[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45-7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0-14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require
admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to
re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the
605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the
ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and
19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and
neutropenia were each associated with increased mortality, and the mortality of patients with all
four characteristics was 100%. Hemodialysis was also associated with increased mortality in a
Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox
model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were
each independent risk factors for mortality in the 6 months following ICU admission.
Full-text · Article · Sep 2009 · Journal of Transplantation
[Show abstract][Hide abstract] ABSTRACT: We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.
Full-text · Article · Feb 2009 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Treatment for steroid-resistant acute graft-versus-host disease (GVHD) has had limited success. ABX-CBL is a hybridoma-generated murine IgM monoclonal antibody against the CD147 antigen, weakly expressed on human leukocytes and up-regulated on activated lymphocytes. A prospective, multicenter, open-label, randomized clinical trial comparing ABX-CBL to antithymocyte globulin (ATG) for treatment of steroid-resistant acute GVHD was conducted in 95 patients at 21 centers. Forty-eight patients received ABX-CBL daily for 14 consecutive days followed by up to 6 weeks of ABX-CBL twice weekly. Forty-seven patients received equine ATG, 30 mg/kg every other day for a total of 6 doses with additional courses as needed. By day 180, overall improvement was similar in the patients receiving ABX-CBL and in those receiving ATG (56% versus 57%, P = .91). Patient survival at 18 months was less favorable on ABX-CBL than on ATG (35% versus 45%), with the 95% confidence interval ruling out that ABX-CBL provides at least a 10.4% improvement. Data from this trial suggest that ABX-CBL does not offer an improvement over ATG in the treatment of acute steroid-resistant GVHD. This prospective, multicenter, randomized clinical trial for steroid-resistant acute GVHD serves as a model for future evaluation of new agents.
[Show abstract][Hide abstract] ABSTRACT: While autologous HSCT appears to induce remissions and improve quality of life in the majority of patients, it remains unclear whether either myeloablative or lymphoablative autologous HSCT can cure autoimmune disorders, and randomized controlled trials are needed to confirm the benefit and cost-effectiveness of this therapy. There are currently 2 disparate philosophical approaches to the design of these trials. One approach is to apply aggressive malignancy-specific myeloablative regimens. Although more intensive lymphoablative regimens could be designed, since cancer-specific myeloablative regimens are more intensive than currently utilized lymphoablative regimens, myeloablative regimens may result in longer duration of disease remission. The other philosophical approach is to use lymphoablative regimens that are disease specific and nonmyeloablative (i.e., do not irreversibly damage the hematopoietic stem cell compartment), maximize drugs already used to treat each disease, and avoid agents in the regimen that could cause further damage to already disease-injured organs. It appears that lymphoablative regimens are safer than myeloablative regimens, and it appears that even if relapse occurs, durable long-term remission may be achieved with conventional treatment to which the patient's disease was previously refractory. If considered on a disease-specific basis, the high disease-related mortality of SSc could justify the higher treatment-related mortality associated with a myeloablative regimen. However, since radiation is already considered a relative contraindication for SSc and radiation-induced and SSc-related microvascular compartment injuries are similar, and because TBI is associated with late myelodysplasia, leukemia, and lymphomas, some investigators have voiced concern over use of a TBI-based myeloablative regimen to treat SSc (19,59). The controversy that surrounds the competing visions of lymphoablative versus myeloablative autologous HSCT regimens for autoimmune disease has yet to be resolved. Further experience will likely indicate the superiority of one of these approaches when both safety and efficacy are considered. Since both lymphoablative and myeloablative protocols are being offered for a select group of severely ill patients with autoimmune disorders refractory to conventional therapy, subspecialists who refer patients for such therapy should be aware of the emerging body of literature that at the very least suggests that lymphoablative regimens will be associated with less morbidity and mortality. Sharing of such information is crucial if patients are to provide consent that is truly informed.
