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1.
Curr Oncol ; 27(6): e596-e606, 2020 12.
Article in English | MEDLINE | ID: mdl-33380875

ABSTRACT

Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Humans , Marital Status , Quality of Life
2.
Bone Marrow Transplant ; 53(1): 34-38, 2018 01.
Article in English | MEDLINE | ID: mdl-29084203

ABSTRACT

Single-agent high-dose melphalan (HDM, 200 mg/m2) has been the most commonly used conditioning regimen prior to autologous stem cell transplant, since its introduction in 1992. We used a more aggressive alkylator-based conditioning regimen in an attempt to overcome early relapse and combat drug resistance. We present a retrospective comparison and long-term follow-up of newly diagnosed patients with multiple myeloma (MM) treated with induction followed by either high-dose carmustine (BCNU) and HDM, or HDM alone, both followed by autologous stem cell transplant (ASCT). Between 1997 and 2002, 104 patients were treated with BCNU/HDM; from 2001 to 2008, 103 patients were treated with HDM alone. Median follow-up of survivors was 78 and 68 months for the BCNU/HDM and HDM groups, respectively. The median PFS was significantly increased with the BCNU/HDM regimen (40.4 vs 20.5 months, P<0.001). Median overall survival was increased with the BCNU/HDM regimen when compared with HDM alone (88.4 vs 67.2 months, P=0.07), but the difference was not statistically significant. Transplant-related mortality was similar in both groups (2.9% with BCNU and HDM vs 3.9% with HDM alone). Our findings suggest that the BCNU/HDM preparative regimen should be investigated further and potentially compared in a prospective randomized manner with HDM alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Melphalan/therapeutic use , Multiple Myeloma/drug therapy , Transplantation Conditioning/methods , Transplantation, Autologous/methods , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carmustine/pharmacology , Female , Humans , Male , Melphalan/pharmacology , Middle Aged , Multiple Myeloma/pathology , Retrospective Studies
3.
Cancer Chemother Pharmacol ; 80(2): 421-431, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28685347

ABSTRACT

PURPOSE: Manganese porphyrins are redox-active drugs and superoxide dismutase mimics, which have been shown to chemosensitize lymphoma, a cancer which frequently occurs in dogs. This study aimed to identify critical information regarding the pharmacokinetics and toxicity of Mn(III) meso-tetrakis (N-n-butoxyetylpyridium-2-yl) porphyrin, (MnTnBuOE-2-PyP5+, MnBuOE) in dogs as a prelude to a clinical trial in canine lymphoma patients. METHODS: A single-dose pharmacokinetic (PK) study in normal dogs was performed to determine the plasma half-life (t 1/2) of MnBuOE. A dose reduction study was performed to establish the maximum tolerated dose (MTD) of MnBuOE. The safety and PK of a multi-dosing protocol was assessed. RESULTS: Peak plasma drug concentration occurred 30 min post-injection. The t 1/2 was defined as 7 h. MnBuOE induced an anaphylactic reaction and prolonged tachycardia. The MTD was defined as 0.25 mg/kg. The dogs were given MTD 3×/week for 2-3 weeks. The highest recorded tissue drug levels were in the lymph nodes (4-6 µM), followed by kidney and liver (2.5, 2.0 uM, respectively). CONCLUSIONS: We obtained critical information regarding the PK and toxicity of MnBuOE in dogs. The acute drug reaction and tachycardia post-injection have not been described in other species and may be specific to canines. The high tissue drug levels in lymph nodes have not been previously reported. MnBuOE accumulation in lymph nodes has important implications for the utility of adjuvant MnBuOE to treat lymphoma. With MnBuOE lymph node accumulation, reduction in the dose and/or administration frequency could be possible, leading to reduced toxicity.


Subject(s)
Antineoplastic Agents/administration & dosage , Kidney/metabolism , Liver/metabolism , Lymph Nodes/metabolism , Metalloporphyrins/administration & dosage , Anaphylaxis/chemically induced , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Dog Diseases/drug therapy , Dogs , Half-Life , Lymphoma/drug therapy , Lymphoma/veterinary , Male , Maximum Tolerated Dose , Metalloporphyrins/pharmacokinetics , Metalloporphyrins/toxicity , Species Specificity , Tachycardia/chemically induced , Tissue Distribution
4.
Bone Marrow Transplant ; 50(2): 197-203, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25402415

ABSTRACT

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.


