Fanconi’s Anemia: Research in Another Form of Community

1. Fanconi’s Anemia: Research in Another Form of Community Sadie P. Hutson, PhD, RN, WHNP Department of Family/Community Nursing ETSU College of Nursing

2. Fanconi’s Anemia (FA) is a model for studies of individuals within families facing chronic illness and an inherited predisposition to cancer.

3. History: Guido Fanconi • Fanconi Anemia (Fanconi pancytopenia syndrome): 1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme” • Fanconi Syndrome (renal Fanconi syndrome): 1936 – Ricketts, growth retardation, proteinuria, glucosuria, and proximal renal tubular acidosis Alter, FA101 (2006)

4. * FA Background • Fanconi’s Anemia • ~1400 cases in literature • Median survival >30 years (SCT) • Aplastic anemia • Acute myeloid leukemia (AML) • Early onset solid tumors

5. Fanconi’s Anemia (FA) - Definition • Autosomal recessive • Physical findings • Aplastic anemia • Leukemia • Solid tumors • Genetic instability • DNA repair defect • >12 genes • More to come Alter, FA101 (2006)

6. * Fanconi’s Anemia Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: W.B. Saunders, Inc., 1993: pp. 216-316.)

7. FA: Physical Findings Part 1 Finding% of Patients Skin – pigmented and/or café au lait 55 Short stature 51 Upper limbs - radii, thumbs 43 Abnormal gonads, male 32 Head 26 Eyes 23 Renal 21 Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: W.B. Saunders, Inc., 1993: pp. 216-316.)

8. FA: Physical Findings Part 2 Finding% of Patients Low birth weight (<5 ½ lbs) 11 Developmental delay 11 Ears, hearing 9 Lower limbs 8 Cardiopulmonary 6 Gastrointestinal 5 No findings 25 Short and/or skin only 11 Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: W.B. Saunders, Inc., 1993: pp. 216-316.)

9. Autosomal Recessive Inheritance

10. FA Laboratory Findings • Low blood counts (pancytopenia) • Large red cells (macrocytosis) • Increased fetal hemoglobin • Increased chromosome breakage in lymphocytes or fibroblasts cultured with DNA crosslinking agents such as diepoxybutane (DEB) or mitomycin C (MMC) Alter, FA101 (2006)

11. FANC Genes Faivre L, Guardiola P, Lewis C, et al: Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood 2000 Dec 15; 96(13): 4064-70

12. FA: Complications • Acute Leukemia • Myelodysplastic Syndrome • Solid Tumors • Liver tumors

13. FA Neoplastic Complications *Primarily oropharynx, gynecologic, esophagus Rosenberg PS, Greene MH, Alter BP: Cancer incidence in persons with Fanconi anemia. Blood 2003 Feb 1; 101(3):6. Rosenberg PS, Socie G, Alter BP, Gluckman E: Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 2005 Jan 1; 105(1): 67-73

14. FA Literature: Types of Solid Tumors 100 cancers in 86 patients

15. FA and Solid Tumors • FA diagnosis preceding tumors • Cumulative incidence of cancer is 75% by age 45. • Cancer diagnosis preceding FA diagnosis • Magnitude of the contribution of FA to “young, atypical” cancer patients is unknown.

16. Preimplantation Genetic Diagnosis Alter, FA101 (2006)

17. FA Summary 1 • Patients with FA have a high risk of malignancies (tumors and leukemia) • These patients lack the usual risk factors seen in the general population • BMT increases the risk of oral cancers, beginning after 5 years • Leukemia may recur long after BMT Alter, FA101 (2006)

18. FA Summary 2 • “Older” patients who present with cancer may be diagnosed with FA after the cancer, or may never know they have FA • “Younger” patients with cancer may present very young; they too may never be diagnosed as FA Alter, FA101 (2006)

19. * FA and Community • Community- A group of people with diverse characteristics who are linked by social ties, share common perspectives, and engage in joint action in geographical locations or settings (MacQueen et al., 2001) • Culture as a part of community

20. FA as a Culture • A rare disease of distinct and common features • Given the genetic basis of the disease, families as a whole (thorough shared experiences) make up a larger culture. • Families are unified through the US and Canadian-based family support organizations • These organizations publicize cutting edge research and clinical knowledge related to FA • Support groups online and at summer camps • Sponsor the majority of activities in the US related to FA • Organizations protect their members from researchers, media, etc. • Gaining the trust of the families is rarely ever accomplished unless the individual has a good rapport with the family support organizations

21. Current Research Studies with FA Families • IBMFS NCI Protocol 02-C-0052 • www.marrowfailure.cancer.gov • Sibling Sub-Study- Protocol 02-C-0052 • Utilization of SCT in FA

22. Sibling Study • Rationale • Sibling relationships are important • Serious childhood illness places great demands on family life • Siblings of children with serious childhood illness experience emotional and behavioral problems • Little is known about the experiences of families with an inherited predisposition to cancer

23. Research Question What is the experience of siblings of patients with Fanconi’s Anemia?

24. Study Design Qualitative descriptive approach • Comprehensive summary of events • Enhances understanding of what it is like to experience a particular situation

25. Methodology: Protocol • The Sibling Study was a sub-study of a National Cancer Institute (NCI) protocol • Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes (IBMFS)

26. Informants • 7 siblings in 5 families enrolled in NCI IBMFS protocol • 3 females; 4 males • Ages 11-21 years • White, non-Hispanic • Average yearly household income of parents >$80,000 (4/5 families) • All informants living in the US • Family Case Study

