How I treat my

Cancer Associated Thrombosis

Avi Leader, MD

Hematology Institute, Rabin Medical Center

May 2020

Epidemiology• Cancer increases risk of VTE by 4-6 fold

• About 20% of VTE cases occur in cancer patients

• A cancer patient has a ~15% likelihood of suffering a VTE event during his cancer journey

• VTE patients with cancer have increased rates of major and clinically relevant non-major bleeding (9.2%) and recurrent thrombosis (7.6%) compared to VTE patients without cancer (2.0% and 2.1%, respectively, RIETE data)

• VTE is the second leading cause of death in cancer patients

• Increased incidence of arterial thrombosis

1Mosarla, JACC 2019

Pathogenesis of increased thrombotic risk in cancer

Overview

1. Preventing thrombosis in cancer outpatients– Risk assessment– LMWH vs. DOAC as thromboprophylaxis

2. Treating cancer-associated VTE in the DOAC era

3. Practical aspects of AC management (in CAT)

4. Treating recurrent VTE

5. Approach to DIC

6. Arterial thrombosis in cancer

Case #1

• 55 year old male with no prior medical Hx

• Newly diagnosed locally advanced pancreatic cancer– External tumor compression of splenic vein and SMV

– Candidate for ambulatory chemotherapy (mFOLFIRINOX)

• ECOG1 | BMI = 26

• WBC = 9K/µL | PLT = 150K/µL | Hb = 10.8 gr%

• Creatinine, liver enzymes and albumin = normal

• PTT, PT, Fibrinogen normal

Thrombotic risk? Anticoagulation indicated? What else?

Risk assessment in cancer outpatients: Khorana Score

Khorana, Blood 2008; Ay, Blood 2010; Khorana, Thr Res, 2018; van Es, JTH 2020

VTE @ 6 months• High ≥ 3 = 17.7%• Int-High 2 = 9.6%• Int-low 1 = 3.8%• Low 0 = 1.5%

VTE @6mo IPD (van Es)• High = 9.8%• Low-int = 6.4%• High vs. non-high OR

• Non-lung = 3.2• Lung = 1.2

Khorana vs. other VTE RAMs: The best of a bad bunch?

Khorana, Lancet 2018

Thromboprophylaxis is effective in cancer outpatients

Ben Aharon, Acta Oncol 2014; Di Nisio, Cochrane 2016

ASCO & ISTH suggest/recommend TP in high risk outpatients, BUT

Key, JCO 2019; Farge, Lancet Oncology 2019

When is the risk high enough to justify thromboprophylaxis (TP)?

Double blind RCT of apixaban vs. placebo for VTE thromboprophylaxis

Carrier, NEJM 2019

Less thrombosis with apixaban (ITT analysis)

Carrier, NEJM 2019

NNT in ITT = 16• 4.2% apixaban• 10.2% placebo

• HR 0.41• 95% CI: 0.26-0.65

More major bleeding with apixaban

NNH on treatment = 100• 2.1% apixaban• 1.1% placebo

• HR 1.89• 95% CI: 0.39-9.24

Carrier, NEJM 2019

NNH in ITT = 57• 3.5% apixaban• 1.8% placebo

• HR 2• 95% CI: 1.01-3.95

CASSINI double blind RCT

• Excluded: – Primary and secondary brain cancers– Hematological malignancies, except lymphoma– Platelets < 50,000 (withhold Rx if < 25)

• Screening LE US: at baseline (4.5% asymptomatic DVT) and every 8 weeks

Khorana, NEJM 2019

Negative Rivaroxaban RCT (CASSINI )

Khorana, NEJM, 2019

NNT = 35

Primary efficacy endpoint @ 180 days

Oral thromboprophylaxis in cancer: summary

• Apixaban and Rivaroxaban reduce VTE rate over 6 months

• Increased major bleeding

• Favorable NNT – NNH ratio

– Apixaban: NNT = 16 | NNH = 57 (100 on treatment)

– Rivaroxaban: NNT = 35| NNH = 101

• Ongoing CANVAS trial (NCT02744092):

