Challenging Case Study: VTE Treatment- “How Long is Long Enough?” - PowerPoint Presentation

Slide1

Challenging Case Study:VTE Treatment- “How Long is Long Enough?”

Thomas W. Butler, M.D., F.A.C.P.

Associate Professor of Clinical Interdisciplinary Oncology

University of South Alabama

Mitchell Cancer Institute

June 22, 2017

Slide2

Thomas W. Butler, M.D.

Nothing to disclose

Off label use of anticoagulants will be discussed

Slide3

Case Presentation:

60

yr

old CM academic educator (

Dean of Library Services

)

2012: Fatigue, anemia, hyperproteinemia, monoclonal protein

2012: Diagnosis

IgAKappa

myeloma

PMH

2009: Prostate cancer, prostatectomy

Moh’s

surgery skin cancers

Cardiac stenting 75% block

Rotator cuff, tonsillectomy

SH/FH

No tobacco

Occ

ETOH

No FH of thrombosis

ASA 81mg

Slide4

Multiple Myeloma

Extensive marrow involvement: Karyotype

Monosomy 7, dup 1q21, +15, +14, t (11;14)

IgA 4890, IgM <5, IgG 175. B2m 5.4, Alb 2.9

Stage III, CD2 UAMS low risk profile

Skeletal

survey:Lucency

C5

PET: Severe

heterogenous

marrow signal, SUV4, No extramedullary disease, Lytic lesion in L ilium SUV= 5.0, multiple

calvarium

(non PET avid)

Slide5

Clinical Course: UAMC TT4

11/29/12 MVDTPACE: 3 x 10

6

CD34 +

1/14/13: MVDTPAVE

3/13/13: MEL 200 + Auto

transplant

10% by bone marrow, labs, CTPET; Improved sacral lesion

May 2013: MEL 200 + Tandem transplant

July 2013:

Followup

showing

10% PC in BM,

Nl

Hgb

and counts, IgA 643

M protein at 1.0 gm/dl. MRD 1.3% plasma cells

Stability of bone lesions not PET avid

Maintenance with VRD because of cytogenetics

Poor tolerance secondary to edema, neuropathy,

cytopenias

2017

CR by CT/PET, Bone marrow

and IgA 200,

B2m

Small

IgAKappa

. Continuing maintenance. Change to orals for QOL

Slide6

Clinical Course: UAMC TT4 Thrombosis

11/29/12 MVDTPACE: 3 x 10

6

CD34 +

1/14/13: MVDTPAVE

2/2013: Lower extremity edema and pain. Doppler Negative

2/8/13 Hit by car with

fx

tibia plateau, fibula, rib

3/13/13: MEL 200 + Auto

transplant

CLOT R leg DVT + Small PE 1.5mg/kg enoxaparin

4/13/2013

Syptomatic

PTE

10% by bone marrow, labs, CTPET; Improved sacral lesion

May 2013: MEL 200 + Tandem transplant

July 2013:

Followup

showing

10% PC in BM,

Nl

Hgb

and counts, IgA 643

M protein at 1.0 gm/dl. MRD 1.3% plasma cells

Stability of bone lesions not PET avid

Maintenance with VRD because of cytogenetics

Poor tolerance secondary to edema, neuropathy,

cytopenias

4/5/15: Acute DVT Pop/Fem LLE

7/31/16: Chronic

occulsive

LLE venous system, RLE negative for clots

9/26/16: RLE edema severe, Acute RLE thrombosis extensive; Severe thrombosis, Heparin drip without resolution

9/28/16:

Thrombectomy

, Heparin/

Xa

inhibitor

2017:

CR by CT/PET, Bone marrow and IgA, B2m

Small IgA Kappa. Continuing maintenance

.

