Plasma brain natriuretic peptide is associated with hepatic veno-occlusive disease and early mortality after allogeneic hematopoietic stem cell transplantation

Biology of Blood and Marrow Transplantation

et al. 2012

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.

Section: Discussionmentioning

confidence: 99%

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

Biology of Blood and Marrow Transplantation

et al. 2012

“…It would be useful to identify predictive markers of toxicity. Previous reports have correlated high pretransplantation values of C-reactive protein, ferritin, or brain natriuretic peptide (BNP) with severe transplantation-related toxicity [35-37]. Likewise, haptoglobin levels have been inversely associated with gemcitabine hematological toxicity [38].…”

Section: Discussionmentioning

confidence: 99%

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

Biology of Blood and Marrow Transplantation

et al. 2015

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days −8 to −3). Gemcitabine was infused continuously at 10 mg/m2/minute over 4.5 hours (days −8 and −3). Busulfan dosing targeted 4000 μM-minute/day (days −8 to −5). Melphalan was infused at 60 mg/m2/day (days −3 and −2). Patients with CD20+ tumors received rituximab (375 mg/m2, days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography–positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation.

“…It would be useful to identify predictive markers of toxicity. Previous reports have correlated high pretransplantation values of C‐reactive protein, ferritin, or B‐type natriuretic peptide with severe transplantation‐related toxicity . Likewise, haptoglobin levels have been inversely associated with gemcitabine hematologic toxicity .…”

Section: Discussionmentioning

confidence: 97%

Double epigenetic modulation of high‐dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor‐risk relapsed lymphoma

et al. 2016

Cancer

BACKGROUND More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel. METHODS Patients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days −11 through −3 at doses from 15 to 35 mg/m2 daily (dose levels 1–3), followed by oral vorinostat (1000 mg once daily on days −11 through −3), gemcitabine (2775 mg/m2 over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m2 × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day −9. RESULTS In total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16–65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2–7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m2 daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8–27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma. CONCLUSIONS Double epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation.