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1.
Bone Marrow Transplant ; 47(7): 946-51, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22056644

ABSTRACT

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunosuppression Therapy/methods , Multiple Sclerosis/therapy , Adult , Antilymphocyte Serum/therapeutic use , Female , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Multiple Sclerosis/drug therapy , Multiple Sclerosis/pathology , Multiple Sclerosis/surgery , Transplantation, Autologous , Treatment Outcome , Whole-Body Irradiation
2.
Bone Marrow Transplant ; 46(3): 350-5, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20479709

ABSTRACT

Lenalidomide and other new agents have considerable activity in multiple myeloma (MM) and have changed the landscape of treatment. Data suggest that lenalidomide therapy before autologous hematopoietic stem cell transplantation has a detrimental effect on stem cell mobilization. This retrospective study examined the efficacy of plerixafor in combination with G-CSF among patients with MM previously treated with lenalidomide (median, 4 cycles; range, 1-20 cycles). Data were analyzed for 60 patients who received plerixafor plus G-CSF for frontline mobilization in a phase 3 clinical trial or an expanded access program (n=20) or for remobilization in a compassionate use program (n=40). The overall median number of CD34+ cells collected was 5.6 × 10(6) per kg (range, 0.45 × 10(6)-37.2 × 10(6)). The minimum number of CD34+ cells (2 × 10(6) per kg) was collected from 86.7% of patients in a median of 1 day. This minimum was collected from 100% of patients who underwent frontline mobilization and 80% of patients who underwent remobilization. These data suggest that CD34+ hematopoietic stem cells can be successfully and predictably collected with combination plerixafor plus G-CSF for primary or secondary mobilization in the majority of patients with MM who have been previously treated with lenalidomide.


Subject(s)
Hematopoietic Stem Cell Mobilization/methods , Heterocyclic Compounds/administration & dosage , Multiple Myeloma/blood , Multiple Myeloma/therapy , Thalidomide/analogs & derivatives , Antigens, CD34/biosynthesis , Antineoplastic Agents/administration & dosage , Benzylamines , Blood Component Removal , Cyclams , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/pathology , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/surgery , Retrospective Studies , Thalidomide/administration & dosage
3.
Vet Res Commun ; 30(8): 881-901, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17139538

ABSTRACT

We have used a murine MSCV-based bicistronic retroviral vector, containing the common gamma chain (gammac) and enhanced green fluorescent protein (EGFP) cDNAs, to optimize retroviral transduction of canine cells, including an adherent canine thymus fibroblast cell line, Cf2Th, as well as normal canine CD34(+) bone marrow (BM) cells. Both canine cell types were shown to express Ram-1 (the amphotropic retroviral receptor) mRNA. Supernatants containing infectious viruses were produced using both stable (PA317) and transient (Phoenix cells) amphotropic virus producer cell lines. Centrifugation (spinfection) combined with the addition of polybrene produced the highest transduction efficiencies, infecting approximately 75% of Cf2Th cells. An average of 11% of highly enriched canine CD34(+) cells could be transduced in a protocol that utilized spinfection and plates coated with the fibronectin fragment CH-296 (Retronectin). Indirect assays showed the vector-encoded canine gammac cDNA produced a gammac protein that was expressed on the cell surface of transduced cells. This strategy may result in the transduction of sufficient numbers of CD34(+) BM cells to make the treatment of canine X-linked severe combined immunodeficiency and other canine genetic diseases feasible.


Subject(s)
Antigens, CD34/metabolism , Bone Marrow Cells/metabolism , Dogs , Genetic Vectors/genetics , Stem Cells/virology , Transduction, Genetic/veterinary , Animals , Cell Line , Fibroblasts , Genes/genetics , Mice , Retroviridae/genetics , Thymus Gland/cytology , Transduction, Genetic/methods
4.
Am J Transplant ; 6(1): 89-94, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16433761

ABSTRACT

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/etiology , Adolescent , Adult , Aged , Calcineurin Inhibitors , Cohort Studies , Female , Humans , Hypertension, Renal/epidemiology , Hypertension, Renal/etiology , Incidence , Kidney/radiation effects , Male , Middle Aged
5.
Bone Marrow Transplant ; 36(5): 443-51, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15995712

ABSTRACT

We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.


