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1.
Neth J Med ; 78(4): 183-190, 2020 07.
Article in English | MEDLINE | ID: mdl-32641557

ABSTRACT

With the introduction of conjugate pneumococcal vaccines, changes in causative serotypes and clinical presentations of Streptococcus pneumoniae infections are occurring. During the 2017-2018 winter, an unusual number of patients with a severe manifestation of pneumococcal disease was admitted to a tertiary care intensive care unit (ICU) in the Netherlands. We describe some of the cases in depth. Given our observed change in infecting serotypes and extreme clinical manifestations of pneumococcal disease, a systematic clinical registry of pneumococcal infections in the ICU may be a valuable addition to pneumococcal disease surveillance.


Subject(s)
Pneumococcal Infections/microbiology , Pneumococcal Vaccines/immunology , Population Surveillance , Streptococcus pneumoniae/genetics , Vaccines, Conjugate/immunology , Adult , Aged , Female , Humans , Intensive Care Units , Male , Middle Aged , Netherlands , Pneumococcal Infections/immunology , Serogroup , Streptococcus pneumoniae/immunology
2.
Hum Immunol ; 81(8): 407-412, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32471661

ABSTRACT

Testing for anti-human leukocyte antigen (HLA) antibodies has now become standard practice in allogeneic hematopoietic stem cell transplantation (HSCT), and anti-HLA antibodies (both donor specific and non-donor specific) are being identified and have many potential consequences. Most studies suggest that donor-specific HLA antibodies lead to adverse outcomes, though little is reported on non-donor specific anti-HLA antibodies. We present the results of a retrospective cohort analysis of 157 patients who received HSCT at the University of Rochester over a period of four years. We identified 45 patients (28.7%) who had detectable anti-HLA antibodies, while only one patient (0.6%) had donor-specific anti-HLA antibodies. Patients with prior pregnancies and multiple transfusions were at increased risk to develop antibodies. In our cohort, the presence of non-donor specific anti-HLA antibodies did not significantly impact overall survival, progression free survival, graft failure, or transplant-related mortality.


Subject(s)
Antibodies/immunology , HLA Antigens/immunology , Female , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/methods , Histocompatibility/immunology , Histocompatibility Testing/methods , Humans , Male , Middle Aged , Retrospective Studies , Tissue Donors , Transplantation, Homologous/methods
3.
Bone Marrow Transplant ; 52(2): 270-278, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27991895

ABSTRACT

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.


Subject(s)
Aspergillosis , Aspergillus , Candida , Candidiasis , Cord Blood Stem Cell Transplantation , Hematologic Neoplasms , Registries , Adolescent , Adult , Aged , Allografts , Aspergillosis/etiology , Aspergillosis/mortality , Aspergillosis/therapy , Candidiasis/etiology , Candidiasis/mortality , Candidiasis/therapy , Child , Child, Preschool , Disease-Free Survival , Female , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Humans , Infant , Male , Middle Aged , Survival Rate
4.
Leukemia ; 28(10): 1960-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24577530

ABSTRACT

Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzofurans/therapeutic use , Leukemia/drug therapy , Neoplastic Stem Cells/drug effects , Triterpenes/therapeutic use , Animals , Antigens, CD34/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Leukocytes, Mononuclear/cytology , Mice , Mitochondria/metabolism , Neoplastic Stem Cells/cytology , Phenotype , Reactive Oxygen Species/metabolism , Sirolimus/analogs & derivatives , Sirolimus/therapeutic use , Stem Cells/drug effects , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
5.
Leukemia ; 28(3): 658-65, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23989431

ABSTRACT

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.


Subject(s)
Bone Marrow Transplantation , Neoplasm, Residual , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Protein-Tyrosine Kinases/antagonists & inhibitors , Remission Induction , Survival Rate , Transplantation Conditioning , Adult , Animals , Female , Guinea Pigs , Humans , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Transplantation, Homologous , Young Adult
6.
Bone Marrow Transplant ; 48(11): 1444-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23749109

ABSTRACT

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10(6) cells/kg on day 1 vs 2.92 × 10(6) cells/kg, P=0.0231; myeloma: 4.16 × 10(6) vs 3.69 × 10(6) cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10(6) cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Granulocyte Colony-Stimulating Factor/economics , Hematopoietic Stem Cell Mobilization/economics , Hematopoietic Stem Cell Transplantation/economics , Adult , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Retrospective Studies , Rituximab , Transplantation, Autologous/economics , Transplantation, Autologous/methods , Treatment Outcome , Young Adult
7.
Bone Marrow Transplant ; 48(5): 691-7, 2013 May.
Article in English | MEDLINE | ID: mdl-23085827

