1. Goals of This Talk: Review potential benefits of protons Clinical protocols using protons Review- What have we learned to date?

2. Goals of This Talk: Review potential benefits of protons Clinical protocols using protons Review- What have we learned to date?

3. Reasons for BMT in Leukemia Poor prognosis chromosomal abnormalities Prior myelodysplasia Secondary AML Prolonged Induction Relapsing/Refractory Disease

4. Reasons for BMT in Leukemia Poor prognosis chromosomal abnormalities Prior myelodysplasia Secondary AML Prolonged Induction Relapsing/Refractory Disease

5. E.D. Thomas - 1990 Nobel Prize in Medicine Pioneered bone marrow transplant conditioning regimen Established single fraction, low dose rate TBI regimen along with Cytoxan Used dogs and Cobalt sources in 1950s and 1960s.

6. E.D. Thomas - 1990 Nobel Prize in Medicine Pioneered bone marrow transplant conditioning regimen Established single fraction, low dose rate TBI regimen along with Cytoxan Used dogs and Cobalt sources in 1950s and 1960s

7. Late Effects Cataracts Growth & development Fertility & sexual function Pneumonitis Veno-occlusive disease Renal damage Psychosocial development Secondary malignancies

8. Late Effects Cataracts Growth & development Fertility & sexual function Pneumonitis

9. Late Effects Veno-occlusive disease Renal damage Psychosocial development Secondary malignancies

10. Late Effects Cataracts Growth & development Fertility & sexual function Pneumonitis

11. Late Effects Veno-occlusive disease Renal damage Psychosocial development Secondary malignancies

12. Late Effects Cataracts Growth & Development Fertility & Sexual Function Pneumonitis Veno- occlusive disease Renal damage Psychosocial development Secondary malignancies

13. Late Effects: Posterior subcapsular cataract Almost all patients w/ single fraction 18% with fractionated Surgery almost always well tolerated Steroids increase risk Cataracts

14. Late Effects: Endocrine dysfunction growth hormone esp.. poor in those receiving prior craniospinal XRT subclinical hypothyroidism in ~70% subnormal sex steroid concentrations Growth plate damage Seen in chemo only regimens also Seen in chemo only regimens also Growth & Development

15. Late Effects: > 95 % of males w/ permanent azoospermia –no change w/ fractionation Most female patients stop menstruating, but some can recover ( 20%) Some pregnancies documented Fertility & Sexual Function

16. Late Effects: –Clinical Symptoms dyspnea fever non-productive cough hypoxia –Within 90 days of transplant –High mortality Classical ground glass appearance Pneumonitis

17. Late Effects: –Pathology edema and fibrin exudation endothelial hypertrophy thickened alveolar septa Late Pneumonitis w/ pulmonary fibrosis Pneumonitis

18. Late Effects: TBI –Total dose –Dose rate –Fractionation Other Chemo –Bleomycin –Cytoxan –Ara C –Busulfan Infectious –CMV –Pneumocystis –Fungal Patient Factors –Age –Increased wt –Male gender –CML –GVHD Disease –Malignancy –Remission status –Original Stage Lung XRT –Mean Lung Dose –V20 –Previous thoracic irradiation Pneumonitis

19. Late Effects: –Clinical Symptoms sudden weight gain jaundice hepatomegaly ascites high bilirubin –Incidence 10 - 20 % of patients, ~50% mortality Pathology - obliteration of small vessels More frequent w/ Busulfan Veno- occlusive disease

20. Late Effects: Increase Cr, BUN, Decrease GFR Anemia, HTN, peripheral edema, inc. LDH Increased risk Ara CAmphotericin B GVHDBusulfan TBI dose Cyclosporine Renal Damage

21. Late Effects: Influenced by genetics, chemotherapy ( alkylating agents) Witherspoon et al (Seattle) reported RR=6.69 in 2246 patients Many B-cell lymphomas, sarcomas Patients with genetic immunodeficiency at higher risk (i.e.. Wiskott Aldrich) Secondary malignancies