Subject(s)
Cord Blood Stem Cell Transplantation , Hematopoietic Stem Cell Transplantation , Living Donors , Lymphoma/therapy , Transplantation Conditioning , Adult , Aged , Cord Blood Stem Cell Transplantation/methods , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Lymphoma/mortality , Male , Middle Aged , Recurrence , Transplantation Conditioning/methods , Transplantation, Autologous , Transplantation, Homologous , Treatment Outcome
6.
Bone Marrow Transplant ; 31(11): 1053-5, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12774059

ABSTRACT

Congenital sideroblastic anemia (CSA) is a dyserythropoietic disorder that leads to transfusion dependency and subsequent iron overload. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) was performed for a patient with CSA, who had contraindications to conventional allografting. Conditioning was fludarabine, low-dose total body irradiation and antithymocyte globulin, followed by peripheral blood stem cell transplant. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. Complete donor chimerism was observed day +131. Early after transplant, the patient became transfusion independent, allowing a regular phlebotomy program. On day +190, refractory lactic acidosis followed by fatal cardiovascular collapse developed, without evidence of infection. Data from this case demonstrates that NST may correct the erythropoietic defect of CSA.


Subject(s)
Anemia, Sideroblastic/congenital , Anemia, Sideroblastic/therapy , Hematopoietic Stem Cell Transplantation/methods , Vidarabine/analogs & derivatives , Adult , Antilymphocyte Serum/therapeutic use , Fatal Outcome , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Transplantation Conditioning/methods , Transplantation, Homologous , Vidarabine/therapeutic use , Whole-Body Irradiation
7.
Arthritis Rheum ; 44(8): 1848-54, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11508438

ABSTRACT

OBJECTIVE: The realization that fetal cells pass into the maternal circulation and can survive for many years has raised the question of whether fetal microchimerism can cause subsequent disease in the mother. Available data suggest that fetal-maternal transfusion may be related to some autoimmune diseases, notably systemic sclerosis (SSc). The goal of the current work was to identify and quantify tissue-specific fetal microchimerism in women with SSc. METHODS: We analyzed multiple tissue specimens obtained at autopsy from women with SSc as well as women who had died of causes unrelated to autoimmunity, using fluorescence in situ hybridization to detect the presence of male cells in women with sons. Tissues analyzed included adrenal gland, heart, intestine, kidney, liver, lung, lymph node, pancreas, parathyroid, skin, and spleen. RESULTS: Male cells were observed in tissue from at least 1 site in each woman with SSc and were found most frequently in spleen sections. After spleen, male cells were observed most frequently in lymph node, lung, adrenal gland, and skin tissue. The only tissue type in which male cells were not seen in any patient was pancreatic tissue. Male cells were not observed in tissue from women who had died of causes unrelated to autoimmunity. CONCLUSION: The results of this study suggest that fetal cells migrate from the peripheral circulation into multiple organs in women with SSc. All of the women studied had previously given birth to sons, so it is likely that these cells are of fetal origin. While the relevance of this finding to the pathogenesis of SSc remains to be elucidated, the presence of fetal cells in internal organs suggests that they could play a role in disease pathogenesis and that they may preferentially sequester in the spleen. The presence of these male cells may also be a result of disease, possibly through the migration of terminally differentiated and/or progenitor cells to areas of tissue damage.


Subject(s)
Fetus/cytology , Maternal-Fetal Exchange , Scleroderma, Systemic/etiology , Adult , Aged , Cell Nucleus/chemistry , Chimera/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Pregnancy , Scleroderma, Systemic/genetics , Spleen/chemistry , Tissue Distribution , Y Chromosome
8.
Bone Marrow Transplant ; 28(1): 1-12, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11498738