– Comparing DOACs, LMWH and warfarin in VTE prophylaxis in cancer

• Suggest3/recommend2/may-use1 DOACs as primary thromboprophylaxis

– starting chemotherapy | Khorana score ≥2

– no drug‐drug interactions | No high risk for bleeding

– up to 6 months

• Suggest LMWH, if concern over DOACs and thromboprophylaxis considered

• ITAC recommends LMWH for pancreatic cancer (grade 1B) 2

TP in ambulatory cancer pts: ISTH/ITAC/ASCO Guidelines

1Wang, JTH 2019; 2Farge, Lancet Oncol 2019; 3Key, JCO 2019

Case #2

• 50 year old female with no prior medical Hx

• Newly diagnosed IgG-Kappa multiple myeloma– Pathological fracture of Rt femur with internal fixation > 1 month ago

– Mobility restored

– Starting RVd as an outpatient

• ECOG1 | BMI = 27

• WBC = 7K/µL | PLT = 150K/µL | Hb = 10.2 gr%

• Creatinine, liver enzymes = normal; Hypoalbuminemia

• PTT, PT, Fibrinogen normal

Thrombotic risk? Thromboprophylaxis indicated? If so, which?

Risk of ATE and VTE in multiple

myeloma

1Cornell, Frontiers in Oncology 2019

VTE risk prediction in MM: IMPEDE-VTE

Sanfilippo, Am J Hem 2019

VTE risk prediction in MM: IMPEDE-VTE

Sanfilippo, Am J Hem 2019; Chalayer, Am J Hem 2019

Type of thromboprophylaxis in MM with len1/thal2-based Rx

1Larocca, Blood 2012 2Palumbo , JCO 2011

Oral thromboprophylaxis in IMID-treated multiple myeloma

• Phase 2 pilot studies suggest safety and efficacy of apixaban (N=50-104) 1,2

– Myelaxat: DVT in 2/104; MB in 1/104; CRNMB in 11/104 2

• Numerically lower bleeding rates in LMWH vs. ASA RCTs– No major bleeding (0/342); 1/342 minor bleeding 3

– Major bleeding in 3/667; 10/667 minor bleeding 4

• Ongoing studies:– Thromboprophylaxis in newly diagnosed Multiple Myeloma (TiMM) [2015-002668-18]

1Cornell, BJH 2020; 2Pegourie, Am J Hem 2019; 3Larocca, Blood 2012; 4Palumbo , JCO 2011

TP of outpatients with MM: ITAC and ASCO Guidelines

• Immunomodulatory drugs & steroids or other systemic anticancer therapy

– Pharmacologic thromboprophylaxis is recommended (Grade 1A) 1,2

– Aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients 2

• ITAC: low dose VKA also an option

• ME: Consider using IMPEDE-VTE to assess thrombotic risk– HAS-RISc being validated

1Farge, Lancet Oncol 2019; 2Key, JCO 2019

What is the thrombotic risk in acute myeloid leukemia (AML)?

1Libourel, Blood 2016; 2Mitrovic, Thrombosis Res 2015

Any thrombosis

Venous thrombosis

Arterialthrombosis

Median follow up

Younger adults1

(18-65 yrs); n=272

8.7% 4.7% 4% 478 days

Elderly adults1

(>60 yrs); n=132

10.4% 4.4% 5.9% NS

• Most thrombotic events (66%) occurred before the 2nd course of chemotherapy

• Risk may be even higher in acute promyelocytic leukemia2

A high D-dimer level predicts ATE/VTE in newly diagnosed AML

1Libourel, Blood 2016

What is the thrombotic risk in ALL?

Rank, Blood 2018

• Cumulative incidence: 7.9% (6.6-9.1%) over 2.5 yrs• Risk factors: age > 10yrs; mediastinal mass at Dx;

enlarged lymph nodes.

