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

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

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

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

E.D. Thomas 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.

E.D. Thomas 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

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

Late Effects Cataracts Growth & development Fertility & sexual function Pneumonitis

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

Late Effects Cataracts Growth & development Fertility & sexual function Pneumonitis

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

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

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

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

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

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

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

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

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

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

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