ABSTRACT

We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow harvests and 174 peripheral blood stem cell mobilizations were performed on 187 patients. Disease indications were multiple sclerosis (76 patients), rheumatoid arthritis (37 patients), scleroderma (26 patients), systemic lupus erythematosus (19 patients), juvenile chronic arthritis (13 patients), idiopathic autoimmune thrombocytopenia (8 patients), Behcet's disease (3 patients), undifferentiated vasculitis (3 patients), polychondritis (1 patient) and polymyositis (1 patient). Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe. Methods of PBSC mobilization included G-CSF (5, 10, or 16 microg/kg/day) or cyclophosphamide (2 or 4 g/m2) with either G-CSF (5 or 10 microg/kg/day) or GM-CSF (5 microg/kg/day). Bone marrow harvests were without complications and did not affect disease activity. A combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of cyclophosphamide and g-csf (P = 0.003). Three patients died as a result of cyclophosphamide-based stem cell collection (2.6% of patients mobilized with cyclophosphamide). When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen. Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation. Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.


Subject(s)
Autoimmune Diseases/therapy , Hematopoietic Stem Cells/cytology , Adolescent , Adult , Antigens, CD34 , Autoimmune Diseases/complications , Cell Separation/methods , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Cyclophosphamide/toxicity , Female , Global Health , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/toxicity , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/toxicity , Hematopoietic Stem Cell Mobilization/methods , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors
9.
Transfus Clin Biol ; 8(3): 231-4, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11499966

ABSTRACT

Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy in attempts to eradicate underlying diseases and achieve allogeneic engraftment. Preclinical studies and clinical observations have shown that to achieve engraftment conditioning regimens could be markedly reduced in intensity with reduction in treatment toxicities. The use of potent pre- and postgrafting immunosuppression facilitated stable mixed hematopoietic chimerism in a preclinical canine model. The initial clinical experiences with attenuated conditioning regimens have shown promise as a modality to achieve human stem cell transplantation with an improved safety profile. This may allow offering potentially curative hematopoietic stem cell transplantation (HSCT) to a more representative patient population (older and sicker) who are currently not eligible for such therapy. Obtaining a state of mixed hematopoietic chimerism could prove curative of the disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. On the other hand, patients with hematopoietic malignancy will likely require conversion to full donor hematopoeisis by virtue of graft-versus-host (GVH) reactions directed against both recipient hematopoiesis and underlying malignancy. The infusion of additional donor lymphocytes has been proposed by many groups to augment graft versus tumor responses, but most likely more specific strategies will need to be developed to improve efficacy and avoid nonspecific GVH reactions.


Subject(s)
Hematopoietic Stem Cell Transplantation , Transplantation Conditioning/methods , Animals , Bone Marrow/drug effects , Bone Marrow/radiation effects , Chimera , Cyclosporine/administration & dosage , Cyclosporine/therapeutic use , Dogs , Drug Administration Schedule , Graft Rejection/epidemiology , Graft Survival , Graft vs Host Reaction , Graft vs Leukemia Effect , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Lymphocyte Transfusion , Models, Animal , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Safety , Transplantation Conditioning/adverse effects , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Whole-Body Irradiation
10.
Front Biosci ; 6: G13-6, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11487474

ABSTRACT

Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy to achieve allogeneic engraftment and control of underlying disease. For engraftment purposes, preclinical studies and clinical observations have shown that conditioning regimens can be markedly reduced in intensity, resulting in reduced treatment toxicities. Preclinical canine studies demonstrated that the use of potent pre- and postgrafting immunosuppression allows for reduction in conditioning regimens while facilitating development of stable mixed chimerism. If attenuated conditioning regimens can be successfully translated to human stem cell transplantation, an improved safety profile will allow potentially curative treatment to a more representative patient profile not currently offered such therapy. Mixed chimerism could prove curative of disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. For patients with hematopoietic malignancy, spontaneous conversion to full donor hematopoeisis after stem cell transplant may prove curative by virtue of graft versus host reactions directed against the malignancy, however infusion of additional donor lymphocytes may be needed to treat persistent disease.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Animals , Dogs , Graft vs Leukemia Effect , Hematologic Neoplasms/therapy , Humans , Transplantation Chimera , Transplantation Tolerance
11.
Ann N Y Acad Sci ; 938: 328-37; discussion 337-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11458521

ABSTRACT

Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.