Full-text · Article · Dec 2006 · Arthritis & Rheumatology
[Show abstract][Hide abstract] ABSTRACT: In 87 patients with aplastic anemia who failed to respond to immunosuppressive treatment, we determined the minimal dose of total body irradiation (TBI) required when added to antithymocyte globulin (ATG, 30 mg/kg x 3) plus cyclophosphamide (CY, 50 mg/kg x 4) to achieve engraftment of unrelated donor marrow. TBI was started at 3 x 200 cGy, to be escalated or deescalated in steps of 200 cGy depending on graft failure or toxicity. Patients were aged 1.3 to 53.5 years (median, 18.6 years). The interval from diagnosis to transplantation was 3 to 328 months (median, 14.6 months). Donors were HLA-A, -B, -C, -DR, and -DQ identical for 62 patients, and nonidentical for 1 to 3 HLA loci at the antigen or allele level for 25. The dose-limiting toxicity was diffuse pulmonary injury. The optimum TBI dose was 1 x 200 cGy. Nine patients did not tolerate ATG and were prepared with CY + TBI. Graft failure occurred in 5% of patients. With a median follow-up of 7 years, 38 (61%) of 62 HLA-identical, and 10 (40%) of 25 HLA-nonidentical transplant recipients are surviving. The highest survival rate with HLA-identical transplants was observed at 200 cGy TBI. Thus, low-dose TBI + CY + ATG conditioning resulted in excellent outcome of unrelated transplants in patients with aplastic anemia who had received multiple transfusions.
[Show abstract][Hide abstract] ABSTRACT: The optimal postremission treatment for elderly patients with acute myelogenous leukemia (AML) is presently unknown, but recent studies report the feasibility of autologous stem cell transplantation in this population. To better understand the long-term outcome of autologous transplantation in AML patients > or =60 years of age, we evaluated high-dose chemoradiotherapy preparative conditioning followed by transplantation of peripheral blood progenitor cells procured after a single cycle of cytarabine-based consolidation chemotherapy as postremission therapy in 27 patients aged 60 to 71 years (median age, 65 years) with newly diagnosed AML in first complete remission (CR). The median follow-up from CR for all patients was 13.6 months (range, 6.0-123.1 months). The median follow-up from remission for surviving patients was 81 months (range, 41.4-123.1 months). Seven patients are alive in continuous CR, 19 died from relapse, and 1 died as a result of treatment-related infection. Leukemia-free survival and overall survival are 10.3 and 13.4 months, respectively. Actuarial leukemia-free and overall survival at 3 years are 25% +/- 9% and 28% +/- 9%, respectively. Our results demonstrate that autologous transplantation of peripheral blood progenitor cells is well tolerated and feasible for patients > or =60 years of age with AML in first CR. Future investigation should focus on a randomized study evaluating a larger group of elderly patients in first CR comparing autologous stem cell transplantation with conventional cytarabine-based consolidation chemotherapy to identify the optimal postremission therapy.
Preview · Article · Apr 2006 · Biology of Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Management of patients with multiple-relapsed lymphoma meets with little success. The optimal use of available drugs in this situation is often unknown. Gemcitabine has documented efficacy in this setting. Pharmacodynamic data suggest that the optimal use may involve a fixed-rate infusion and coadministration with platinum compounds. In this study we explored the use of gemcitabine starting at a dose of 800 mg/m(2) administered at a fixed infusion rate of 10 mg/m(2) per minute with cisplatin 35 mg/m(2) intravenously, both given on day 1, and dexamethasone 20 mg daily for 4 days; the treatment was given every 2 weeks (days 1 and 15 of a 28-day cycle) for the treatment of relapsed Hodgkin's and non-Hodgkin's lymphoma. Dose escalation of gemcitabine was allowed according to phase I criteria. Twenty-two patients with a median of 4 prior treatments were enrolled (Hodgkin's lymphoma, n = 7; B-cell non-Hodgkin's lymphoma, n = 9; T-cell non-Hodgkin's lymphoma, n = 6). Ten patients had relapsed after prior autologous transplantation. Grade 4 thrombocytopenia and neutropenia were the dose-limiting toxicities and occurred in 9 patients (41%) and 4 patients (18%), respectively. Initial dose escalation of gemcitabine was not possible. Responses were observed in 45% of the patients: 2 of 5 with T-cell non-Hodgkin's lymphoma (1 patient withdrew after first treatment and was evaluable only for toxicity), 4 of 7 with Hodgkin's lymphoma, and 4 of 9 with B-cell non-Hodgkin's lymphoma. The coadministration of gemcitabine 800 mg over 80 minutes with low-dose cisplatin and dexamethasone is feasible and sufficiently active in a heavily pretreated patient population with lymphoma.
No preview · Article · Jul 2004 · Clinical lymphoma
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.
Full-text · Article · Dec 2003 · Journal of Clinical Investigation
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to assess the relationship between involved field radiation therapy (IFRT) and treatment-related morbidity and mortality in patients receiving high-dose chemotherapy (HDC), total body irradiation (TBI) and autologous peripheral stem cell transplant (PSCT) for Hodgkin's and non-Hodgkin's lymphoma. Between January 1994 and May 2002, 156 patients underwent HDC, TBI and autologous PSCT. Localized external beam radiation therapy was given to 21 patients for consolidation, or to achieve control of symptomatic or active disease prior to or after transplant. Among patients who had IFRT prior to autologous PSCT, five treatment-related deaths were observed, compared to seven deaths in 135 patients who had autologous PSCT without IFRT (P<0.01). Most deaths were attributable to sepsis and multiorgan failure. A higher incidence of pneumonitis was also noted in patients exposed to mediastinal irradiation. No adverse impact on long-term survival could be demonstrated. Involved field radiation prior to TBI is associated with higher treatment-related mortality in lymphoma patients undergoing autologous peripheral stem cell transplant, necessitating careful monitoring.
Preview · Article · Nov 2003 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Treatment for extensive indolent lymphoma should combine optimization of efficacy without excessive toxicity. Rituxan may be an ideal agent for combinations with chemotherapy because of its non-cross-resistant toxicity profile and the potential for synergism. We present the results of 32 patients with indolent B-cell NHL who received a novel three-drug combination designed with the intent of preservation of both efficacy and quality of life. Patient characteristics were as follows, median age, 58 years (36-75 years); histology, follicular 16, SLL/CLL five, lymphoplasmacytic six, marginal cell five; relapsed or refractory, 10; untreated, 22. Patients first received cyclophosphamide 800 mg/m(2) and mitoxantrone 8 mg/m(2), iv on the same day, every 3 weeks for two cycles. Subsequently, patients received rituximab followed by mitoxantrone 8 mg/m(2) every 2 weeks for four cycles. The regimen, and particularly rituximab, was extremely well tolerated. Grade I/II, infusion-related toxicity was noted in 10%. Six patients achieved a PR and 23 a CR for an overall response of 90% (95% CI: 79-100%). The actuarial median TTP for all patients was 30 months. Molecular remissions were noted in 8/14 patients tested in CR. We conclude that the cyclophosphamide-mitoxantrone-rituxan (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-related morbidity is nearly completely eliminated.
No preview · Article · Sep 2003 · Hematological Oncology
[Show abstract][Hide abstract] ABSTRACT: Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha (TNF-alpha), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation.
[Show abstract][Hide abstract] ABSTRACT: Treatment with the anti-CD20 antibody rituximab prior to stem cell collection may lead to tumor-free stem cell collections in patients with B-cell lymphoma undergoing autologous stem cell transplantation. To test the feasibility of obtaining polymerase chain reaction (PCR)-negative stem cell collection, 30 patients with a variety of B-cell lymphomas were enrolled in a protocol employing a common MINE (mitoxantrone/ifosfamide/etoposide) salvage regimen with rituximab (in vivo purging). Rituximab 400 mg/m2 was administered weekly for 3 weeks on days 1, 6, and 8 in relation to the last MINE cycle, which was followed by growth factor-stimulated peripheral stem cell collection. The median number of CD34(+) cells/kg was 2.5 million cells/kg collected over a median of 5 days. Polymerase chain reaction amplification for the t (14;18) or the heavy-chain gene rearrangement was performed prior to treatment and on the leukapheresis sample. Out of 15 patients who had a positive PCR signal prior to treatment, 10 had PCR-negative stem cell collections, whereas 5 had PCR-positive stem cell collections. After high-dose chemotherapy and stem cell transplant, all patients with a PCR-positive signal pretreatment became PCR negative. We conclude that rituximab may increase the yield of tumor-free stem cells. Higher rates of PCR negativity have been reported when more intense and protracted chemoimmunotherapy regimens have been employed. The magnitude of clinical benefit and the significance of the PCR analysis in stem cells after rituximab requires larger studies.
No preview · Article · Oct 2002 · Clinical lymphoma
[Show abstract][Hide abstract] ABSTRACT: Lipid oxidation products promote atherosclerosis and may also affect osteoporosis. We showed previously that oxidized lipids including 8-isoprostaglandin E2 (isoPGE2) inhibit osteoblastic differentiation of preosteoblasts. Since osteoporosis is mediated both by decreased osteoblastic bone formation and by increased osteoclastic bone resorption, we assessed whether oxidized lipids regulate the osteoclastic potential of marrow hematopoietic cells. Treatment of marrow-derived preosteoclasts with isoPGE2 enhanced osteoclastic differentiation as evidenced by increased tartrate-resistant acid phosphatase (TRAP) activity and multinucleation, which were inhibited by calcitonin, and increased numbers of resorption pits. The enhanced osteoclastic differentiation by isoPGE2 was observed whether preosteoclasts were in coculture with stromal cells or in monoculture in the presence of receptor-activated NFkappaB ligand (RANKL) and macrophage colony-stimulating factor. Receptor antagonist studies suggest that isoPGE2 effects were mediated by prostaglandin receptor subtypes EP2/DP on preosteoclasts and subtype EP1 and thromboxane receptors on stromal/osteoblast cells. The enhanced TRAP activity was also inhibited by cAMP-dependent protein kinase inhibitors, and isoPGE2 elevated intracellular cAMP levels of preosteoclast monocultures. Other oxidized lipids also enhanced the TRAP activity of preosteoclast monocultures. These data suggest that isoPGE2 enhances osteoclastic differentiation of marrow preosteoclasts and that this regulation occurs via the cAMP-dependent protein kinase pathway.