VTE rate remains high despite LMWH prophylaxis in ALL + ASP

1 Sibai, BJH 2020; 2 Orvain, Blood 2020

• LMWH reduces VTE rate but probably not sufficient 1

• VTE incidence of 16% despite prophylactic measures 2

1Greiner, Haematologica 2019; 2Male, Haematologica 2019; 3O’Brien, Thrombosis Haem 2019

THROMBOTECT1 takes the lead in ALL 2

• Apixaban prophylaxis being assessed in children with ALL and CVC (PREVAPIX-ALL) 3

Overview1. Preventing thrombosis in cancer outpatients

2. Treating cancer-associated VTE

– DOAC vs. LMWH

– Treatment duration

3. Practical aspects of AC management (in CAT)

4. Treating recurrent VTE

5. Arterial thrombosis in cancer

Higher risk of recurrent thrombosis in VTE & cancer (vs. no cancer)

Prandoni, Blood, 2002

Case #3

• 51 year old male with morbid obesity (125 kg)

• Newly diagnosed colon cancer– Hemicolectomy and wedge resection of antrum due to suspected GIST in 7/2019

• Post-operative PETCT (8/2019)– Incidental bilateral pulmonary embolism and Lt leg DVT

– Breast mass, compatible with breast cancer – for investigation

• SMA, CBC and PT-PTT-FIB unremarkable

Which anticoagulant?

CLOT1

32

Why LMWH for cancer-associated thrombosis?

1Lee et al. N Engl J. Med. 2003; 2Lee et al. Jama. 2015

CATCH2

DOACs in Cancer associated VTE

1 Young, JCO 2018; 2 Raskob, NEJM 2017; 3McBane, JTH, 2019; 4Agnelli, NEJM 2020

Eliquis

ADAM VTE 3, Caravaggio 4

Rivaroxaban Select-d 1

Edoxaban

Hokusai-Cancer 2

Dalteparin(CLOT regimen)

Young, JCO 2018

...אבל, כרוך בפחות אירועים תרומבוטיים חוזריםxareltoטיפול ב , בסרטן

Young, JCO 2018

xareltoיותר דימום עם

Raskob, NEJM 2017

Hokusai-Cancer

Hokusai-Cancer

Raskob, NEJM 2017

• Select-d: Rivaroxaban (vs. dalteparin)

– ↓ recurrent VTE

– ↑ bleeding

DOACs in Cancer associated VTE

Young, JCO, 2018

Outcome (6 months) Dalteparin (95% CI) Rivaroxaban (95% CI) HR (95% CI)

VTE recurrence 11% (7-16%) 4% (2-9%) 0.43 (0.19-0.99)

Major bleeding 4% (2-8%) 6% (3-11%) 1.83 (0.68-4.96)

Clinically relevant non-major bleeding

4% (2-9%) 13% (9-19%) 3.76 (1.63-8.69)

Increased bleeding with DOACs especially in GI cancers

• Where?– Upper GI major bleeding (in all GI cancers) 2

• Select-d amended to exclude gastroesophageal cancers1

– Urothelial CRNMB 1

• Why?– Intraluminal tumors and post-operative bleeding– Mucosal toxicity associated with anticancer therapy (e.g. 5-FU)?

• Who is at risk?– GI cancer – Urothelial cancer ± nephrostomy– Additional bleeding risk factors 2

1Young, JCO 2018; 2Raskob NEJM 2018; 3Kraaijpoel, Thromb Haem 2018

Are all major bleeds equal in Hokusai-cancer?

Kraaijpoel, Thrombosis & Haemostasis, 2018Cancer Associated Thrombosis Work Group40

More upper GI bleeding, in all types of GI cancer (including pancreas & hepatobiliary)

Apixaban for VTE in cancer

Agnelli, NEJM 2020

Hokusai, Select-d & Carravagio meta-analysis

Mulder, Blood 2020

• Type of VTE

– Upper limb DVT & Catheter related thrombosis

– DVT in unusual sites (sinus vein thrombosis/ splanchnic vein thrombosis etc...)

• Hematological malignancies (esp. acute leukemia) & brain cancer

• Thrombocytopenia (platelets < 50-100K)

• Concomitant drug use

– Antiplatelet drugs (except aspirin 75mg)

– Inhibitors/inducers of PGP / CYP3A4

• CKD ≥ stage IV (eGFR <30 ml/min)

• eGFR 30-50 in only 7.3% in Hokusai-cancer 1

Not enough data for specific populations

1Raskob, NEJM 2018

ISTH SSC Guidance statement for acute CAT 1

• Low risk of bleeding & no drug–drug interactions (DDI’s) → Specific DOACs

• High bleeding risk ± DDI’s Prefer → LMWH

• Shared decision-making:

