High-Dose Infusional Gemcitabine Combined with Busulfan and Melphalan with Autologous Stem-Cell Transplantation in Patients with Refractory Lymphoid Malignancies

Abstract

We developed a new high-dose combination of infusional gemcitabine with busulfan/melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m2/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each dose immediately preceded busulfan (adjusted targeting AUC 4,000 μM.min−1/day × 4 days) or melphalan (60 mg/m2/day × 2 days). We enrolled 133 patients (80 Hodgkin’s lymphoma (HL), 46 non-Hodgkin’s lymphoma (NHL), 7 myeloma), median 3 prior regimens; primary refractory disease in 63% HL/45% NHL and PET-positive tumors at transplant in 50% patients. Two patients died from early posttransplant infections. The major toxicity was mucositis. The daily and 3-dose schedules caused substantial cutaneous toxicity. In contrast, the 2-dose schedule was better tolerated, which allowed us to extend the infusions from 15 to 270 minutes. Pretransplant values of C-reactive protein, b-type natriuretic peptide, ferritin or haptoglobin did not correlate with toxicity. Overall response and complete response rates were 87%/62% (HL), 100%/69% (B-LCL), 66%/66% (T-NHL), and 71%/57% (myeloma). At median follow-up of 24 months (3–63), the event-free/overall survival rates are 54%/72% (HL), 60%/89% (B-LCL), 70%/70% (T-NHL) and 43%/43% (myeloma). In conclusion, gemcitabine/busulfan/melphalan is a feasible regimen with substantial activity against a range of lymphoid malignancies. This regimen merits further evaluation in phase II and III trials.

Carmustine, etoposide, cytarabine and melphalan versus a newly designed intravenous busulfan-based Busulfex, etoposide and melphalan conditioning regimen for autologous hematopoietic cell transplant: a retrospective matched-pair analysis in advanced Hodgkin and non-Hodgkin lymphomas

“…Furthermore, little is known regarding the comparative toxicity and efficacy of various regimens applied in lymphomas. Thus, no safe conclusions can be made due to the lack of randomized trials, and conditioning regimens for AHCT in lymphomas melphalan or busulfan, etoposide and cyclophosphamide) [45] resulting in a lower outcome than achieved post-BuEM, and TRM at 100 days of 5.5% versus zero in the BuEM group [46]. It is noteworthy that our findings suggest that administration of BuEM contributes to superior OS in patients with HL despite their prevalent poor risk features.…”

Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: a review

“…However, Bu was used under the control of daily monitoring and adaptation in accordance with area under the curve analysis. Nieto et al 77 reported another study comparing GemBuM with BEAM and BuM (Bu administered as a single dose). Toxicity seemed equivalent between regimens; however, there were better survival results with GemBuM.…”

“…SOS was not reported. Nieto et al 77 used a single dose of Bu in combination with Gem and melphalan in 133 HL, 47 NHL and 7 myeloma cases. Toxicity appeared equivalent to other conditioning treatments, except for cutaneous toxicity, which was related to gemcitabine dose.…”

“…The OS was longer for the Bu group than the BCNU group, with 2-year OS rates of 70% and 46%, respectively. 77 BuCyE was also evaluated in combination with 90 Yttrium tiuxetan in 19 patients in relapse or with refractory LBCL. Three-year OS and EFS rates were 52.6% and 26.3%, respectively, in a population that previously received two lines of treatment.…”

Lymphomas

“…The GN-BVC regimen added gemcitabine and vinorelbine, two agents with demonstrated effi cacy in HL, and decreased the dose of BCNU with improvements in pulmonary toxicity and with encouraging FFP and OS (Arai et al 2010 ). The novel non-BCNU regimen using high-dose gemcitabine combined with busulfan and melphalan (GemBuMel) demonstrated an acceptable toxicity profi le and high activity as conditioning for adults with relapsed HL (Nieto et al 2011 ). These regimens have yet to be studied in the pediatric setting and studies in adults are limited by small patient numbers.…”