Preview · Article · May 2002 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Calcification is a common complication of atherosclerosis and other chronic inflammatory processes that involves infiltration of monocytes and accumulation of macrophages.
To determine whether these cells modulate vascular calcification in vitro, calcifying vascular cells (CVCs), a subpopulation of osteoblast-like cells derived from the artery wall, were cocultured with human peripheral blood monocytes for 5 days. Results showed that alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation, was significantly greater in cocultures than in cultures of CVCs or monocytes alone. Both ALP activity and matrix mineralization increased in proportion to the number of monocytes added. Activation of monocyte/macrophages (M/Ms) by oxidized LDL further increased ALP activity in cocultures. However, neither conditioned medium from oxidized-LDL-activated M/Ms or transwell coculture had this effect on CVCs, which suggests a need for cell-to-cell contact. In contrast, conditioned medium from lipopolysaccharide-activated M/Ms increased ALP activity of CVCs. ELISA showed that lipopolysaccharide-activated M/Ms secreted tumor necrosis factor-alpha, and neutralizing antibody to tumor necrosis factor-alpha attenuated the induction of ALP activity by the conditioned media.
These results suggest that M/Ms enhance in vitro vascular calcification via 2 independent mechanisms: cell-cell interaction and production of soluble factors such as tumor necrosis factor-alpha.
[Show abstract][Hide abstract] ABSTRACT: The structure of a small-molecule, non-peptide chemotactic factor has been determined from activity purified to apparent homogeneity from Helicobacter pylori supernatants. H. pylori was grown in brucella broth media until one liter of solution had 0.9 absorbance units. The culture was centrifuged, and the bacteria re-suspended in physiological saline and incubated at 37 degrees C for 4 h. A monocyte migration bioassay revealed the presence of a single active chemotactic factor in the supernatant from this incubation. The chemotactic factor was concentrated by solid phase chromatography and purified by reverse phase high pressure liquid chromatography. The factor was shown to be indistinguishable from diethyl phthalate (DEP) on the basis of multiple criteria including nuclear magnetic resonance spectroscopy, electron impact mass spectroscopy, UV visible absorption spectrometry, GC and high pressure liquid chromatography retention times, and chemotactic activity toward monocytes. Control experiments with incubated culture media without detectable bacteria did not yield detectable DEP, suggesting it is bacterially derived. It is not known if the bacteria produce diethyl phthalate de novo or if it is a metabolic product of a precursor molecule present in culture media. DEP produced by H. pylori in addition to DEP present in man-made products may contribute to the high levels of DEP metabolites observed in human urine. DEP represents a new class of chemotactic factor.
No preview · Article · Jan 2002 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Stem cell mobilization may be inadequate in many lymphoma patients in need for autologous stem cell transplant (SCT). In this study, we sought to evaluate a potential role of amifostine as a stem cell chemoprotective agent in lymphoma patients receiving DHAP chemotherapy in preparation for high-dose chemotherapy (HDC) and stem cell transplant (SCT). In the beginning of the DHAP course, patients were randomized 1:1 to receive amifostine at 740 mg/m(2). Stem cells were mobilized with GCSF after the last cycle of DHAP. Stem cell collection started upon ANC recovery over 1000/mm(3). Standard 10 lt. apheresis daily with a goal of a minimum of 2 x 10(6) stem cells/kg were performed. Twenty-one patients have been enrolled; 10 received amifostine pretreatment (age, 20-64) and 11 were randomized to the control arm (age, 18-63). Prior chemotherapy was balanced in the two groups. The median number of DHAP treatments for each group was 2. Amifostine was well tolerated and was associated with higher stem cell collection. Toxicity and time to engraftment were comparable between the two groups. Our preliminary results may suggest a role of amifostine in protecting stem cells during salvage chemotherapy, thus facilitating stem cell collection.
No preview · Article · Jan 2002 · Journal of Hematotherapy & Stem Cell Research