– Reduction in recurrence but higher bleeding rates with specific DOACs

• Patient values to consider 2

– No interference with cancer treatment | Efficacy

– Safety | Oral administration over injection | Price

• Similar recommendations from ITAC3 and ASCO4

1Khorana, JTH 2018; 2Noble, Haematologica, 2015; 3Farge, Lancet 2019; 4Key, JCO 2019

“Rather than view the DOACs as an oral revolution sent to

usurp the evil injections of LMWH, we should consider them

welcome additions to our armory against CAT”

Noble, Thrombosis Res, 2018

Approaching AC decision after 3-6 months Rx for VTE

Rodger & Le Gal, Blood adv 2018

• Don’t routinely use extended lower dose DOAC Rx in CAT

– Ongoing trials of Apixaban 5mg bid vs. 2.5mg for 12 mo., after 6 mo. CAT Rx

• API-CAT (NCT03692065): Breast, prostate, colon- rectum

• EVE-Extended (NCT03080883): All histologies

• Case fatality from recurrent VTE appears higher than from major bleeding1

• Fatal rec. VTE in cancer = 1.9/100 pys | rec. VTE Case fatality rate = 14.8%

• Fatal MB in cancer = 0.8/100 pys | MB Case fatality rate = 8.9%

• Different balance compared to some estimates from non-cancer patients

Little is known on DOACs in CAT beyond 6-12 months

1Abdulla A…… Lee AYY, Thrombosis Haemostasis 2020

CAT pts alive at 6 mo. remain at high risk of rVTE, CRB and death

1Schmidt…… Lee AYY, Thrombosis Res 2020

Napolitano, JCO 2014

Consider residual vein thrombosis?

Cancer-DACUS study

Jara-Palomares, Br J cancer 2018

Risk adapted model using d-dimer and Hs-CRP?

• Minimum of 3 months for acute DVT and 6 months for acute PE 1

• Continue if 1:

– Metastatic disease or progressive cancer

– Requires ongoing chemotherapy or a thrombogenic regimen

– Previous history of VTE or high-risk cancer

• Promising investigational biomarkers:

• Residual vein thrombosis2; d-dimer and CRP3

When to discontinue AC in CAT?

1Lee, Blood, 2017; 2Napolitano, JCO 2014; 3Jara-Palomares, Br J cancer 2018

Overview1. Preventing thrombosis in cancer outpatients

2. Treating cancer-associated VTE

3. Practical aspects of AC management (in CAT)a. High bleeding risk; Thrombocytopenia

b. Drug-drug interactions; High body weight; Bariatric surgery;

c. Indications for monitoring drug levels

4. Treating recurrent VTE

5. Arterial thrombosis in cancer

Practical aspects of DOAC management (in CAT)

• Assess nausea/vomiting potential & thromboembolic risk– “Just in case” LMWH prescription vs. switching to LMWH 1

• Consider LMWH over DOACs if invasive procedures anticipated soon– 24hr vs. 48hr break

• Assessing bleeding risk

• Thrombocytopenia: avoid if platelets are/expected < 50-100K

• DOAC-drug interactions– Anti-cancer, Anti-emetic; Anti-convulsive

1Riess, The Oncologist, 2018

Case #3 - continued

• 51 year old male with morbid obesity (125 kg)• Colon cancer

– Hemicolectomy and wedge resection of antrum due to suspected GIST in 7/2019

• Incidental bilateral pulmonary embolism and Lt leg DVT– LMWH treatment for two months | Did not tolerate treatment– Apixaban started (reluctantly) | DOAC levels requested but not done

• 3 weeks after starting apixaban (5mg*2) treatment– Recurrent iliofemoral DVT

• Almost unmeasurable apixaban levels at trough at the time of event– Patient reports full adherence to apixaban

Reason/s for failure? Proposed management - TBD later

DOACs in high body weight

• Pharmacokinetic studies suggested lower peak and trough concentrations associated with HBW

• ISTH GLs recommend against DOACs when BMI > 40 or weight > 120kg1

• Recent data suggest comparable safety of DOAC and VKA in HBW2

– For VTE and AF

1Martin, JTH 2016; 2Kushnir, Lancet Haematol 2019

DOACs generally avoided in patients with upper GI surgery

Martin, Am J Med 2017

Criteria for DOAC dose-reduction in Acute VTE

Shulman, Blood 2017

||In the European product monograph for rivaroxaban “increased risk of bleeding”:• Patients with uncontrolled severe arterial hypertension• Receiving concomitant treatment affecting hemostasis.

