Goals of This Talk:

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

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

14. Growth & Development 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

15. Fertility & Sexual Function 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

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

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

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

19. Veno- occlusive disease 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

20. Renal Damage Late Effects: • Increase Cr, BUN, • Decrease GFR • Anemia, HTN, peripheral edema, inc. LDH • Increased risk • Ara C Amphotericin B • GVHD Busulfan • TBI dose • Cyclosporine

21. Secondary malignancies 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)