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Amifostine (AF) Cytoprotetion (CP) of Escalating Doses of Melphalan (MEL) and Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Final Results of a Phase I & II study

Diana Stripp, MD

University of Pennsylvania Cancer
Last Modified: May 12, 2001

Presenter: G. L. Phillips
Affiliation: University of Maryland / Greenebaum Cancer Center

Background:

1. Alkylating agents show a steep dose response curve.
2. Regimen related toxicity (RRT) is dose- limiting with AHSCT
3. Growth factors and stem cell transplantation permits dose escalation to non- hematologic organ limit.
4. Melphalan dose at 220 mg/ m2 (MEL220) produced severe mucosal RRT, Moreau et al, BJH 1996;95;527-30
5. As AF provides CP with certain convetional-dose therapies, it may allow dose escalation (thus increase the maximal tolerated dose (MTD) of high dose therapy (HDT) requiring AHSCT) by decreasing the RRT.

Materials and Methods:

1. AF (740mg/m2 IV over 15min) was given 24hrs and 15 min prior to MEL following premedications including dexamethasone, anitemetics, IV hydration and Ca gluconate.
2. Initial MEL dose was 220mg/m2 IV over 15 min. Escalation of MEL 20 mg/m2 increments in groups of 4 pts, with plans to stop if > Gr III RRT developed in one pt.
3. Definition of mucositis: Gr I - not requiring IV narcotics for pain control; Gr II - requiring IV narcotics for pain control; Gr III - life threatening mucositis.

Results:

1. 49 pts ineligible for other HDT/AHSCT protocols, including AML (n=5), metastatic breast cancer (n=12), myeloma (n=14), NHL/HD (n=14/2), and ovaria cancer (n=2).
2. Mel 220 mg/m2 was given in 11 patients, 240 mg/m2 in 5 patients, 260 mg/m2 in 7 patients and 280mg/m2 in 18 patients, and 300 mg/m2 in 8 patients, without > Gr II mucositis.
3. One pt (MEL220) with known anthracycline- induced cardiomyopathy died of cardiotoxicity day +28; 2 pts died of MODS (multi-organ dysfunctional syndrome) at MEL 300 mg/m2.
4. Currently 19 pts are alived, 1 without progression, day +14-777.
5. Relapse/progression in 20 pts. 3 died of NRM, one new pt died of pulmonary hemorrhaged following tumor lysis.
6. NED survivors at all doses and with all diagnoses.
7. No intolerable toxicity with AF.

Authors' Conclusions

1. MEL 280 mg/m2 , AHSCT and AF can be given to advanced pts with substantial mucosal morbidity (Gr II mucositis) but no increased mortality.

Clinical/Scientific Implications:

This Phase II outcome is too early to interpret in the current trial to answer the question whether increased MEL MTD translates into better treatment result. Thus it is unclear if AF has an impact on AHSCT outcome.