Labeled enoxaparin dose reduction if eGFR < 30ml/min = 1mg/kg once daily

DOAC dosing in VTE (eGFR<30): ESC PE guidelines1

• Dabigatran is not recommended in patients with CrCl <30 mL/min.

• Edoxaban should be given at a dose of 30 mg OD in CrCl 15 - 50 mL/min – not recommended in patients with CrCl <15 mL/min.

• Rivaroxaban and apixaban used with caution in CrCl 15 - 29mL/min,– not recommended in patients with CrCl <15 mL/min.

• Anticoagulation in hemodialysis or ESRD<15 is a complicated issue – Reviewed elsewhere2

1Konstantinides, Eur Heart J 2019; 2Konigsbrugge and Ay, RPTH 2019

Bleeding (but not VTE) risk is increased when eGFR < 30

Catella, JTH 2020Ongoing clinical trial for VTE and GFR < 30: VERDICT trial, NCT02664155

DOAC dose in AF and advanced renal disease (eGFR<30)

1Konigsbrugge and Ay, RPTH 2019

Inappropriate DOAC dosing in AF leads to adverse outcomes

Yao, JACC 2017

Assessing the bleeding risk in cancer patients with AC

• Risk of bleeding is increased in cancer patients receiving AC for VTE 1,3

• Presentation and course of AC-associated bleeding are not more severe in cancer 2

• Risk factors for AC-associated bleeding in cancer

– CKD ≥ stage III 3 | Platelets < 100K x 109/L 3

– Metastases 3 | GI primary 3

– Age > 75 yrs 4 | Intracranial malignancy (extracranial bleeding) 4

– 1⁰ brain cancer (ICH) 5

• Pilot data supporting safety of DOACs vs. LMWH in 1⁰ & 2⁰ brain cancer 6

1Prandoni, Blood 2002; 2Kraaijpoel, Thromb Haem 2018; 3Angelini, Am J Hem 2019; 4Kamphuizen, JTH 2018; 5Mantia, Blood 2017; 6Carney, JTH 2019

Case #4

• 41 year old female with no prior medical Hx

• Multifocal Glioblastoma multiforme diagnosed ~2 months earlier– Completed radiotherapy. One week into 2nd temozolomide course.

– 6 temozolomide courses planned

• Newly diagnosed iliofemoral deep vein thrombosis

• Unremarkable CBC and SMA

Anticoagulation? If so, which? IVC filter?

High risk of ICH (± LMWH) in 1⁰ and 2⁰ brain cancer

• 14.7% to 22% had major ICH @ 1 year 1,2

– Highest risk: Renal cell carcinoma and melanoma 1

• No increase in major ICH with LMWH in brain metastases 1

• Increased major ICH with LMWH in 1⁰ brain tumors (HR 3.37 to 13.26) 2

– ICH → inferior OS

– PANWARDS to stratify bleeding risk??

• Hypothesis-generating data supporting safety of DOACs vs. LMWH 3,4

1Donato, Blood 2015; 2Mantia, Blood 2017; 3Carney, JTH 2019; 4Raskob, NEJM 2018

DOACs may be comparable to LMWH in 2⁰ brain cancer• 96 patients with brain metastases (41 DOAC, 55 LMWH)

• Definitive international registry underway

Leader A, Hamulyák EN et al, ISTH 2020 (PB2116)

0 50 100 150 200 250

FUDays

0.000

0.025

0.050

0.075

0.100

0.125

Pro

babi

lity

LMWHDOACType of anticoagulant at study index

Cumulative Incidence Functions

0 50 100 150 200 250

FUDays

0.000

0.025

0.050

0.075

0.100

0.125

Pro

babi

lity

LMWHDOACType of anticoagulant at study index

Cumulative Incidence Functions

HR 0.77 (95% CI: 0.23-2.59)

for DOAC vs. LMWH

Pro

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f an

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CH

Case #4 - continued

• 41 year old female with no prior medical Hx

• Multifocal Glioblastoma multiforme diagnosed ~2 months earlier

• Newly diagnosed iliofemoral deep vein thrombosis– LMWH started

• 2 weeks into LMWH treatment (day 18 of temozolomide course):

– Platelets = 10,000/micL

– HIT immunoassay negative

– No bleeding

Management?

