1. To Be or Not To Be: Ethical Issues in Curative Therapies for Sickle Cell Disease Lakshmanan Krishnamurti, MD Kathleen Spencer, RN, MSN, CPNP

2. Aflac Cancer and Blood Disorders Center Objectives Rationale and indications for hematopoietic cell transplantation (HCT) for individuals with sickle cell disease (SCD) Understand basic ethical principles Understand ethical principles surrounding sickle cell disease and transplantation

3. Aflac Cancer and Blood Disorders Center State of the Art of HCT for SCD Excellent results in children with HLA identical sibling donor Challenge: donor availability, awareness/access, gonadal toxicity HCT from unrelated donors feasible. Additional challenge: Rate of CGVHD BMT for Adults effective Additional challenge: Prior organ damage HCT from Haploidentical family donors feasible, expands donor pool Challenge: Engraftment 3

4. Aflac Cancer and Blood Disorders Center Steinberg, M.H. (2008) Sickle cell disease and associated hemoglobinopathies. In Cecil Medicine. 23rd ed. Goldman, L., Ausiello, D., et al., Eds. Saunders/Elsevier, Philadelphia. pp. 1217–1226.

5. The Rationale for HCT in SCD Hyposthenuria Proteinuria Silent infarct Dactylitis Pulmonary hypertension Pain is major cause of morbidity Multi-organ damage Impaired quality of life Decreased life span by ~30 years Pathology for the Health Professions, Dajmanov, Ivan. Editor. 4 th Edition Chapter 9 Figure 9-10, Page 208. Feb 2011, Elsevier Saunders, St. Louis MO

6. Aflac Cancer and Blood Disorders Center Disease modifying therapy Hydroxyurea Chronic Transfusions Decreased complications but 6 Supportive Care Prevention of complications Symptom relief Survival to adulthood but Curative Therapy HCT ?Gene therapy High rate of Cure but Ongoing morbidity, Impaired QoL, Premature mortality Therapeutic Options for SCD TRM, CGVHD Gonadotoxicity

7. Platt et al.NEJM 330 (23): 1639, Figure 2 June 9, 1994 Dramatic increase in mortality risk in Adults Established organ damage rather than predicted risk Impact of HRQOL and access to care Increased Risk of Premature Mortality in Adults with SCD

8. Aflac Cancer and Blood Disorders Center Conditioning Regimens for SCD 8

9. Aflac Cancer and Blood Disorders Center Current outcomes of HLA identical sibling donor HCT for SCD 1000 patients, 23 countries, 88 transplant centers Myeloablative regimen in 87% BU/CY/ATG/CsA/MTX commonest regimen Bone marrow 84%, also UCB, PBSC 3 year OS 94% EFS 90%. OS stable after 2 yrs Acute Grade II-IV 14 % CGVHD 13% Increased GVHD, decreased EFS with age Cappelli et al ASH 2015 9

10. Outcome after HCT among engrafted patients No painful crises No episodes of acute chest syndrome No episodes of splenic or hepatic sequestration No RBC transfusions No stroke, TIA or hemorrhagic CNS events

11. Aflac Cancer and Blood Disorders Center Outcomes of HCT for SCD Brain MRI stable or improved Decrease in TCD velocities Full Scale IQ unchanged Gonadal toxicity in 80%, especially females Unchanged or improved pulmonary function. Results reproduced worldwide 11

12. Indications for Hematopoietic Stem cell Transplantation in Sickle Cell Disease Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic malignancies. Manual of Clinical Hematology, 3 rd edition 2002:399-409

13. Aflac Cancer and Blood Disorders Center Results of SCURT (BMT CTN 0601): Unrelated Donor for SCD Graft rejection in 3 (10%), all by day +100 and with autologous reconstitution 7 deaths, all age >14 yrs: 1 after BMT #2, 6 due to GVHD (143-960 days post) EFS=76% OS=86% Primary endpoint of trial met Shenoy, ASH 2015

