• Factors influencing results

•   - RT exposure rate

•   - Dose /#

•   - Interval between #

•   - RT source

• Fractionated TBI more tolerated

• MTD is 16Gy if given in single #

• 2 trials evaluated single dose TBI vs # regimen – increased survival (EFS) in # (AML)

• Hyperfractionation with lung shielding - decreased interstitial pneumonitis of 4%, from 50% with single-fraction TBI without lung shielding

• Cy most commonly combined with TBI

• Cytarabine (AraC), etoposide, melphalan, and busulfan have been combined with high-dose TBI – no evidence of superiority

• CHEMOTHERAPY BASED REGIMENS:

• Preferred to RT since most may have received dose RT before transplant

• Alkylating agents preferred, due to favorable toxicity profile (marrow toxicity as dose-limiting toxicity)

• Alkylators are not cell cycle specific - killing non‐dividing, resting tumor cells

Busulfan:

• Profound toxic effect on nondividing marrow cells including early myeloid precursors

• IV form - pharmacokinetic data demonstrated less individual variation, and retrospective comparisons indicated less liver toxicity 

• Earlier available in oral form - substantial variability in plasma levels between patients, variable pharmacokinetics, toxicity, and response in patients receiving the same weight-based or BSA–based dose.

Busulfan:

• Bu + Cy – original regimen – Bu 4mg/kg/day x 4days and Cy 50mg/kg/day x 4days

• Modified Bu-Cy – decreased Cy dose to 120mg/kg – decreased toxicity with no increased relapse

• S/E – Myelotoxicity, Nausea, vomiting, mucositis, grand mal seizures, VOD, reversible cosmetic skin discoloration

• Bu + Fludarabine – Inhibit DNA repair and show synergism to other alkylators

BCNU:

The MTD, as a single agent - 120 mg/m2

BCNU + cisplatin and CY increase lung injury.

BCNU + carboplatin and CY - increased VOD

1st regimen – BACT – BCNU, Ara-C, Cy, Thioguanine

S/E – VODS, pulmonary fibrosis, renal failure, secondary leukemia, nausea, vomiting, skin flushing, dizziness, hypotension

Doses of BCNU exceeding 450 mg/m2 are associated with unacceptable pulmonary toxicity

Melphalan:

Single doses of MEL, 150–240 mg/ m2 followed by autologous stem‐cell infusion - multiple myeloma and breast cancer

MEL 100 mg/m2 – RIC in MM

Fludarabine + MEL – RIC for allotransplant

SA Melphalan 200mg/m2 vs Melphalan 140mg/m2 + TBI – survival advantage with SA melphalan

S/E – nausea, vomiting, mucositis, diarrhea, sporadic occasionally lerhal cardiac toxicity, renal tubular injury

Melphalan:

Single doses of MEL, 150–240 mg/ m2 followed by autologous stem‐cell infusion - multiple myeloma and breast cancer

MEL 100 mg/m2 – RIC in MM

Fludarabine + MEL – RIC for allotransplant

SA Melphalan 200mg/m2 vs Melphalan 140mg/m2 + TBI – survival advantage with SA melphalan

S/E – nausea, vomiting, mucositis, diarrhea, sporadic occasionally lerhal cardiac toxicity, renal tubular injury

Treosulfan:

• Water-soluble prodrug of a bifunctional alkylating agent 

• Combined with fludarabine and other agents as conditioning for autologous and allogeneic HCT.

• DLT - mucositis, diarrhea, and dermatitis

• The combination of treosulfan and fludarabine with or without low-dose TBI was associated with high engraftment rates, decreased regimen-related toxicity and TRM and improved survival in patients with myeloid malignancies undergoing allogeneic HCT

• TBI Vs Chemo regimen: In CML BU-Cy found to be equivalent to Cy/TBI in 2 trials

Treosulfan:

• Water-soluble prodrug of a bifunctional alkylating agent 

• Combined with fludarabine and other agents as conditioning for autologous and allogeneic HCT.

• DLT - mucositis, diarrhea, and dermatitis

• The combination of treosulfan and fludarabine with or without low-dose TBI was associated with high engraftment rates, decreased regimen-related toxicity and TRM and improved survival in patients with myeloid malignancies undergoing allogeneic HCT

• TBI Vs Chemo regimen: In CML BU-Cy found to be equivalent to Cy/TBI in 2 trials

Antibodies targeting T lymphocytes - ATG and alemtuzumab

• Incorporated into high-dose and RIC regimens to decrease the incidence of graft rejection and to prevent GVHD.

• ATG exert its immunomodulatory effects through in vivo host and donor T-lymphocyte depletion, modulation of cell surface molecules mediating interactions of lymphocytes and the endothelium, modulation and depletion of APCs, and the induction of reg T lymphocytes.

• Efficacy of ATG in preventing graft rejection and GVHD affected by several factors - dose administered, its source and formulation (rabbit vs horse; thymoglobulin, ATG-Fresenius vs Atgam), timing of administration, the degree of HLA disparity between host and donor, the graft source (marrow vs GCSF-mobilized PBSCs), and the intensity of the conditioning regimen