Managing antithrombotic therapy in thrombocytopenia1

• Thrombocytopenia does not reduce the risk of recurrent arterial/venous thrombosis

• Threshold for changes in anticoagulation = 50,000/µL

– Lower for single antiplatelet therapy (APT) = 20-30,000/µL?? 2

• High bleeding risk

– 30-day bleeding rate (17%) >> arterial TE in AF and plt<50K (3%) 3

• Lower thrombotic risk: non-acute VTE, Catheter-related thrombosis, low risk AF

• High thrombotic risk in acute VTE (i.e. < 30 days)

• Options: Hold | Reduce dose | Continue ± ↑ platelet transfusion threshold

1Leader, Crit Rev Oncol Hematol 2018; 2Feher, Oncologist 2017; 3Livneh…. Leader, under review 2020

Managing antithrombotics in thrombocytopenia (2)

CAT and thrombocytopenia, ISTH guidelines 1

• Acute CAT & platelets < 50,000/µL

– high thrombotic risk: Full LMWH with platelet Tx (target ≥ 40-50,000/µL)

– lower thrombotic risk or sub-acute/chronic CAT

• Platelets 25-50,000/µL: Reduce LMWH dose

• Platelets < 25,000/µL: Hold

• DOACs when platelets < 50,000/µL : May not be appropriate

1Samuelson-Bannow, JTH 2018

We really don’t know, and there is reason to exercise caution, because:

1. Patients with platelets < 100K (Riva) or < 50K (apix/edox) excluded

2. Increased clinically rel. and/or major bleeding with edoxaban and rivaroxaban1,2

– ISTH guidance suggests LMWH over DOAC for CAT with high risk of bleeding3

3. Increased major bleeding with prophylactic DOAC doses vs. placebo in cancer4,5

4. No cohorts of DOAC use in CAT and thrombocytopenia

Can DOACs be safely used for CAT in thrombocytopenia?

1Young, JCO 2018; 2Raskob, NEJM 2018; 3Khorana, JTH 2018;4Carrier, NEJM 2019; 5Khorana, NEJM 2019

MATTER study

NCT03288441

– Population: Hematological malignancy, platelets < 50,000/L & antithrombotic Rx

1. Incidence and predictors of bleeding and thrombosis?

2. Optimal management strategy?

– Design: Prospective observational cohort study (FU = 30 days)

a) Variables: Management and markers of hemostasis at baseline

b) Primary outcome: Composite of major bleeding and thrombosis

• 18 Centers in the Netherlands, Italy, Israel and USA (260 enrolled from 19 centers)

• Interim analysis: August 2020 (N_target = 300)

Case #4 - continued

• 41 year old female with no prior medical Hx

• Multifocal Glioblastoma multiforme diagnosed ~4 months earlier

– Good response (MRI) | Temozolomide dc’d and TCP resolved

– Receiving carbamazepine due to seizures

• Iliofemoral deep vein thrombosis ~2 months earlier– LMWH Rx

• LMWH poorly tolerated. Patient read about DOACs.

DOACs viable option? Any issues?

Interactions between DOACs & cancer Rx are a concern

• DOACs are substrates of P-gp and/or CYP3A4

– PgP/CYP3A4 inhibited or induced by some targeted cancer therapies.

