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

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

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

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

5. Late Effects - Growth Development 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

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

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

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

9. Late Effects - Pneumonitis 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

10. Late Effects - Veno-occlusive Disease –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

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

12. Late Effects - 2nd Malignancies 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)