Subject(s)
HLA Antigens , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Lymphoma/mortality , Lymphoma/therapy , Unrelated Donors , Acute Disease , Adolescent , Adult , Age Factors , Aged , Allografts , Chronic Disease , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/mortality , Graft vs Host Disease/therapy , Humans , Male , Middle Aged , Risk Factors , Survival Rate
5.
Cell Death Dis ; 5: e1470, 2014 Oct 16.
Article in English | MEDLINE | ID: mdl-25321477

ABSTRACT

The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies.


Subject(s)
Apoptosis , Glucose Transporter Type 1/metabolism , Glucose/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Aerobiosis/drug effects , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxyglucose/pharmacology , Disease Progression , Gene Deletion , Glycolysis/drug effects , Humans , Membrane Proteins/metabolism , Metabolic Networks and Pathways/drug effects , Molecular Targeted Therapy , Proto-Oncogene Proteins/metabolism
6.
Cancer Invest ; 31(4): 215-20, 2013 May.
Article in English | MEDLINE | ID: mdl-23473080

ABSTRACT

A small subset of cells in a patient with leukemia, termed leukemic stem cells (LSCs) have been shown to be responsible for the proliferation of disease. LSCs are thought to derive from normal hematopoietic stem cells, but are phenotypically distinguishable in that they are CD90(-), CD117(-), and CD123(+). Research in mouse models provides several potential therapeutics to target these cells in human patients. Eliminating LSCs should provide an efficient, potentially curative treatment option for leukemia patients.


Subject(s)
Hematopoietic Stem Cells/pathology , Leukemia/pathology , Neoplastic Stem Cells/pathology , Animals , Humans
7.
Bone Marrow Transplant ; 48(7): 926-31, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23334274

ABSTRACT

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥ 12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥ 13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥ 38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.


Subject(s)
Cord Blood Stem Cell Transplantation , Fever/epidemiology , Fever/therapy , Graft Survival , Transplantation Conditioning , Adolescent , Adult , Child , Female , Fever/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/therapy , Humans , Immunosuppressive Agents/administration & dosage , Incidence , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/analogs & derivatives , Neutrophils , Risk Factors , Syndrome , Tacrolimus/analogs & derivatives
8.
Leukemia ; 27(1): 113-7, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22772060

ABSTRACT

MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.


Subject(s)
Fusion Proteins, bcr-abl/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Acute/drug therapy , Mutation/genetics , Piperazines/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Aurora Kinases , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Acute/genetics , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prognosis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Remission Induction , Young Adult
10.
Bone Marrow Transplant ; 47(8): 1051-5, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22080963

ABSTRACT

Plerixafor, given on day 4 of G-CSF treatment is more effective than G-CSF alone in mobilizing hematopoietic progenitor cells. We tested a strategy of preemptive plerixafor use following assessment of the peak mobilization response to 5 days of G-CSF. Patients were eligible for plerixafor if, on day 5 of G-CSF, there were <7 circulating CD34+ cells/µL or if <1.3 × 10(6) CD34+ cells/kg were collected on the first day of apheresis. Plerixafor (0.24 mg/kg s.c.) was given on day 5 of G-CSF followed by apheresis on day 6. This was repeated for up to two additional doses of plerixafor. The primary end point of the study was the percentage of patients who collected at least 2 × 10(6) CD34+ cells/kg. Twenty candidates for auto-SCT enrolled on the trial. The circulating CD34+ cell level increased a median of 3.1 fold (range 1-8 fold) after the first dose of plerixafor and a median of 1.2 fold (range 0.3-6.5 fold) after the second dose of plerixafor. In all, 15 out of 20 (75%) patients achieved the primary end point. In conclusion, the decision to administer plerixafor can be delayed until after the peak mobilization response to G-CSF has been fully assessed.