Subject(s)
Graft vs Tumor Effect/immunology , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adult , Animals , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Cyclosporine/therapeutic use , Disease Progression , Dogs , Forecasting , Graft Enhancement, Immunologic/adverse effects , Graft Enhancement, Immunologic/methods , Graft Survival , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Histocompatibility , Humans , Immunosuppressive Agents/therapeutic use , Lymphocyte Transfusion , Methotrexate/therapeutic use , Middle Aged , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Neoplasms/therapy , Prednisone/therapeutic use , Radiation Chimera , T-Lymphocytes, Cytotoxic/immunology , Tissue Donors , Transplantation Conditioning/adverse effects , Transplantation, Homologous , Treatment Outcome , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use , Whole-Body Irradiation
12.
Blood ; 97(11): 3390-400, 2001 Jun 01.
Article in English | MEDLINE | ID: mdl-11369628

ABSTRACT

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)


Subject(s)
Aging , Graft vs Tumor Effect , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Aged , Cause of Death , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Cyclosporine/therapeutic use , Female , Graft Rejection , Histocompatibility Testing , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia, Myeloid, Acute/therapy , Leukocyte Count , Male , Middle Aged , Multiple Myeloma/therapy , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Neutrophils , Platelet Count , Remission Induction , Survival Rate , T-Lymphocytes/immunology , Transplantation Conditioning , Whole-Body Irradiation/adverse effects
13.
Bone Marrow Transplant ; 28(11): 1083-6, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11781620

ABSTRACT

A 51-year-old patient with refractory CLL elected to participate in a trial of nonmyeloablative trans- plantation from an HLA-matched unrelated donor. He received low-dose fludarabine/TBI, with infusion of donor PBPC and cyclosporin (CsA)/MMF. Early post transplant he experienced explosive tumor growth with respiratory insufficiency. After immunosuppression discontinuation and rituximab administration, no response was observed. This prompted treatment with cyclophosphamide (2 g/m(2)/day x 2), paclitaxel (250 mg/m(2) over 24 h), doxorubicin (50 mg/m(2)), solumedrol (500 mg/day), and a second dose of rituximab, from days +11 to +14. A rapid response was achieved. Chemotherapy did not cause an obvious compromise of donor stem cell engraftment or establishment of stable donor chimerism.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Immunosuppressive Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Antineoplastic Agents/administration & dosage , Combined Modality Therapy/methods , Humans , Immunosuppressive Agents/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Middle Aged , Transplantation, Heterologous
14.
Biol Blood Marrow Transplant ; 7(10): 543-51, 2001.
Article in English | MEDLINE | ID: mdl-11760086

ABSTRACT

Human CD34+ cells have been shown to retain long-term hematopoietic engrafting potential in preclinical and clinical studies. However, recent studies of human and murine CD34- stem cells suggest that these are functionally important early progenitors. Using autologous transplantation, we investigated whether canine CD34 and CD34- marrow cells could be transduced and give rise to long-term hematopoiesis. CD34+Lin- and CD34-Lin- cell populations purified by fluorescence-activated cell sorting were separately cocultivated with retroviral vectors LN (CD34+Lin-) and LNY (CD34-Lin-), which carry the neomycin (neo) gene. After myeloablative total body irradiation (920 cGy), 3 dogs received transplants of both CD34+Lin- cells and CD34-Lin- cells and 2 dogs received only CD34-Lin- cells. Untransduced autologous marrow cells were given to ensure hematopoietic recovery. Using CFU-C assays, transduction efficiencies of CD34+Lin- cells ranged from 6% to 18% with no CFU-C formation from CD34-Lin- cells. PCR-based detection of the neo gene from WBCs was used to detect transduced cells weekly after transplantation. Additional PCR studies in 3 dogs given both CD34+Lin- and CD34-Lin- cells were performed on monocytes, granulocytes, and T cells (2 dogs, one at 7.5 months and the other at 9 months) and granulocytes (1 dog at 12 months). LN was detected up to 12 months posttransplantation in WBCs and mono-myeloid and lymphoid populations from 3 dogs receiving transplants of transduced CD34+Lin- cells. LNY was not detected at any time after transplantation in 5 dogs that received transduced CD34-Lin- cells. Whereas canine CD34+Lin- marrow cells contributed to long-term multilineage hematopoiesis, progeny of CD34-Lin- progenitor cells were not detected after transplantation in these experiments.


