited thrombophilias common in whites (i.e., Factor V Leiden,
Prothrombin G20210A) are very low in AAs, suggesting that other inherited thrombophilias
may be associated with VTE in AAs.
• Objective: To identify SNPs associated with VTE in AAs.
• Most significant SNPs assoc with VTE (294 AA VTE/3,661 AA controls)
– ITPR3 (inositol 1,4,5-triphosphate receptor type 3) (OR=1.65)
– CLEC7A (C-type lectin domain family 7, member A) (OR=2.16)
•
•
ITPR3 SNPs associated with coronary artery aneurysm in Kawasaki disease, type 1
diabetes mellitus and other autoimmune disorders
CLEC7A encodes for dectin-1 mutation; dectin-1 mediates formation of neutrophil
extracellular traps (NETs). NETs are thrombogenic (Ateriosclero Thromb Vasc Biol
2013;33:147-51).
Risk Assessment for Recurrence and
Optimal Agents for Extended Treatment
of Venous Thromboembolism
Agnelli G & Becattini C. American Society of Hematology
Education Program. Hematology 2013; 471-477.
DURATION OF TREATMENT FOR VTE
. It’s now about risk:benefit ratio with continued therapy
Points to consider
• Long-term use of warfarin ~0.8%/year fatal
• Relapses of VTE are each about 10% fatal
• Strategy now seems to nibble from each end of
risk by identifying those clearly at high risk and
those clearly at low risk, thus isolating the group
in between while seeking equipoise
• No matter how long you treat, with cessation of
therapy, the VTE relapse rate asymptotically
approaches yet NEVER reaches baseline
RECURRENCE RATE OF VTE
Baglin, T. Lancet. 2003; 362(9383):523-526.
PROLONG Study
Palareti G. N Engl J Med. 2006; 355:1780-1789.
META-ANALYSIS OF RESIDUAL
VEIN THROMBOSIS
IDIOPATHIC (UNPROVOKED) DVT
Carrier M. J Thromb Haemost. 2011 Mar 7. [Epub ahead of print]
CLINICAL TRIALS OF NEW ORAL ANTICOAGULANTS
AND ASPIRIN FOR EXTENDED TREATMENT OF VENOUS
THROMBOEMBOLISM
Study
Active
Comparator
Expected
VTE
reduction
Observed
VTE
reduction
Major bleeding
Active
Comparator
Major or CRNM
bleeding
Active
Comparator
5.3%
1.8%
5.6%
10.2%
6.1%
1.2%
4.3%
2.7%
RE-SONATE
Dabigatran
150 mg BID
Placebo
70%
92%
0.3%
RE-MEDY
Dabigatran
150 mg BID
Warfarin
(INR 2-3)
Absolute
increase in
VTE risk
<2.8%
Absolute
increase
0.5%
0.9%
EINSTEIN
Ext
Rivaroxaban
20 mg daily
Placebo
70%
82%
0.7%
AMPLIFY
Ext
Apixaban
5.0 mg BID
Apixaban
2.5 mg BID
Placebo
41%
80%
0.1%
81%
0.2%
WARFASA
Aspirin
Placebo
40%
40%
0.3%*
0.3%*
1%*
1%*
ASPIRE
Aspirin
Placebo
30%
26%
0.9%*
0.7%*
1.1%*
0.6%*
* Incidence per patient-year
1.8%
0.5%
3.2%
Agnelli G et al. New Engl J Med 2013; 368:699-708
Agnelli and colleagues have studied longer term thromboprophylaxis in patients with VTE after
6-12 months of rather routine therapy. Patients (N=2486) were randomized at equipoise to
then receive 1) placebo, 2) apixaban 5 mg BID (essentially a therapeutic dose) or apixaban 2.5
mg BID (essentially a prophylactic dose) for 12 months
New Concepts in the Laboratory Diagnosis
of von Willebrand Disease
Interactive Registry on Acquired von Willebrand Syndrome avwsSmall.jpg intreavws.com
Abs 331: Critical Importance Of VWF Propeptide (VWFpp) In The Diagnosis
Of Type 1 Von Willebrand Disease (VWD) Haberichter SL et al
1. Historically VWFpp was known as VWF:AgII
2. A subtype of Type 1 VWD is due to increased clearance of the variant
protein; is associated with ultralarge HMW VWF multimers; is due to
decreased proteolysis by ADAMTS13
3. Measurement of VWFpp: helps to establish if low VWF levels are due to
decreased synthesis or increased clearance.