Subject(s)
Anti-HIV Agents/administration & dosage , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Heterocyclic Compounds/administration & dosage , Adolescent , Adult , Aged , Benzylamines , Cyclams , Female , Humans , Leukocyte Count , Male , Middle Aged , Time Factors
11.
Bone Marrow Transplant ; 47(5): 700-5, 2012 May.
Article in English | MEDLINE | ID: mdl-21804612

ABSTRACT

Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25-67 years, seven males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab and TBI, all administered 1 day before re-transplantation. All patients received T-cell replete PBSCs from the same or a different haploidentical donor (n=10) or from the same matched sibling donor (n=1). Neutrophil counts promptly increased to >500/µL for 10 of the 11 patients at a median of 13 days. Of these, none developed grade III/IV acute GVHD. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Salvage Therapy/methods , Transplantation Conditioning/methods , Adult , Aged , Alemtuzumab , Antibodies, Monoclonal, Humanized/therapeutic use , Cyclophosphamide/therapeutic use , Female , Graft Survival , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Reoperation , Retrospective Studies , Transplantation, Homologous/adverse effects , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use
12.
Bone Marrow Transplant ; 47(6): 817-23, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22139069

ABSTRACT

The impact of activating KIR (aKIR) and inhibitory KIR (iKIR) on OS, relapse-related mortality (RRM) and acute GVHD (aGVHD) was prospectively studied in 84 adults with high-risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic SCT (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM is dependent on GVL effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both GVH and rejection directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (P=0.009) and RRM was lower (P=0.036) in patients missing HLA-C group2 ligand to donor iKIR. OS was higher if patients had >1 missing ligand (P=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was better with donor aKIR 2DS2 (P=0.028). There was a trend towards shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes were too small to provide inferential statistics. Findings in lymphoid malignancy patients should be further studied. These results suggest that the absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.


Subject(s)
HLA-C Antigens/metabolism , Hematologic Neoplasms , Peripheral Blood Stem Cell Transplantation , Receptors, KIR/metabolism , Transplantation Conditioning , Adolescent , Adult , Aged , Disease-Free Survival , Female , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Histocompatibility Testing , Humans , Living Donors , Male , Middle Aged , Retrospective Studies , Risk Factors , Survival Rate , Transplantation, Homologous
13.
Bone Marrow Transplant ; 47(6): 810-6, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21986636

ABSTRACT

Allogeneic hematopoietic SCT is an effective treatment in accelerated (AP) or blast phase (BP) CML. Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic hematopoietic SCTs performed from 1999 to 2004 in advanced-phase CML, using the data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185) and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or BM (53%) hematopoietic SCT after myeloablative (78%) or non-myeloablative (22%) conditioning. In all, 52% in CP2, 49% in AP and 46% in BP received IM before hematopoietic SCT. Disease-free survival was 35-40% for CP2, 26-27% for AP and 8-11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by the stages of CML or pre-hematopoietic SCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of the outcomes of allogeneic hematopoietic SCT for advanced-phase CML in the IM era.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Piperazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Transplantation Conditioning , Adolescent , Adult , Aged , Benzamides , Child , Disease-Free Survival , Female , Humans , Imatinib Mesylate , Male , Middle Aged , Retrospective Studies , Siblings , Survival Rate , Transplantation, Homologous
14.
Bone Marrow Transplant ; 46(6): 847-51, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20856212

ABSTRACT

Positron emission tomography (PET) in conjunction with computed tomography is a frequently used modality for staging patients with lymphoma. Utility of PET-computed tomography before or early following auto-SCT has not been as rigorously evaluated. We retrospectively analyzed patients who received auto-SCT for treatment of relapsed or refractory non-Hodgkins lymphoma or Hodgkins disease between the years of 1996 and 2007. Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (pre-PET), and/or a PET scan 6-14 weeks following transplantation (post-PET) were included. A total of 90 patients were identified for analysis. The median follow-up time is 3.3 years, with a range of 0.13-12.0 years. The median PFS was 4.6 years, and median OS was 5.1 years. At the time of this analysis, 34 patients (37%) experienced disease relapse, and 25 (27%) of the patients died from disease progression. In multivariate Cox proportional hazards analysis, post-PET did not predict for outcome, pre-PET positivity predicted for decrease in PFS. In conclusion, post-PET scan did not predict for PFS or OS in multivariate analysis. Positive pre-PET scan did predict for PFS as seen in previous studies, and may help identify patients who would benefit from innovative post transplant therapies.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hodgkin Disease/diagnosis , Positron-Emission Tomography/methods , Predictive Value of Tests , Adolescent , Adult , Aged , Female , Fluorodeoxyglucose F18 , Hodgkin Disease/therapy , Humans , Lymphoma, Non-Hodgkin , Male , Middle Aged , Prognosis , Retrospective Studies , Time Factors , Transplantation, Autologous , Treatment Outcome , Young Adult
15.
Bone Marrow Transplant ; 43(4): 327-33, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18850014

