[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: Based on favorable results from randomized clinical trials, oral posaconazole has been approved for prophylaxis in neutropenic patients and stem cell transplantation (SCT) recipients. However, routine use of a prophylactic drug may yield different results than those from clinical trials. We collected data on the efficacy, safety, breakthrough infections, and antimicrobial resistance associated with standard long-term posaconazole prophylaxis in adult allogeneic SCT recipients at the UCLA Medical Center. Oral posaconazole (200 mg 3 times daily) was started on day 1 after SCT and continued until day 100. After day 100, posaconazole was continued in patients who still required corticosteroids for prevention or treatment of graft-versus-host disease. From January 2007 through December 2008, 106 consecutive patients received prophylactic posaconazole. Breakthrough invasive fungal infections on posaconazole occurred in 8 patients (7.5%) within 6 months after SCT; 3 additional patients developed invasive fungal infection after discontinuation of prophylactic posaconazole. The infective organisms were Candida (8 cases), Aspergillus (2 cases), and Aspergillus plus Coccidioides immitis (1 case). There were no Zygomycetes infections. Only 2 (both Candida glabrata) of 9 infecting isolates tested were resistant to posaconazole (minimal inhibitory concentration >1 μg/mL). Mortality from invasive fungal infection occurred in 4 patients (3.7%). Except for nausea in 9 patients, no clinical adverse event or laboratory abnormality could be attributed to posaconazole. Mean peak and trough plasma posaconazole concentrations were relatively low (<400 ng/mL) in neutropenic patients with oral mucositis and other factors possibly affecting optimal absorption of posaconazole. These results demonstrate that standard long-term oral posaconazole prophylaxis after allogeneic SCT is safe and associated with few invasive mold infections. However, breakthrough infections caused by posaconazole-susceptible organisms (frequently Candida) may occur at currently recommended prophylactic doses. Thus, strategies to improve posaconazole exposure, including the use of higher doses, administration with an acidic beverage, and restriction of proton pump inhibitors, need to be considered when using prophylactic posaconazole.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2010; 17(4):507-15. DOI:10.1016/j.bbmt.2010.04.017 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.
Bone marrow transplantation 03/2010; 45(6):979-84. DOI:10.1038/bmt.2010.35 · 3.57 Impact Factor
[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.
Journal of Transplantation 09/2009; 2009(2):917294. DOI:10.1155/2009/917294
[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.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2009; 15(2):249-56. DOI:10.1016/j.bbmt.2008.11.028 · 3.40 Impact Factor
[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.
[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.
Biology of Blood and Marrow Transplantation 04/2006; 12(4):466-71. DOI:10.1016/j.bbmt.2005.12.027 · 3.40 Impact Factor
[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.
[Show abstract][Hide abstract] ABSTRACT: Graft versus host disease is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Galectin-1, a mammalian lectin that modulates T cell function and apoptosis, has been shown to be immunomodulatory in animal models of autoimmune disease. We investigated the efficacy of galectin-1 in a murine model of graft versus host disease and found that 68% of galectin-1-treated mice survived, compared to 3% of vehicle-treated mice. Galectin-1-treated animals also had reduced inflammatory infiltrates in tissues compared to animals treated with vehicle alone. Galectin-1 did not affect engraftment of donor hematopoietic cells. However, galectin-1-treated animals demonstrated increased cellularity in bone marrow and spleen with increased numbers of splenic B cells and CD4 T cells compared to those animals treated with vehicle alone. Galectin-1 treatment also significantly improved reconstitution of normal splenic architecture following transplant. Production of type I cytokines interleukin-2 (IL-2) and interferon-gamma was reduced in splenocytes derived from galectin-1-treated transplanted mice when compared to animals treated with vehicle alone, while production of the type II cytokines, IL-4 and IL-10, was similar between the two groups of animals. Although splenocytes from galectin-1-treated transplanted animals responded to both third party antigens and leukemic challenge, host alloreactivity was significantly reduced when compared to cells from vehicle-treated animals. These results demonstrate that galectin-1 therapy is capable of increasing survival and suppressing the graft versus host immune response without compromising engraftment or immune reconstitution following allogeneic hematopoietic stem cell transplant.
[Show abstract][Hide abstract] ABSTRACT: In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.
[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.
[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.
Bone Marrow Transplantation 11/2003; 32(9):863-7. DOI:10.1038/sj.bmt.1704238 · 3.57 Impact Factor