• ↑ bleeding and thrombosis in non-cancer with DOAC & CYP3A4/PgP Inh’s 1,6

– Signal of ↑ bleeding with edoxaban and strong PGP inh. in cancer 2

• Interactions may be clinically relevant1,2 →→ under investigation (TacDOAC registry)

• Drug-drug interactions (DDIs) influence choice of anticoagulation in cancer 3,4

• No theoretical concern that DOACs affect anti-cancer medication 5

1Momin, Eur Heart J 2017; 2Raskob, NEJM 2018 (supp); 3Khorana, JTH 2018; 4Delluc, JTH 2019; 5Reiss, Criticial Rev Oncol/hematol 2018; 6Bellesoeur, Criticial Rev Oncol/hematol 2018

Selected drug-drug interactions with DOACs

1Witt, Blood advances 2018

Selected drug-drug interactions with DOACs in cancer

Lee, Blood 2013; Bellesoeur, Criticial Rev Oncol/hematol; 2018 Kraaijpoel, Blood 2018; Mosarla, JACC 2019

emend

Management of potential DDIs (in cancer)• ASH 2018 VTE GLs1: use alternative anticoagulant rather than DOAC, IF

– Inhibitors or inducers of P-glycoprotein (P-gp)– Strong inhibitors or inducers of cytochrome P450 (CYP) enzymes

• What are the culprit drugs? – Non-inclusive lists exist | high level of suspicion and consult pharmacologist

• Consider renal & hepatic function, type of interaction and indication, in decision making

• Options | Consult specialist1. Alternative anticancer/supportive medication or alternative anticoagulation2. Measure DOAC levels??

→ No dose adjustment data available→ Let’s discuss

1Witt, Blood advances 2018

Assays for DOAC drug level measurement

Connors J, Blood 2018

My two cents worth on DOAC drug level measurement

• High inter and intraindividual variability

• Wide ranges for peak and trough values– Dabigatran levels not superior to clinical criteria for dose reduction1

• Hypothesis-generating data suggest that trough and peak DOAC levels may be associated with adverse clinical outcomes in selected non-cancer patients3,4

• ASH guidelines currently against anticoagulant monitoring for LMWH/DOAC5

• Levels can mainly give red or green lights, combined with the clinical context

• Potential utilities– Absorption issues | Theoretical drug-drug interactions | ESRD | Extremes of body weight

– Treatment failure | Possibly to guide use of antidotes when timing is borderline

1Chan, JTH 2015; 2Connors J, Blood 2018; ; 3Testa, JTH 2018; 4Testa, JTH 2019; 5Witts, Blood advances 2018

ISTH SSC on Hemostasis and malignancy

International registry on DOACs and targeted cancer RxRabin sub-study on DOAC levels

Category (disease commonly used) Medications

BTK inhibitors (CLL and lymphoma) Ibrutinib

Acalbrutinib

BCR-ABL inhibitors (CML) Imatinib

Nilotinib

EGFR, ALK inhibitors (lung cancer) Osimertinib

Alectinib

HER2 inhibitors (breast cancer) Lapatinib

Cyclin-dependent kinase inhibitor (breast

cancer)

Palbociclib

BRAF inhibitor (melanoma) Vemurafenib

VEGF inhibitors (various cancer) Sunitinib

Cabozantinib

mTOR inhibitor (various cancer) Everolimus

Treating CAT: Summary

Ay, Ann Oncol 2019Don’t routinely use reduced-dose (“extended”) DOAC in CAT

Also see ISIM guidelines

Overview1. Preventing thrombosis in cancer outpatients

2. Treating cancer-associated VTE

3. Practical aspects of AC management (in CAT)

4. Treating recurrent VTE

5. Arterial thrombosis in cancer

Case #3 - continued

• 51 year old male with morbid obesity (125 kg)• Colon cancer

– Hemicolectomy and wedge resection of antrum due to suspected GIST in 7/2019

• Incidental bilateral pulmonary embolism and Lt leg DVT– LMWH treatment for two months | Did not tolerate treatment– Apixaban started (reluctantly) | DOAC levels requested but not done

• 3 weeks after starting apixaban (5mg*2) treatment– Recurrent iliofemoral DVT

• Almost unmeasurable apixaban levels at trough at the time of event– Patient reports full adherence to apixaban

Proposed management?