ABSTRACT

We report the outcome of early donor lymphocyte infusions (DLIs) after T-cell depleted non-myeloablative transplantation using stem cells from HLA-matched or mismatched donors. Sixty-nine patients with high-risk hematologic malignancies received DLI following fludarabine, CY and alemtuzumab with infusion of stem cells from a matched sibling (52) or partially matched family member donor (17). Patients received the first infusion at a median of 50 days after transplant, and doses ranged from 1 x 10(4) CD3+ cells/kg to 3.27 x 10(8) CD3+ cells/kg, depending on clinical status and the physician's discretion. A median cell dose of 1 x 10(5) CD3+ cells/kg in the mismatched setting and 1 x 10(6) CD3+ cells/kg in the matched sibling setting appears safe with only 1 of 7 (14%) and 4 of 31 patients (13%), respectively, experiencing severe acute GVHD at these doses. Importantly, 38% of patients with persistent disease before DLI attained a remission after infusion. Nine of the 69 patients remain alive and disease-free 32-71 months after the first DLI. In conclusion, low doses of DLI can be safely provided soon after T-cell depleted non-myeloablative therapy and provide a chance of remission. However, long-term survival still remains poor, primarily because of relapse in these patients.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Lymphocyte Transfusion/methods , T-Lymphocytes/immunology , Acute Disease , Adolescent , Adult , Aged , Cohort Studies , Graft Survival/immunology , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , HLA Antigens/immunology , Hematologic Neoplasms/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Lymphocyte Transfusion/adverse effects , Middle Aged , Myeloablative Agonists/therapeutic use , Prospective Studies , Survivors , T-Lymphocytes/cytology , Tissue Donors , Transplantation Conditioning/methods , Treatment Outcome , Young Adult
16.
Leukemia ; 22(12): 2184-92, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18784741

ABSTRACT

Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.


Subject(s)
Apolipoprotein E4/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Apolipoprotein E4/metabolism , Apoptosis/physiology , Cholesterol, VLDL/blood , Cohort Studies , Female , Genetic Predisposition to Disease/epidemiology , Genotype , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lipoprotein Lipase/genetics , Lipoprotein Lipase/metabolism , Male , Risk Factors , Sex Distribution , Survival Analysis
17.
Cytotherapy ; 10(3): 289-302, 2008.
Article in English | MEDLINE | ID: mdl-18418774

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) infection and its treatment causes significant morbidity following allogeneic stem cell transplantation (SCT) for malignancies. We studied the phenotype, function and growth kinetics of CMV pp65 antigen (Ag)-specific T cells expanded in a short-term culture for adoptive therapy. METHODS: Peripheral blood mononuclear cells (PBMC) from CMV-seropositive donors were cultured in various conditions with CMV pp65((495-503)) peptide to determine the most effective method for generating CMV-specific T cells. CMV-expanded cultures were tested for frequency, phenotype and functionality using peptide-MHC tetramer analysis, cytokine flow cytometry and cytolytic assays. A patient undergoing allogeneic SCT was administered CMV pp65-specific T cells generated from the donor based on these data, and recipient PBMC were analyzed following T-cell infusion. RESULTS: CMV pp65-specific T cells were consistently generated from CMV-seropositive donors at high frequencies (20-40% of CD8+ T cells), secreted interferon-gamma (IFN-gamma) in response to CMV peptide and had lytic activity against CMV peptide-expressing targets. Cultured CMV-specific T cells were infused into a SCT recipient without toxicity. DISCUSSION: Stimulating donor PBMC to generate functional, Ag-specific T cells for infusion into SCT recipients was accomplished consistently using readily available technology. We observed no toxicity in one patient receiving T cells and were able to monitor infused cells. These findings support further study of this approach as a prophylaxis against the risk of infection in patients receiving allogeneic transplantation from CMV-seropositive donors.