Subject(s)
Antigens, CD34/physiology , Stem Cell Transplantation/methods , Animals , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Cell Culture Techniques , Cell Lineage , Dogs , Genetic Vectors , Graft Survival/immunology , Hematopoiesis/immunology , Models, Animal , Retroviridae/genetics , Transduction, Genetic , Transplantation, Autologous/methods
16.
Transplantation ; 70(10): 1437-42, 2000 Nov 27.
Article in English | MEDLINE | ID: mdl-11118086

ABSTRACT

BACKGROUND: The aims of this study were to ex vivo expand canine dendritic cells and determine their phenotype and functional characteristics. METHODS: CD34+-selected cells and CD34+-depleted canine bone marrow (BM) cells were cultured in Iscove's modified medium for 14 days. Cytokines added to the cultures included human granylocyte/macrophage colony-stimulating factor 5 ng/ml, hFlt3 ligand 200 ng/ml, and human tumor necrosis factor-alpha 10 ng/ml. Cultured cells and purified subpopulations were assessed for cell surface antigen expression, morphology, and function by flow cytometric analysis, electron microscopy, and an allogeneic mixed lymphocyte reaction at day 14. RESULTS: Two main cell populations were identified, DR++(bright)/CD14- and DR+(dim)/CD14+. Ex vivo expanded CD34+-selected cells showed increased allostimulatory activity compared to both cultured CD34+-depleted cells and mononuclear cells. In contrast, ex vivo expansion from CD34+-depleted cells was unsuccessful. After sorting cells from the ex vivo expanded CD34+-selected bone marrow to enrich for DR++/CD14- cells, a 42-fold increase (median) of allostimulatory activity was observed as compared with sorted DR+/CD14+ cells (P=0.02). CONCLUSIONS: Cells with dentric cell-like phenotypes and functions can be cultured from canine CD34+-selected bone marrow cells. Future studies will address the roles of these cells in engraftment, graft versus host reactions and graft-host tolerance in a canine hematogoietic stem cell transplantaton model.


Subject(s)
Antigens, CD34/analysis , Bone Marrow Cells/cytology , Dendritic Cells/cytology , Stem Cells/immunology , Animals , Bone Marrow Cells/ultrastructure , Dogs , Humans , Lymphocyte Culture Test, Mixed , Microscopy, Electron , Stem Cells/physiology
17.
Biol Blood Marrow Transplant ; 6(5): 476-95, 2000.
Article in English | MEDLINE | ID: mdl-11063377

ABSTRACT

The purpose of this review is to analyze the current status of high-dose chemotherapy (HDCT) with autologous stem cell transplantation for patients with breast cancer. Current results from the major prospective phase 2 and phase 3 trials in metastatic breast cancer (MBC) and high-risk primary breast cancer (HRPBC) are reviewed. Prognostic factors and future research directions are also discussed. The encouraging results of phase 2 trials suggested a benefit for HDCT in HRPBC and some categories of patients with MBC. Some investigators have argued that patient selection might have been a critical factor in those studies. Recently reported randomized trials in patients with chemosensitive MBC have included only small numbers of patients in complete remission and thus have not adequately addressed the relative value of HDCT versus maintenance standard-dose chemotherapy in this patient subset. Although initial results of 2 studies have been reported, most randomized phase 3 studies of HDCT in HRPBC require longer follow-up before definitive conclusions can be made about its efficacy in this setting. We conclude that the role of HDCT for HRPBC or MBC patients has not yet been fully defined. Longer follow-up of the ongoing randomized trials is necessary, and their mature results will help clarify this important question. In the meantime, it is imperative that research continues, to enhance the efficacy of the procedure. This may come through incorporating more active drugs into HDCT regimens and combining HDCT with novel strategies aimed at eradication of posttransplantation minimal residual disease.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Hematopoietic Stem Cell Transplantation , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Bone Marrow Diseases/chemically induced , Bone Marrow Diseases/therapy , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Cell Separation , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Combined Modality Therapy , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Forecasting , France , Humans , Life Tables , Multicenter Studies as Topic , Neoplasm Metastasis , Neoplasm Recurrence, Local , Patient Selection , Philadelphia , Prognosis , Prospective Studies , Randomized Controlled Trials as Topic , Remission Induction , Research Design , Retrospective Studies , Risk , Salvage Therapy , Treatment Outcome , United States
18.
Blood ; 96(12): 3991-4, 2000 Dec 01.
Article in English | MEDLINE | ID: mdl-11090091