14. Aflac Cancer and Blood Disorders Center Results of SCURT (BMT CTN 0601): Unrelated Donor for SCD Shenoy, ASH 2015 CI gr II-IV (d+180)=31% CI gr III-IV=16% CI (1yr)=62% CI extensive=38% Chronic GVHD was the leading cause of toxicity and morbidity Other toxicities: –Infections in 76%, EBV and CMV reactivation in 23% (each) –PRES with hypertension and seizures in 35%, all in 1 st 6 mo post-BMT, all recovered without sequelae

15. Aflac Cancer and Blood Disorders Center Haploidentical Donors Expands Donor Pool for Sickle Cell Disease 14 patients transplanted from haploidentical donors Median age 30 ( range 15-46yrs) 3 developed posterior reversible encephalopathy 1 had seizure 6 rejected the graft and had autologous recovery No acute or chronic GVHD 1 patient with EBV viremia, 1 with TB, 1 with pulmonary infiltrates of unknown etiology Bolanos-Meade et al Blood Oct 2012

16. Aflac Cancer and Blood Disorders Center Bioethics is the discipline of ethics dealing with moral problems arising in the practice of medicine and the pursuit of biomedical research. Physicians may confront ethical dilemmas regularly in their individual relationships with patients and in institutional and societal decisions on health care policy. 16

17. Aflac Cancer and Blood Disorders Center Ethics Belmont report (1974) identified respect of persons, beneficence and justice as basic ethical principles Beauchamp and Childress identified the ethical principles as nonmaleficence, beneficence, autonomy and justice “ The four clusters of principles do not represent a general moral theory. They only provide a framework for identifying and reflecting on moral problems.” –Beauchamp and Childress 17 Principles of Biomedical Ethics 7 th Edition Tom L. Beauchamp and James F. Childress 2012

18. Aflac Cancer and Blood Disorders Center Nonmaleficence Do no harm Harm during and after transplant can be to the patient, donor and/or family/caregiver With or without a HCT there may be harm to the patient Unless there is a sufficient reason not to, one has an obligation not to do that which is likely to produce more harm than good 18

19. Aflac Cancer and Blood Disorders Center Clinical Vignette 19 15 yo female with Hgb SS diagnosed via GA newborn screening First major hospitalization at 4 years of age Complications include: 3 hospitalizations for pain crisis, Echocardiogram in 2011 showed borderline TRJ velocity of 2.3 m/s, 2 hospitalizations for acute chest syndrome (ACS), Abnormal transcranial dopplers and MRIs (2006, 2007 and 2011) and on chronic transfusions to prevent stroke Currently doing well in 10 th grade (A’s and B’s) No MSD options; 8/8 matched unrelated bone marrow donor

20. Aflac Cancer and Blood Disorders Center Clinical Vignette 15 yo underwent 8/8 matched unrelated bone marrow transplant Complications before day+100: acute graft versus host disease of the skin responsive to steroids and posterior reversible encephalopathy syndrome (PRES) Complications after day +100: extensive chronic graft versus host disease (skin, joints, mouth, liver and lungs) Now patient is 18 yo with DL CVL, on 17 different medications (includes immunosuppressants as treatment of cGVHD) 20

21. Aflac Cancer and Blood Disorders Center Beneficence Unless there is a sufficient reason not to, one has an obligation do what is more likely to do more good than harm. For patients who are competent, one ought normally to give most weight to what the patient sees as beneficial Welfare of the patient is the ultimate goal What is the benefit of HCT to a patient with SCD? 21

22. Aflac Cancer and Blood Disorders Center Clinical Vignette 7 yo male with Hgb SS 11 hospitalizations since 2 years of age (ranging from 2-6 days) for pain crisis and ACS Lives with mother, father and two younger siblings (4 yo brother and 2 yo sister) 4 yo brother is a 8/8 match to the patient 22

23. Aflac Cancer and Blood Disorders Center Clinical Vignette 7 yo now day +360 status post matched sibling bone marrow transplant No history of acute of chronic GVHD Back in the 2nd grade and playing soccer No hospitalizations since his transplant No pain crisis or ACS 23

