Activity of single-agent melphalan 220–300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma

Abstract

Summary:High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m 2 plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D þ 100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL þ AF þ AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median followup in these latter patients of D þ 1163 (range D þ 824 to D þ 1630); one of these patients had a nonmyeloablative allograft as consolidation on D þ 106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure.Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL þ AF þ AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens. For non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) patients who are not treated successfully with conventional therapy, high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) has proven curative in a substantial number of cases, and is the standard of care in some situations. 1 That said, many of the elements of HDC þ AHSCT are not standardized; 1-5 specifically, no one HDC regimen has been proven optimal. 1-8 Nonetheless, carmustine (BCNU), etoposide (VP16-213), cytarabine (Ara-C) and melphalan (MEL) -the so-called BEAM regimen 9 -is widely utilized, and had no obvious superior in recent large but nonrandomized analyses. 7,8 However, and admittedly minimizing the uncertain role of cotransplantation of clonogenic lymphoma cells, 10,11 BEAM permits a substantial number of relapses, and increasing the activity of BEAM (or other regimens) without excessive toxicity could be very us...

A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplantation in Multiple Myeloma

“…23 Amifostine has been used to safely increase total melphalan dose up to 300mg/m2 in B-cell lymphoma with acceptable toxicities. 24 The initial report of a randomized phase I/II study comparing MEL200 vs. MEL280 + amifostine as conditioning for first ASCT in MM demonstrates higher rates of CR and near CR, albeit with more regimen-related gastrointestinal toxicity in the MEL280 arm. 25 It remains to be seen whether the higher rate of major response with MEL280+amifostine will translate into longer PFS and OS.…”

Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation

“…Spencer et al [45] used amifostine 910 mg/m 2 before melphalan 200 mg/m 2 and noted a moderate decrease in the incidence of mucositis without compromising DFS. Phillips et al [46] showed that melphalan can be dose escalated up to 280 mg/m 2 with the use of amifostine 740 mg/m 2 given 24 hours, and 15 minutes before melphalan to treat patients with lymphoma. Reece et al used this regimen in patients with myeloma and obtained a 4-year PFS of 28% and OS of 58%.…”

“…Mel-Amifostine [45,46] Mel 280 mg/m 2 Amifostine 740 mg/m 2 [50] added 166-Holmium DOTMP to high-dose melphalan in preparation for autologous HSCT. The regimen had urinary and renal toxicity in the form of thrombotic microangiopathy and hemorrhagic cystitis.…”

BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma

“…24 Dose intensification of conditioning regimen can be potentially dangerous: a study in 56 MM patients added idarubicin and CY to melphalan 200 mg/m 2 , but this was followed by a treatment-related mortality of 20% (vs 0% in the standard arm with melphalan 200 mg/m 2 ), which lead to early discontinuation of the study. 25 Another investigational strategy has been to increase the dose of single-agent melphalan to 4200 mg/m 2 with the concurrent use of the cytoprotective agent amifostine, 26,27 but data are too preliminary to justify the use of this approach in routine clinical practice.…”