2/6/17: Doppler RLE: No acute findings but chronic changes CFV/Pop. Post

phlebitic

syndrome slow to resolve and affecting QOL

Slide7

The Problem

Cancer is a

thrombophilic

malady

Cancer-associated thrombosis (CAT)

pathophysiologically

different

Risks variable

Benefits variable

Risk assessment needs to be refined objectively

Slide8

The Problem

Duration of therapy

First thrombosis/PTE

Recurrent thrombosis/PTE

Benefit/Risk Ratio

Evidence-based

Non cancer patients

Patients with malignancy

Co morbidities

Multi-variables and confounding factors

Slide9

Objective Considerations

Evaluate clinical risk scores

Utilize risk scores for continued therapy versus windows of treatment for high risk situations

Alternative dosing of anticoagulants

Pathophysiologic markers of risk

Clinical trials

Slide10

Length of Therapy (LOT): One Approach To CAT (Cancer Associated Thrombosis)

Approach

Initial

CAT

Relapse CAT

Phase III in Cancer Patients

None

None

Phase III in Non-Cancer Patients

(Extrapolate)

++

+-

Clinical Risk Model

NO Phase III

NO Phase III

Biological-Based

Risk Model

NO Phase III

NO Phase III

Others

Discussion

Discussion

Slide11

Phase III Lee, et al. 2003

CLOT: LMWH > VKA

In patients with

cancer

and acute venous thromboembolism,

dalteparin

was more

effective

than an oral anticoagulant in

reducing the risk of recurrent thromboembolism

without

increasing the risk of

bleeding

Length of therapy 6 months

Randomized for type of therapy not length

12

mo

followup

(2005: JCO)

Difference survival for patients without metastatic disease

Slide12

Treatment of CAT

Study

Design

LOT (

mo

)

N

Recurrent

VTE (%)

Major

Bleed (%)

Death

(%)

CLOT

Lee, 2003

Dalteparin

OAC

6

336

336

9

17 0.002

6

4 NS

39

41 NS

CANTHENOX

Meyer, 2002

Enoxaparin

OAC

3

67

71

11

21 0.09

7

16 0.09

11

23 0.03

LITE

Hull, 2003

Tinzaparin

OAC

3

80

87

6

11 0.03

6

8 NS

23

22 NS

ONCENOX

Deitcher

,

2003

Enoxap

(low)

Enoxap

(high)

OAC

6

32

36

34

3.4

3.1

NS

6.7

NS

ND

Slide13

Recommendations:

ACCP

ASCOBCSHESCESMO

Bach M, et al 2016

Slide14

Predictors of Recurrent VTE: RIETE Registry

Recurrent PE

Age < 65 (OR

= 3.0)

<3 month from cancer diagnosis (OR

= 2.0)

PE at entry (OR = 1.9)

Recurrent DVT

Age < 65 (OR = 1.6)

<3 month from cancer diagnosis (OR = 2.4)

Patients with Leukocytosis

Increased risk recurrent VTE

Increased risk of death

OR = 2.7

Slide15

Ottawa VTE Risk Score RIETE Registry 2017

Prediction

1st 6

months

11,123 patients

2343 low

4525 intermediate

4255

high

risk

477

VTE

recurrences

Accuracy

and discriminating power was modest with low sensitivity, specificity and positive predictive value.

Slide16

Biomarkers For CAT (Khorana 2010)

Blood counts

Platelet count

Leukocyte count

Hemoglobin

D-dimer

Soluble p-

selectin

Tissue factor (TF)

C-reactive protein (CRP)

Factor VIII

Slide17

Kaplan-Meier estimates of the risk of VTE in patients with risk scores 0, 1, 2, and ≥ 3 according to the risk scoring model developed by Khorana et al.16 The cumulative probability of VTE showed statistically significant association with the risk scores (lo...

Cihan Ay et al. Blood 2010;116:5377-5382

©2010 by American Society of Hematology

Slide18

Kaplan-Meier estimates of the risk of VTE in the expanded risk scoring model including sP-selectin and D-Dimer.

Cihan Ay et al. Blood 2010;116:5377-5382

©2010 by American Society of Hematology

Slide19

Activation Markers For Coagulation in Cancer

Activated cells: Platelets Endothelial cellsActivation peptides Prothrombin F1+2Enzyme inhibitor complexes Thrombin-Antithrombin/TAT Plasmin-A2AP/PAPFibrin monomersFibrinogen or Fibrin Degradation ProductsD-DimerEV (Procoagulant extracellular vesicles) Difficult!