Shulman, Blood 2017Approach to recurrent VTE on AC

1Shulman, Blood 2017; 2Farge, Lancet Oncol 2019; 3Key, JCO 2019

Treating recurrent VTE in cancer

Or switch to DOAC2

IVC filter is a weak recommendation by

some3

Do’s and don’ts with breakthrough VTE

Shulman, Blood 2017

Overview1. Preventing thrombosis in cancer outpatients

2. Treating cancer-associated VTE

3. Practical aspects of AC management (in CAT)

4. Treating recurrent VTE

5. Arterial thrombosis in cancer– Ischemic stroke | MI | peripheral thromboembolism

– Acute thrombotic events in active cancer

– NOT discussed: CV morbidity in cancer survivors

• 68 year old female

31/1/2019: Metastatic gastric adenocarcinoma

6/3/2019: Ischemic stroke – ESUS → Full dose Enoxaparin

13/3/2019: Upper GI bleeding and Type 2 MI → Enoxaparin stopped

18/3/19: 1st line FOLFOX started

21/3/2019: Recurrent upper GI bleeding → Palliative radiotherapy

2/5/19: Pulmonary embolism & splenic infarct → Full dose Enoxaparin

Is outpatient treatment with a DOAC an option?

Case #5

Increased arterial thrombosis risk in newly diagnosed cancer

Navi, JACC 2017

279,719 pairs

• ↑ ischemic stroke1 | ↑ myocardial infarction 1

– HR 2.2, 95% CI: 2.1-2.3 1

– Overall: up to 4.7% (95% CI: 4.6-4.8%) at 6 months 1,2

• ~ Resolved at 1 year 1

• High risk of recurrent ATE after ischemic stroke 3,4

– 16% recurrent stroke at 6 months

• Overall, ATE < VTE (2.6% vs. 8.4%) 2 | ATE = VTE in high risk cancers 2

• Associated with increased mortality (HR ~ 3) 1,3

– vs. non-cancer 1 | vs. no ATE 2

Arterial thromboembolism (ATE) in Cancer

1Navi, JACC 2017; 2Grilz, Haematologica 2018; 3Navi, Neurology 2014; 4Parikh, J Stroke Cerebrovasc Dis 2017;

Lung, RCC, MPN

Male, ↑ Age, Smoking, HTN

Factors associated with arterial thrombosis in cancer

1Navi, J Am Coll Cardiol 2017; 2Grilz, Haematologica 2018

Arterial thrombosis

Cancer type

Cancerbiology

CV risk factors

Anti-cancer drugs

Cancer stage

Drugs associated with arterial thrombosis in cancer

1Choueiri, JCO 2010; 2Scappaticci, JNCI 2007; 3Jain, blood adv 2019; 4Aronson, Thr Res 2018;5Haque, Jama Oncol 2016; 6Abdel-Qadir, Eur J Cancer 2016; 7Tully, Cancer 2016; 8Proverbs-Singh, JNCI 2012

Anti-VEGF Rx 1,2

(e.g. bevacizumab, sunitinib, sorafenib)

BCR-ABL TKIs 3

(ponatinib, nilotinib, dasatinib)

Immunomodulators4

(e.g. thalidomide, lenalidomide)

Aromatase inhibitors 5,6

Platinum-basedchemotherapy

(cisplatin) 7,8

• Treatment 1

– Anticoagulation? | Especially if NBTE not ruled out

– Antiplatelet?

• Prospective randomized pilot study in cancer-associated ischemic stroke 2

• Prevention

– For high risk patients?

• E.g. Prior ATE, CV risk factors

How to manage cancer-associated arterial thrombosis?

1Dardiotis, Int J Onc 2019; 2NCT01763606

• Patients with ATE have an increased risk of undiagnosed cancer 1,2,3

– Up to 3.5% (95% CI: 3-3.9%) at 12 months 1 | Esp. in 6 months after ATE

• RR highest in unexplained ATE 3 (up to 3.49)

– age≤50 years

– no prior cardiovascular (CV) disease

– no modifiable CV risk factors

• Practice points

– Increase awareness in unsuspected ATE similar to unprovoked VTE

– Screening not routinely recommended

Should we suspect cancer if ATE and no CV risk factors?

1Sundbøll, Circulation 2018; 2Navi, Blood 2018; 3Leader, EHA 2020 (#S325)

• Atrial fibrillation (ISTH GLs: Delluc, JTH 2019)

• NBTE

• Non-thrombotic cancer-associated cardiovascular disease (Cardiomyopathy, HTN)

Beyond the scope of this lecture…..

94

Incidental and subsegmental PEAC in palliative

care settingRabbits

avileader@yahoo.com | 0544437212

Distal DVT CVCs