27. Data Collection and Analysis • In-depth semi-structured interviews, in home communities of informants • Average length: 1.5 hours • Audio-taped, transcribed verbatim • Follow-up interview; Follow-up email • Qualitative Content Analysis • Codes Categories Themes

28. Major Themes of the Sibling Experience • Containment • Invisibility • Worry • Despair

29. Containment “Everyone is born with a mixed bag of [sic] Pandora’s Box, if you will. You’ve just got to make sure you keep the snap of that lid shut...guess that’s your only option, all this vile [stuff] is coming out of the box and you’ve got to deal with it. (16-21)” • Meaning of FA • Parental silence

30. Invisibility “I kind of felt like I fell through the cracks a little bit, for a little while. I think I was in some ways left to fend for myself. It was really kind of a long process with me ignoring everything. Just going about my feeling with it or dealing with it…” (11-15) • People-pleasing • Being busy • Caretaking and protecting • Staying under the radar

31. Worry “I'm worried about what my friends will say about my family. I worry that some of them are acting really strange. You worry if they are going to reject you or like ignore you for a long period of time.” (11-15) • Friends’ perceptions of the family • Future plans and being successful • Worries about the ill brother or sister • FA effect on siblings’ own families

32. Despair “Well, sometimes we are happy because nothing goes wrong. And sometimes [my sister] doesn’t go to the hospital for a while, because she doesn’t need platelets or blood or white cells. Sometimes we are happy, but that is kind of for a short period of time, because she always gets a chemical reaction. It’s kind of sad. (Tearful). (11-15)” • Sadness • Jealousy • Loneliness and abandonment • Uncertainty

33. Summary of Major Findings • Siblings need psychosocial attention • Siblings need to be involved from the time of diagnosis, especially BMT donors • Findings may be generalizeable to other severe chronic childhood illness • Health care system must recognize “unaffected” family members as individuals in need of care

34. Utilization of Stem Cell Transplantation for Fanconi’s Anemia: A Survey of the Patients in the US and Canada

35. SCT Survey Background • Allogeneic stem cell transplantation (SCT) is currently the only available treatment option that can cure aplastic anemia and prevent leukemia in FA patients. • The 10-year probability of survival following an HLA-matched sibling donor transplant is greater than 60% BUT • There is only a 44% probability of 10-year survival for patients receiving alternative donor transplants • Current survival results seem to be improving, but the follow-up time is shorter

36. SCT Study Purpose • The purpose of this study is to survey those families who are members of the FARF and Fanconi Canada to: • gain a clearer understanding of the components of the decision-making process with regard to SCT in FA; • understand the relation of prior therapies to the decision for and outcome of SCT; and • explore the post-transplant cancer incidence.

37. Study Objectives • To survey families who are members of the FARF and Fanconi Canada in order to explore: 1. The number of patients for whom SCT was considered; 2. The number who chose SCT; • The number of HLA-matched sibling donor transplants; • The number of alternative donor transplants; 3. The reasons why SCT was not utilized; 4. The role of the potential risk of post-transplant cancer on the decision regarding SCT; 5. How SCT decisions may have evolved over time in the context of changing perceived risks; 6. Who was influential in making the final decision about SCT; 7. The role of assisted reproductive technologies (i.e. PGD) in making SCT a treatment option; 8. The number of patients who were first treated with ATG + cyclosporine (CSA) and the outcome of subsequent treatment with androgens or SCT; and 9. Neoplastic outcomes post-transplant.

38. SCT Survey Hypotheses & Methods 1. The perceived risks of adverse outcomes influence the utilization of SCT. 2. Certain prior therapies may impact on the outcome of SCT. • 2-phase self-report survey targeting adult patients with FA, mothers, fathers, and significant others/spouses • FARF & Fanconi Canada as sponsors • Investigators blinded to the mailing lists • Study funding by the Clinical Genetics Branch, NCI

39. SCT Survey Progress to Date • Surveys mailed in Canada on November 27, 2006 • Surveys mailed in the US on November 28, 2006 • Point person at CGB batching and scanning surveys • Database development in progress • Phase 2 mailing targeted for January 8, 2007

40. * Long Term Studies Needed for FA • 1. Consider expanding sibling study to other IBMFS diseases of childhood; collaborate with other scholars (Dr. Sally Kinsey-Leeds, UK); • 2. Design studies leading to clinical interventions; • 3. Role of PGD and psychosocial implications for families and children, especially donors for children who did not survive transplant; and • 4. Psychosocial consequences of genetic information: creating a new “patient”

41. * Making Linkages • ETSU- dedication to serving vulnerable populations • Importance of furthering research infrastructure (Appalachian Center for Translational Research In Disparate Populations) • National Institute of Nursing Research- research priorities

42. In Closing... • Research Goals • To develop connections within and among the academic and clinical settings, and collaborate within interdisciplinary teams; • To make meaningful contributions to expand the reach of the nursing discipline, build science and improve the clinical care of patients with inherited cancer predisposition syndromes

43. Acknowledgments • Drs. Blanche P Alter, Mark H Greene, and the entire CGB staff. • Westat IBMFS Study Team • T32 Institutional NRSA in Psychosocial Oncology • NCI CRTA Pre-doctoral Fellowship • American Cancer Society Doctoral Degree Scholarship in Cancer Nursing • Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health • ETSU Center for Nursing Research • Fanconi Anemia Research Fund • Fanconi Canada • Camp Sunshine (Maine) • Patients and families participating in our research