Forty-nine patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma underwent autologous hematopoietic stem cell transplantation (autoHSCT) using the regimen of busulfan (Bu), ...cyclophosphamide (Cy), and etoposide (E) that was originally developed for allogeneic HSCT. Eighteen patients treated before 1999 received Cy 2.5 g/m
2 on days −3 to −2 and E 1800 mg/m
2 on day −3 after oral (PO) administration of Bu 1 mg/kg every 6 hours × 4 days for a total of 16 doses beginning on day −7. After April 1999, 31 patients similar in all pretransplantation risk assessments received the same regimen except that intravenous (IV) Bu was substituted for PO Bu and pharmacokinetic-directed (PKD) dosing was attempted to achieve an area under the concentration time curve of 1000-1500 μmol/min for each dose. Nonrelapse mortality was 28% for PO Bu patients versus 3% for the IV PKD group (
P = .01, chi-square test). Actuarial 5-year overall survivals were 28% for patients who received the PO Bu regimen and 58% for patients who received the IV Bu regimen (
P = .010, log-rank test), and progression-free survivals were 17% and 50%, respectively (
P = .008, log-rank test). After substitution of PKD IV Bu in the BuCyE regimen, we observed lower nonrelapse mortality with increased overall and progression-free survivals in patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma who underwent autoHSCT.
Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET ...(median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.
Dexamethasone and other steroids are potent inhibitor of allo reactive T cells and are widely used as therapy for GVHD and other immune mediated clinical syndromes and we hypothesized use of a short ...course of steroids given to sibling donors could potentially decrease the number of allo reactive T cells in the graft, and thereby decrease incidence of graft versus host disease. Here we report the out come of a total of 118 patients who underwent allogeneic matched sibling transplantation between 09/1998 to 05/2006 at the UAB BMT program. Patient characteristics are given in table. Most common conditioning regimen was IV Busulfan (AUC targeted to 1000) and Fludarabine. GVHD prophylaxis was cyclosporine and long course methotrexate in the majority of patients. 74 patients had received ATG. Median patient age is 47.8 (ranges 18–68.2) and median donor age is 44.8 (range 13.3–70.3). Donors were mobilized with rhg-CSF for 4 days and dexamethasone 10mg/m2/day for 3 days followed by stem cell collection. 31 out of the 118 patients developed grade 2–4 aGVHD (26.5%) and 42 patients (35.6%) developed extensive cGVHD. The over all TRM was 29.6%. aGVHD caused an increase in TRM as well as overall mortality; median survival of those with aGVHD was 115 days compared to 481 days among those who did not (PWilcoxon =0.0003). On the other hand, cGVHD was associated with an increased median survival; median survival of those with extensive cGVHD was 589 days compared to 115 days in those without (PWilcoxon <0.0001) The relapse free time is also significantly associated with cGVHD, with less relapses in patients who developed extensive cGVHD. (P Wilcoxon = 0.0328) Development of extensive chronic GVHD was not dependent up on graft content in this population. With the use of dexamethasone during mobilization, the mean number of CD34+ yield was significantly higher (mean 8.9×106; median 7.8× 106 range = 1.8×106–3.97 107) compared to mean 4.9×106 cells/kg, median 3.0× 106 (range = 2.3×105–7.6×107) from a historic cohort of 46 patients at UAB whose donors did not receive dexamethasone (P< 0.0001). On the other hand, the mean number of CD3+ content in the dexamethasone arm was less (mean 3.3× 10 7 cells/kg, range: 8.2×10 6–8.9×10 9) than that in the non-dexamethasone arm (mean of 4.4 × 10 8 cells/kg, range: 6.210 7–4.610 9; P= <0.0001). No adverse event other than that is expected from high dose rhg-CSF was reported by the donors who received the short duration of dexamethasone. We have shown here that dexamethasone can be safely used in donors with a resultant depletion in the number of CD3+ cells without compromising engraftment or increase in relapse. The overall incidence of grade 2–4 acute GVHD (26.5%) among our patients who received dexamethasone + rhg-CSF mobilized PBSC is less than that are reported in literature.