In the former the VWFpp/VWF:Ag ratio is normal [i.e. close to 1]
In the latter, VWFpp/VWF:Ag is increased
The VWFpp has a concentration in plasma of 1 µg/ml
and a T½ of 2-3 hours whereas the mature VWF protein
has a concentration in plasma of 10 µg/ml and a T½ of
8-12 hours
Type 1 Vicenza and similar VWF variants with shorted
T½ are now classified as Type 1C VWD
Racial Genetic Variability Results in Overdiagnosis of
VWD in African Americans Flood VH et al. Blood. 2010 July 15; 116(2): 280–
VWF:Ag higher in AAs than Caucasions but
VWF:RCo are equivalent
Exon 28 1472 DH polymorphism on exon 28 are
overrepresented in AAs (63% vs 17% in
Caucasians)
1472 DH interferes with VWF-ristocetin
interactions with GP1b/IX in vitro
No in vivo consequence but over dx of VWD
Abs 776: GMI 1070: Reduction In Time To Resolution Of VasoOcclusive Crisis and Decreased Opioid Use In a Prospective,
Randomized, Multi-Center Double Blind, Adaptive Phase 2
Study In Sickle Cell Disease Telen MJ et al
GMI 1070 is pan-selectin inhibitor; mice studies indicated importance of selectin from WBCs as mediator of VOC
The median time to resolution of the crisis was reduced by 63 hrs in GMI 1070 group
The median and mean times to hospital discharge were cut by 84 and 55 hours, respectively.
Total opioid use for the GMI 1070 group was reduced 83%
Although the differences were large, most only approached statistical significance
The Ponatinib Problem: Excellent Efficacy vs Emerging
Thrombotic Risks
• BCR-ABL inhibitor (and T315I mutation) that also selectively
inhibits other tyrosine kinases including FLT3, RET, KIT, and
members of the FGFR, PDGFR and VEGFR families of kinases.
• Among 267 pts with chronic-phase CML, 56% had a major
cytogenetic response (51% of patients with resistance to or
unacceptable side effects from dasatinib or nilotinib and 70% of
patients with the T315I mutation) (PACE trial NEJM 2013;369;1783-96) (Abs 1498 and 2738)
• Serious arterial thrombotic events were observed in 9% of
patients over median 15 mos observation
• After an additional 13 mos of exposure (after FDA fast track
approval), cumulative incidence of serious arterial thrombotic
events was 11.8% and of all arterial thrmbotic events=17.1%;
• FDA then suspends sales and marketing of drug; reinstated on
12/20 for aggressive or resistant disease only
4020: Cumulative incidences of cardio-vascular events occurring in CP
CML pts on Ponatinib or on Nilotinib since TKI initiation and on each TKI
Nicolini FE et al for French CML Group
Ponatinib induces significant high CV events in 8/19 CP
CML pts, after a relatively short period of exposure to this
compound as compared to a historical cohort of Nilotinibtreated pts (11/58). The role of prior Nilotinib exposure
remains to be determined. These results should promote
an extreme vigilance especially in older pts with known CV
risk factors that will need to be strictly controlled and
monitored. A preventive anti-thrombotic prophylaxis might
be useful since Ponatinib initiation.
Prospective study of CP
CML on Ponatinib
Historical controls on
Nilotinib as first line tx
Age matched comparison
of arterial events only
while on therapy (64 [P] vs
54 yrs [N]; P=NS)
For pts on P, 6 were in
CHR, 2 in PCyR, 5 in
CCyR, 6 pts were in MMR
0.2% arterial clots with
Dasatinib therapy (abs
1489 Le Coutre PD et al)
https://ash.confex.com/data/abstract/ash/2013/4/7/Paper_59574_abstract_100379_0.gif
1482 Atherothrombotic Risk and TKIs Treatment In CML Patients:
A Role For Genetic Predisposition and Pro-Inflammatory/ProOxidative Status? (Aprile L et al for Italian Study Centers)
• Increased reports of venous and arterial thrombotic
complications in CML pts on 2nd generation TKIs
NILOTINIB (36 pts)
OxLDL (UI/L)
92.7±9.7 (p= 0.021)
TNFa (pg/ml)
10.9±1.9
IL6 (pg/ml)
9.8±1.4
IL10 (pg/ml)
1.03±0.57 (p= 0.00010)
TNFa/IL10
10.5±1.22 (p= 0.00013)
IL6/IL10
9.51±0.86 (p= 0.00016)
sCD40L (pg/ml)
513.9±91.8 (p= 0.0014)
Endogenous Thrombin Production (%) 14.9±3.7 (p= 0.00020)
PAO, ACS, TIA, CVA, etc
9/36 (25%) (p=0.019)
IMATINIB (39 pts)
67.6±6.1
9.5±1.8
8.9±1.3
4.9±1.1
1.94±1.3
1.81±1.16
329.3±59.6
7.4±1.8
3/39 (7.6%)
The link between pro-inflammatory stimuli and lipid peroxidation triggers
accelerated atherogenesis. Enhanced inflammatory milieu observed during nilotinib
treatment could be an additional factor of accelerate atherothrombosis.