Amiral

J,

Seghatchian

J, 2017

Slide20

Cancer-DACUS: Clinical Characteristics- Residual Clot

Napolitano M, et al 2014

Slide21

Cancer-DACUS Randomization

Napolitano M, et al 2014

Slide22

Cancer-DACUS: Results

Napolitano M, et al 2014

Slide23

SWIVTER (Swiss Venous ThromboEmbolism Registry)

No exclusion criteriaConsecutive patients/multicenterData gathered:VTE diagnosisVTE risk factorsPlanned length of anticoagulationCancer vs non-cancerLess than ½ cancer patients with planned extended anticoagulation (Predicted by)Prior PTEContinued cancer therapyAbsence of infection or ICU admission

Spirk

, D, et al , 2011

Slide24

Clinical Trials: SELECT D

Bach M, et al, 2016

Slide25

Clinical Trials: EINSTEIN CHOICE

Bach M, et al,

2016

Slide26

DALTECAN Study: Omitted Slide Added After Completion of Talk

DALTECANTreatment with dalteparin for up to 12 monthsPrimary aim to determine the safety of 6 vs 12 months of dalteparinProspective multicenterRates of bleeding and recurrent VTE evaluated at 1, 2-6, 7-12 monthsDALTECAN Results334 patients enrolled185 completed 6 months109 completed 12 months

Major bleeding 34/334 (10.2%) at:1 month: 12/334 (3.6%)2-6 months: 14/1237 patient-months (1.1%)7-12 months: 8/2086 patient-month (0.7%)Recurrent VTE 37/334 (11.1%) at:1 month: 19/334 (5.7%)2-6 months: 10/296 (3.4%)7-12 months: 8/194 (4.1%)Conclusion:Major bleeding less frequent during dalteparin beyond 6 monthsRisk of major bleeding or VTE recurrence greatest in the 1st month

Francis CW, et al 2015

Slide27

Feasibility Studies: RCT

Noble SI, et al, 2015

Slide28

ALICAT: Anticoagulation with Low-molecular-weight heparin in the treatment of Cancer-Associated Thrombosis

Results Randomized controlled trial Delays in Opening trial/ComplexityInitial plans: Primary Care Physicians (eventually closed to PCP) Hematologists Oncologists6-month period: 5 out of 32 eligible participants consented to randomization. Below the target of 15 out of 62. Conclusion: Not feasible to progress to a full RCT. Embedded study showed barriers to recruitment to RCT

Noble SI, et al 2015

Slide29

Suggested Strategy First CAT

What is the appropriate duration of anticoagulation?Anticoagulation with LMWH mono therapy should be prescribed for a minimum period of 6 months after the diagnosis of cancer-allocated VTE.  Anticoagulation therapy should be continued beyond 6 months if a patient has active malignancy (i.e. persistent malignant disease) or if ongoing anticancer therapy is plannedFor patients with a low risk of recurrence we suggest that anticoagulation be discontinued after 6 months in the absence of active malignancy (i.e. patients are cured or in complete remission), provided that no anti-cancer therapy is ongoing or plannedFor patients at high risk of recurrence we suggest that anticoagulation be continued but with periodic re-evaluation of risks and benefits 

Khorana AA, et al, 2016

Slide30

Suggested Strategy Recurrent CAT

What is the appropriate treatment strategy in patients with recurrent VTE on anticoagulation?We suggest that cancer patients with symptomatic recurrent VTE despite therapeutic anticoagulation with an agent other than LMWH be transitioned to LMWH, assuming no contraindications to LMWHWe suggest that cancer patients with symptomatic recurrent VTE despite optimal anticoagulation with LMWH continue with LMWH at a higher dose, starting at an increase of > 25% of the current dose or resuming the therapeutic weight-adjusted dose if the patient was receiving a non-therapeutic dose at the time of recurrence.We suggest against the use of IVC filters except in the presence of absolute contraindications to pharmacologic anticoagulation (i.e., active bleeding)  If necessary, retrievable filters should be used and a plan created to retrieve the filter when appropriate.

Khorana AA, et al, 2016

Slide31

LOT: Conclusions

No Phase III consensus

Current guidelines

First VTE

Recurrent VTE

Need for RCT

Consider

Biobanking

/Registry

Guidance for

patients/Patient Satisfaction

Education for Physicians

Slide32

Key Points to Optimize Management and Research of Cancer-Associated Thrombosis

“Despite the fact that

thromboembolism

is

relatively common

in oncology patients and the the relationship between

thrombotic risk

and

specific mechanisms

of tumorigenesis has long been known, many cardinal

elements of prevention and treatment remain unresolved

”

Carmona-

Bayonas

, et al, 2017