24. Aflac Cancer and Blood Disorders Center Autonomy Respect for Persons: individual persons have right to make their own choices and develop their own life plan Is the patient able to make an informed decision Do they understand effects of treatment, on health, life, lifestyle, values, family friends, etc. Late effects of HCT in the context of parents making decisions for children Decisions made in “ Hot state vs. cold State” Do families hear, know, and understand risks 24

25. Aflac Cancer and Blood Disorders Center Autonomy: What should a prudent person know? The diagnosis The nature and purpose of the proposed treatment. known risks and consequences of treatment excluding those too remote and improbable doctor’s and hospital’s success and failure rates benefits expected and the likelihood All alternative treatments prognosis if no treatment is given. 25

26. Aflac Cancer and Blood Disorders Center Clinical Vignette 2 yo female with moderately severe SCD Hospitalizations for pain crisis and ACS Donor options include an 8/8 matched sibling Chemotherapy that will be administered prior to the transplant includes Cytoxan-high risk for infertility 26

27. Aflac Cancer and Blood Disorders Center Factors that interfere with Autonomy Reading level of patient Age of patient Education level of patient General understanding of HCT process 27

28. Aflac Cancer and Blood Disorders Center Back to Clinical Vignette Parents make the best decision for this patient with the patient’s ultimate welfare being the goal Patient is now 18 years of age and wants to have children 28

29. Aflac Cancer and Blood Disorders Center Justice Fairness in distribution and access of what is medically needed Due process and open discussion Medical need should not be determined by ability to pay, social worth, obstacles to treatment, patient contribution to illness, and past use of resources No rationing at the bedside HCP is patient advocate and expert contributor to healthcare policy 29

30. Aflac Cancer and Blood Disorders Center Clinical Vignette 12 year old male with SCD Lives in rural GA, approximately 4 hours from Egleston Matched sibling donor option (4 yo brother) Single mother with three children in the household (including patient)-mother works part- time at local factory Insurance: Medicaid 30

31. Aflac Cancer and Blood Disorders Center Justice Can this child come to transplant without private insurance? Does the mother have family support to help with the other children while the patient is admitted for transplant and when they are discharged to the Ronald McDonald House (RMH) (approximately 4 months until they return to their home) 31

32. Aflac Cancer and Blood Disorders Center Back to Clinical Vignette Mother was able to get maternal grandmother to watch other two children while patient is admitted and after transplant while they are required to stay at the RMH Mother was able to take short term disability with reduced pay for at least 6 months Medicaid covered transplant 32

33. Aflac Cancer and Blood Disorders Center Synthesis Ethical principles cannot be used to make decisions in the abstract. take into consideration various social agreements what is in the interest of the patient? what is the standard of care within the profession? what does the patient or his/her surrogate want? Is it consistent with standards of informed consent ? 33

34. Aflac Cancer and Blood Disorders Center Synthesis The least controversial treatment Accords with the interest of the patient Consistent with the standard of care within the profession Agreed to by the patient Consistent with informed consent Satisfies both the principle of non maleficence and beneficence. 34

35. Aflac Cancer and Blood Disorders Center Synthesis: What to do when all conditions are not met Non-maleficence trumps beneficence Patient’s informed decision against a treatment trumps the practitioners recommendation of it This applies whether treatment is indicated or optional When a treatment has both harmful and beneficial outcomes, they must be balanced What to do when parents refuse indicated treatment for a child? 35

36. Aflac Cancer and Blood Disorders Center When a procedure has both harmful and beneficial outcomes 36 Small risk of harm, Significant benefit Medically indicated Significant risk of harm, Small chance of benefit Medically contra-indicated Significant risk of harm, Small chance of benefit Medically Optional

37. Aflac Cancer and Blood Disorders Center Summary: Ethics of HCT for SCD SCD is associated with significant risk of morbidity and mortality especially in adulthood HCT from a matched sibling in patients with symptomatic SCD is associated with significant likelihood of benefit HCT from alternate donors is associated with significant risk and must occur only in clinical trials Particular attention must be given to informed consent Ensure access to HCT to those with limited resources 37