Subject(s)
Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Immunotherapy, Adoptive , Neoplasms/therapy , Stem Cell Transplantation , T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation/drug effects , Cells, Cultured , Clone Cells , Cytokines/metabolism , Cytomegalovirus/drug effects , Epitopes , Hematopoietic Stem Cell Transplantation , Humans , Kinetics , Lymphocyte Activation/drug effects , Neoplasms/immunology , Neoplasms/pathology , Peptides/pharmacology , Phenotype , Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Transplantation, Homologous
18.
Bone Marrow Transplant ; 41(1): 39-43, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17982503

ABSTRACT

Following initial graft rejection, a second attempt at allogeneic immunotherapy is often contemplated, but data on the success is limited. We therefore report on 11 patients with hematologic malignancies, renal cell cancer or marrow failure who underwent a second reduced-intensity regimen for primary or secondary graft failure. Nine of the 11 patients initially engrafted with the second attempt including two of four who used the same donor. One of the patients engrafted after the third attempt using a different donor and conditioning regimen. There were two treatment-related deaths. Four patients died from progressive disease 1-9 months after the second transplant. Two patients are still in recovery phase less than 1 year from the second transplant. Long-term remission is possible and three patients are alive in complete remission.


Subject(s)
Graft Rejection , Hematopoietic Stem Cell Transplantation , Adult , Aged , Carcinoma, Renal Cell/therapy , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Kidney Neoplasms/therapy , Leukemia, Myeloid, Acute/therapy , Middle Aged , Myelodysplastic Syndromes/therapy , Transplantation, Homologous , Treatment Outcome
19.
Blood ; 98(12): 3486-8, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11719394

ABSTRACT

Reduction in the toxicity of allogeneic transplantation with nonmyeloablative induction regimens has expanded the scope of practice to older and more debilitated patients. However, the limited availability of matched sibling donors requires that alternative donor sources be investigated. Reported here are 2 cases of patients with advanced hematologic malignancies without matched siblings, partially matched family members, or matched unrelated donors who successfully underwent nonmyeloablative conditioning therapy followed by infusion of partially matched, unrelated-donor cord blood cells. The patients are in remission and remain 100% donor as assessed by short tandem repeat analysis of the marrow 6 and 12 months following transplantation.


Subject(s)
Fetal Blood/cytology , Graft Survival , Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Mantle-Cell/therapy , Transplantation Conditioning , Adult , Histocompatibility , Humans , Male , Middle Aged , Remission Induction , Tissue Donors , Transplantation, Homologous
20.
Blood ; 98(8): 2301-7, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-11588023

ABSTRACT

Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leukemic stem cells (LSCs), have been documented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found in many leukemic populations. Because these cells are likely to be critical for the genesis and perpetuation of leukemic disease, the present studies sought to characterize unique molecular properties of the LSC population, with particular emphasis on the transcription factor, nuclear factor-kappaB (NF-kappaB). Previous experiments have shown that unstimulated human CD34(+) progenitor cells do not express NF-kappaB. In contrast, primary AML CD34(+) cells display readily detectable NF-kappaB activity as assessed by electrophoretic mobility shift assay and gene expression studies. Furthermore, detailed analyses of enriched AML stem cells (CD34(+)/CD38(-)/CD123(+)) indicate that NF-kappaB is also active in the LSC population. Given the expression of NF-kappaB in leukemic, but not normal primitive cells, the hypothesis that inhibition of NF-kappaB might induce leukemia-specific apoptosis was tested by treating primary cells with the proteasome inhibitor MG-132, a well-known inhibitor of NF-kappaB. Leukemic CD34(+)/CD38(-) cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34(+)/CD38(-) cells showed little if any effect. Taken together, these data indicate that primitive AML cells aberrantly express NF-kappaB and that the presence of this factor may provide unique opportunities to preferentially ablate LSCs.


Subject(s)
Hematopoietic Stem Cells/physiology , Leukemia, Myeloid, Acute/blood , NF-kappa B/blood , Stem Cells/physiology , Actins/genetics , Antigens, CD/analysis , Antigens, CD34/analysis , Bone Marrow Cells/cytology , Cell Cycle , Cells, Cultured , Culture Media, Serum-Free , Enzyme Inhibitors/pharmacology , Flow Cytometry , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/pathology , Humans , Leupeptins/pharmacology , NF-kappa B/antagonists & inhibitors , Reference Values , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured
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