Phase I Study for Poor Prognosis Lymphoma: Modification of the “BEAM” (BCNU +Etoposide+ARA-C+Melphalan) Regimen with Escalating-Dose Melphalan (MEL) Using Amifostine (AF) Cytoprotection and Autologous Hematopoietic Stem Cell Transplantation (AHSCT).

Background: AHSCT is standard therapy for recurrent or progressive, yet chemosensitive lymphoma, both non-Hodgkin’s (NHL) and Hodgkin’s (HL). However, relapse is frequent, and augmentation of existing conditioning regimens (e.g. BEAM) is one approach to reducing these relapses. Since BEAM has considerable regimen related toxicity (RRT), methods to allow safe dose augmentation are needed. Prior experience (

Goals: Determine the maximum tolerated dose (MTD) of escalated dose MEL in BEAM, using AF and AHSCT, in a classical Phase I trial.

Methods: We utilized AF 740mg/m² daily before and during BEAM (i.e., −7 to −1) with MEL, starting at 140 mg/m² (level A) and escalating by 20 mg/m² per 4 - pt. cohorts. AHSCT and other supportive care measures were routine. (Thiotepa was used in patients with a history or at high risk of central nervous system (CNS) disease.) The Berman (

Results: Between 07/30/2003 and 06/28/2006, we entered 18 patients (NHL13 /HL 5), med age 60 (range 23 to 72) years. All had progressed or relapsed; 12 were chemosensitive. To date, 6 patients at level A (140mg/m²), 4 patients at B (160mg/m²), 5 patients at C (180mg/m²) and 3 patients at D (200mg/m²) have been evaluated >D +30. Three patients (2 at level A and 1 at level C) were non-evaluable due to:

1. Removal (pt’s request) during BEAM,

2. Death due to CNS bleeding; and

3. MI (with known pre-existing coronary artery disease), and were replaced.

None of the remaining 15 had Bearman RRT >II; 2 had none and 10 had only grade I RRT. All (save one case of hepatic II RRT) were stomatitis and/or gastrointestinal. All had CD34⁺ > 2.0 x 10e⁶/kg and prompt hematopoietic reconstitution: ANC >0.5 and platelets >20K at median D+ 11 (range +9 to +12) and D+ 12 (range +9 to +24), respectively. No late (i.e., >D+ 30) hematologic or non-hematologic toxicities were noted. At present, 11 patients are alive, 7 in CR, one too early to evaluate at median D+ 469, range + 27 to 999. Conversely, 7 are dead, due to relapse (5), MI (one), and CNS bleeding (1). Responses occurred at all dose levels. In evaluable patients < CR before AHSCT, 9/14 achieved CR (mostly confirmed by imaging studies, notably PET scans) by D +100; 6 remain in CR at median D +593, range +36 to +614, including one patient who had a “consolidation” allogeneic HSCT. Another patient in CR at AHSCT remains in CR at D +514.

Conclusion: Although not strictly proven, we believe the use of AF allows the safe use of escalated doses of MEL in the BEAM regimen >/= 180mg/m². Dose escalation will continue until a MTD is found.