Phase II Study of Propylene Glycol-Free Melphalan (Evomela) Combined with Carmustine, Etoposide, and Cytarabine (BEAM) for Myeloablative Conditioning in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation

Introduction: The BEAM conditioning regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) is widely used as the high dose chemotherapy given to patients with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) who are undergoing autologous stem cell transplant (ASCT). The lyophilized formulation of melphalan (Alkeran) commonly included in the BEAM regimen has several limitation based on its marginal solubility and the requirement to reconstitute it in propylene glycol (PG), which itself is associated with toxicities. PG-free melphalan (Evomela) overcomes these limitations by using the solubilizing agent Captisol, an inactive excipient used in 6 FDA-approved parenteral drug formulations, to improve the stability of the reconstituted melphalan. PG-free melphalan is stable for 8-10 hours after reconstitution, it can be refrigerated (unlike Alkeran), and it avoids the potential toxicities of PG. PG-free melphalan has demonstrated bioequivalence to Alkeran, and it was safe and effective when used as the conditioning regimen for multiple myeloma patients undergoing ASCT. This Phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the BEAM regimen.

Methods: Adult patients with NHL or HL who were eligible for ASCT and gave informed consent were prospectively enrolled after collection of an adequate peripheral blood stem cell product. Carmustine, etoposide, and cytarabine were given at standard doses on Day -6 thru Day -3. PG-free melphalan, 140 mg/m², was diluted with normal saline to a concentration of ≤ 0.45 mg/ml and infused over 30 minutes on Day -2. Autologous stem cells were infused on Day 0. Supportive care was per institutional standards. The primary endpoint was toxicity, and patients were followed post-transplant for toxicity, engraftment, and disease response.

Results: Forty-five patients were enrolled from April 2014 thru June 2015 (mean age 52, range 18-73; 31 males/14 females; 32 NHL [15 diffuse large B-cell, 8 mantle cell, 9 other]/13 HL). Response prior to transplant was complete remission (CR, n=21), partial remission (PR, n=22), or progressive disease (PD, n=2). All patients completed BEAM with PG-free melphalan and stem cell infusion (median 5.1 CD34+ cells/kg), and 40 patients had sufficient follow-up for toxicity and engraftment assessments. The most common Grade 3-4 non-hematologic toxicities were neutropenic fever, (n= 26, 67%), infections (n=16, 41%), and electrolyte abnormalities (hypokalemia and hypophosphatemia in 8 and 23 patients, respectively). Twenty-four patients (60%) had oral mucositis, which was mostly Grade 2 (21 with Grade 2; 3 with Grade 3). Moderate or severe gastrointestinal toxicities were uncommon; 5 patients (12.5%) had Grade 3 diarrhea and 3 (7.5%) had Grade 3 nausea/vomiting. There were no treatment-related deaths. Thirty-nine patients (98%) had neutrophil and platelet engraftment at mean 10 and 21 days, respectively. One patient did not have platelet engraftment by Day +100. Among 36 patients who had response assessment at 60-100 days post-ASCT, 29 (81%) were in CR, 2 in PR, and 6 had PD. There have been three deaths, at 6-12 months post ASCT, all due to progressive disease.

Conclusions: PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing ASCT. It was shown to have a safety profile that compares favorably with Alkeran, and it avoids potential PG-associated toxicities. Of note, Grade 3-4 mucositis, diarrhea, and nausea/vomiting each occurred in fewer than 15% of patients, the engraftment rate was high (98%), and response rates were consistent with expectations.