ABSTRACT

Donor-derived hematopoiesis was assessed in 17 patients who received allogeneic marrow grafts from HLA-matched siblings between 1971 and 1980. Complete blood counts were normal or near normal in all patients except one. Chimerism analyses, using either dual-color XY-chromosome fluorescence in situ hybridization (FISH) or analysis of variable number tandem repeat loci, indicated that 15 out of 16 patients had greater than 97% donor-derived hematopoiesis, whereas 1 patient had indeterminate chimerism. All 12 recipients of grafts from female donors exhibited polyclonal hematopoiesis by X-linked clonal analysis with the use of molecular probes. Of the 17 recipients, 9 exhibited a less than 1.0-kilobase shortening of granulocyte telomere length compared with their respective donors, according to terminal restriction fragment analysis or flow-FISH with a fluorescein-labeled peptide nucleic acid probe. These data suggest that under standard transplantation conditions, the stem cell proliferative potential is not compromised during hematopoietic reconstitution. (Blood. 2000;96:3991-3994)


Subject(s)
Bone Marrow Transplantation , Hematopoiesis/physiology , Telomere/ultrastructure , Adolescent , Adult , Bone Marrow Transplantation/standards , Cell Division/physiology , Child , Child, Preschool , Female , Follow-Up Studies , Granulocytes/ultrastructure , Humans , In Situ Hybridization, Fluorescence , Male , Nuclear Family , Polymorphism, Restriction Fragment Length , Sex Factors , Transplantation Chimera , Transplantation, Homologous , X Chromosome/ultrastructure
19.
Blood ; 95(2): 581-5, 2000 Jan 15.
Article in English | MEDLINE | ID: mdl-10627466

ABSTRACT

The authors have shown accelerated endothelialization on polyethylene terephthalate (PET) grafts preclotted with autologous bone marrow. Bone marrow cells have a subset of early progenitor cells that express the CD34 antigen on their surfaces. A recent in vitro study has shown that CD34(+) cells can differentiate into endothelial cells. The current study was designed to determine whether CD34(+) progenitor cells would enhance vascular graft healing in a canine model. The authors used composite grafts implanted in the dog's descending thoracic aorta (DTA) for 4 weeks. The 8-mm x 12-cm composite grafts had a 4-cm PET graft in the center and 4-cm standard ePTFE grafts at each end. The entire composite was coated with silicone rubber to make it impervious; thus, the PET segment was shielded from perigraft and pannus ingrowth. There were 5 study grafts and 5 control grafts. On the day before surgery, 120 mL bone marrow was aspirated, and CD34(+) cells were enriched using an immunomagnetic bead technique, yielding an average of 11.4 +/- 5. 3 x 10(6). During surgery, these cells were mixed with venous blood and seeded onto the PET segment of composite study grafts; the control grafts were treated with venous blood only. Hematoxylin and eosin, immunocytochemical, and AgNO(3 )staining demonstrated significant increases of surface endothelialization on the seeded grafts (92% +/- 3.4% vs 26.6% +/- 7.6%; P =.0001) with markedly increased microvessels in the neointima, graft wall, and external area compared with controls. In dogs, CD34(+) cell seeding enhances vascular graft endothelialization; this suggests practical therapeutic applications. (Blood. 2000;95:581-585)


Subject(s)
Blood Vessel Prosthesis , Endothelium, Vascular/physiology , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Microcirculation/physiology , Neovascularization, Physiologic , Polytetrafluoroethylene , Animals , Antigens, CD34 , Aorta, Abdominal , Biocompatible Materials , Blood Vessel Prosthesis Implantation , Bone Marrow Cells/cytology , Dogs , Endothelium, Vascular/cytology , Microcirculation/cytology
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