1. 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

2. Thomas W. Butler, M.D. Nothing to disclose
Off label use of anticoagulants will be discussed

3. 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

4. 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)

5. Clinical Course: UAMC TT4
11/29/12 MVDTPACE: 3 x 106 CD34 +
1/14/13: MVDTPAVE
3/13/13: MEL Auto transplant
10% by bone marrow, labs, CTPET; Improved sacral lesion
May 2013: MEL 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

6. Clinical Course: UAMC TT4 Thrombosis
11/29/12 MVDTPACE: 3 x 106 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 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 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

7. The Problem Cancer is a thrombophilic malady
Cancer-associated thrombosis (CAT) pathophysiologically different
Risks variable
Benefits variable
Risk assessment needs to be refined objectively

8. The Problem Duration of therapy Benefit/Risk Ratio
First thrombosis/PTE
Recurrent thrombosis/PTE
Benefit/Risk Ratio
Evidence-based
Non cancer patients
Patients with malignancy
Co morbidities
Multi-variables and confounding factors

9. 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

10. Length of Therapy (LOT): One Approach To CAT (Cancer Associated Thrombosis)
Initial CAT
Relapse CAT
Phase III in Cancer Patients
None
Phase III in Non-Cancer Patients (Extrapolate) ++ +-
Clinical Risk Model
NO Phase III
Biological-Based Risk Model
Others
Discussion

11. 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

12. Treatment of CAT Study Design LOT (mo) N Recurrent VTE (%) Major
Bleed (%)
Death
(%)
CLOT
Lee, 2003
Dalteparin
OAC 6
336 9 NS 39 NS
CANTHENOX
Meyer, 2002
Enoxaparin 3 67 71 11 7
LITE
Hull, 2003
Tinzaparin 80 87 NS 23 NS
ONCENOX
Deitcher, 2003
Enoxap (low)
Enoxap (high) 32 36 34
3.4 NS
6.7 NS ND

13. Recommendations:
ACCP
ASCO
BCSH
ESC
ESMO
Bach M, et al 2016

14. 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

15. 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.

16. 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

17. 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...
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 (log-rank test, P < .001).
Cihan Ay et al. Blood 2010;116:
©2010 by American Society of Hematology

18. Kaplan-Meier estimates of the risk of VTE in the expanded risk scoring model including sP-selectin and D-Dimer.
Kaplan-Meier estimates of the risk of VTE in the expanded risk scoring model including sP-selectin and D-Dimer. The cumulative probability of developing VTE was significantly higher in patients with a high score than in those with a low score (log-rank test, P < .001).
Cihan Ay et al. Blood 2010;116:
©2010 by American Society of Hematology

19. Activation Markers For Coagulation in Cancer
Activated cells:
Platelets
Endothelial cells
Activation peptides
Prothrombin F1+2
Enzyme inhibitor complexes
Thrombin-Antithrombin/TAT
Plasmin-A2AP/PAP
Fibrin monomers
Fibrinogen or Fibrin Degradation Products
D-Dimer
EV (Procoagulant extracellular vesicles) Difficult!
Amiral J, Seghatchian J, 2017

20. Cancer-DACUS: Clinical Characteristics- Residual Clot
Napolitano M, et al 2014

21. Cancer-DACUS Randomization
Napolitano M, et al 2014

22. Cancer-DACUS: Results
Napolitano M, et al 2014

23. SWIVTER (Swiss Venous ThromboEmbolism Registry)
No exclusion criteria
Consecutive patients/multicenter
Data gathered:
VTE diagnosis
VTE risk factors
Planned length of anticoagulation
Cancer vs non-cancer
Less than ½ cancer patients with planned extended anticoagulation (Predicted by)
Prior PTE
Continued cancer therapy
Absence of infection or ICU admission
Spirk, D, et al , 2011

24. Clinical Trials: SELECT D
Bach M, et al, 2016

25. Clinical Trials: EINSTEIN CHOICE
Bach M, et al, 2016

26. DALTECAN Study: Omitted Slide Added After Completion of Talk
Treatment with dalteparin for up to 12 months
Primary aim to determine the safety of 6 vs 12 months of dalteparin
Prospective multicenter
Rates of bleeding and recurrent VTE evaluated at 1, 2-6, 7-12 months
DALTECAN Results
334 patients enrolled
185 completed 6 months
109 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 months
Risk of major bleeding or VTE recurrence greatest in the 1st month
Francis CW, et al 2015

27. Feasibility Studies: RCT
Noble SI, et al, 2015

28. ALICAT: Anticoagulation with Low-molecular-weight heparin in the treatment of Cancer-Associated Thrombosis
Results
Randomized controlled trial
Delays in Opening trial/Complexity
Initial plans:
Primary Care Physicians (eventually closed to PCP)
Hematologists
Oncologists
6-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

29. 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 planned For 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 planned For 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

30. 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 LMWH We 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

31. 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

32. 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