Patient CharacteristicsSEXM=60%F=40%RACEW=84%B=14%O=2%ASBMT RISKHR=41%IR=22%LR=28%OTHER=9%DISEASEAML+ALL=34%NHL=23%Myeloma=7%MDS=6%OTHER=30%CMVPOSITIVE=70%NEGATIVE=30%
A cute graft-
-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it ...is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-
-host disease. We examined outcome following diagnosis of grade II-IV acute graft-
-host disease according to time period, and explored effects according to original graft-
-host disease prophylaxis regimen and maximum overall grade of acute graft-
-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft-
-host disease (n=497 for 1999-2001, n=962 for 2002-2005, n=1,446 for 2006-2010). The median (range) follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the cohort with grade II-IV acute graft-
-host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively (
<0.001). Considering the total study population, univariate analysis demonstrated significant improvements in overall survival and treatment-related mortality over time, and deaths from organ failure and infection declined. On multivariate analysis, significant improvements in overall survival (
=0.003) and treatment-related mortality (
=0.008) were only noted among those originally treated with tacrolimus-based graft-
-host disease prophylaxis, and these effects were most apparent among those with overall grade II acute graft-
-host disease. In conclusion, survival has improved over time for tacrolimus-treated transplant recipients with acute graft-
-host disease.
We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard ...to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC-compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval CI, 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.
SGN-30 is a chimeric monoclonal antibody which recognizes the CD30 antigen found on tumor cells from patients with Hodgkin's disease (HD) and anaplastic large cell lymphoma (ALCL). Preclinical ...studies with this agent have demonstrated anti-lymphoma effects in both in vitro cell line assays and in vivo murine model systems. The results of a multi-dose phase I study showed minimal toxicity associated with doses from 2 to 12 mg/kg administered as six weekly IV infusions over 120 minutes each. Of the 21 patients with Hodgkin's Disease accrued to the phase I study, four patients had stable disease (SD). A phase II multi-dose study is currently underway to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in patients with relapsed or refractory HD or systemic ALCL (sALCL). Fifteen subjects (6M, 9F) with HD have been enrolled, with baseline data as follows: median age 34 (range 20–65), median number of prior therapies 3 (range 1–5), and 11 patients (73%) have disease which progressed after prior high-dose chemotherapy and stem cell transplant. Multiple doses of SGN-30 have been well tolerated in all subjects. Drug-related adverse events have been typically mild and consistent with monoclonal antibody administration. The most common drug-related adverse event has been fatigue. No grade 3/4 events have occurred. Twelve patients are currently evaluable for response, with 6 having had stabilization of their disease. Assessment of duration of disease stabilization and response is continuing. While the acceptable safety profile and frequency of stable disease following therapy in this heavily pretreated patient population are encouraging, a 12 mg/kg/dose regimen is now being tested in subsequent subjects to further explore the dose-response relationship of SGN-30 in Hodgkin's Disease. Further evaluation of this novel immunotherapy in additional HD patients is ongoing.
We report a novel means to purge bone marrow of a specific subset of prostate carcinoma cells based on transductional and genetic selectivity. Using both adenovirus-polylysine-DNA complexes and ...E1A/B-deleted replication-deficient adenoviruses, we have demonstrated a transductional preference of these vectors for the prostate carcinoma cell lines DU 145, LNCaP, and PC-3 over primary human bone marrow cells and the leukemia cell line KG-1. We have also shown a genetic selectivity of an anti-erbB-2 intracellular single-chain antibody (sFv) encoding adenovirus, Ad21, for the erbB-2-positive prostate carcinoma cell lines DU 145 and LNCaP. Delivery of Ad21 resulted in cytotoxicity to the DU 145 and LNCaP, but not PC-3, cell lines and reduced the clonogenic capacity of DU 145 cells cultured alone or mixed with various ratios of irradiated human bone marrow. Finally, quantitative, competitive reverse transcription polymerase chain reaction (QC-RT-PCR) analysis demonstrated that Ad21 could effectively reduce DU 145 and erbB-2-positive primary prostate tumor contamination in bone marrow cultures. Delivery of Ad21 had no effect on the ability of progenitor cells to form colonies. These results suggest that an anti-erbB-2 sFv-encoding adenoviral vector is efficacious for removal of erbB-2-positive prostate carcinoma cells from human bone marrow, and demonstrates a novel method for ex vivo genetic purge of malignant cells from bone marrow for autologous bone marrow transplantation (ABMT) therapy.
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