ABSTRACT

Successful utilization of SCT modalities often requires utilization of both red cell and platelet transfusions. In this retrospective evaluation of clinical factors affecting transplant engraftment and transfusion utilization at a single transplant center in 505 patients from 2005 through 2009, we found that graft type, donor type and the conditioning regimen intensity significantly affected both the neutrophil engraftment time (P<0.001) and the platelet engraftment time (P<0.001). SCT patients required an average of 6.2 red cell units, and 7.9 platelet transfusions in the first 100 days with a wide s.d. Among auto-SCT patients, 5% required neither RBC nor platelet transfusions. Some reduced-intensity transplants were also associated with no transfusion need, and in allogeneic transplants, conditioning regimen intensity was positively correlated with platelet transfusion events as assessed by multivariate analysis. Other patient characteristics such as gender, graft type, donor type, underlying disease and use of TBI were all independently associated with transfusion needs in SCT patients. Further studies are required to understand the means to minimize transfusions and potential related complications in SCT patients.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Platelet Transfusion/methods , Adolescent , Adult , Aged , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Platelet Transfusion/adverse effects , Retrospective Studies , Tissue Donors , Transplantation Conditioning/methods , Young Adult
8.
Bone Marrow Transplant ; 45(1): 39-47, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19483760

ABSTRACT

Plerixafor, a novel CXCR4 inhibitor, is effective in mobilizing PBSCs particularly when used in conjunction with G-CSF. In four cohorts, this pilot study explored the safety of plerixafor mobilization when incorporated into a conventional stem cell mobilization regimen of chemotherapy and G-CSF. Forty (26 multiple myeloma and 14 non-Hodgkin's lymphoma) patients were treated with plerixafor. Plerixafor was well tolerated and its addition to a chemo-mobilization regimen resulted in an increase in the peripheral blood CD34+ cells. The mean rate of increase in the peripheral blood CD34+ cells was 2.8 cells/microl/h pre- and 13.3 cells/microl/h post-plerixafor administration. Engraftment parameters were acceptable after myeloblative chemotherapy, with the median day for neutrophil and plt engraftment being day 11 (range 8-20 days) and day 13 (range 7-77 days), respectively. The data obtained from the analysis of the cohorts suggest that plerixafor can safely be added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. Further studies are warranted to evaluate the effect of plerixafor in combination with chemomobilization on stem cell mobilization and collection on the first and subsequent days of apheresis, and its impact on resource utilization.


Subject(s)
Antiviral Agents/therapeutic use , Blood Component Removal/methods , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Heterocyclic Compounds/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Multiple Myeloma/therapy , Adult , Aged , Antigens, CD34/metabolism , Benzylamines , Combined Modality Therapy , Cyclams , Drug Therapy, Combination , Female , Heterocyclic Compounds/adverse effects , Humans , Male , Middle Aged , Pilot Projects
9.
Leukemia ; 23(8): 1398-405, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19295545

ABSTRACT

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.


Subject(s)
Antineoplastic Agents/pharmacology , Killer Cells, Natural/drug effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Lymphocytosis/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , T-Lymphocyte Subsets/drug effects , T-Lymphocytes, Cytotoxic/drug effects , Thiazoles/pharmacology , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Clinical Trials, Phase II as Topic/statistics & numerical data , Cohort Studies , Colitis/chemically induced , Dasatinib , Female , Humans , Immunophenotyping , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Male , Middle Aged , Multicenter Studies as Topic , Neoplasm Proteins/antagonists & inhibitors , Pleurisy/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Thiazoles/adverse effects , Thiazoles/therapeutic use
10.
Bone Marrow Transplant ; 42(5): 297-310, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18660844

ABSTRACT

Stem cell transplants that follow both myeloablative and non-myeloablative conditioning regimens can result in states of mixed chimerism, which can be stable over time. With widespread availability of Y chromosome FISH in sex-mismatched transplantation and DNA-based methodologies for analysis of chimerism in other donor-recipient pairs, further insights have been gained regarding the implications of the mixed chimeric state. In transplants performed for inherited and acquired marrow failure disorders, disease status can be improved with only 10-20% donor cells, and it appears that stable mixed chimerism at that level is an acceptable outcome often leading to a state of tolerance, but an increasing level of recipient cells often precedes graft rejection. In transplants performed for malignant conditions, increasing levels of mixed chimerism may indicate disease relapse, but some cases with stable levels of mixed chimerism have been compatible with prolonged remission states. Understanding when mixed chimerism is an indication of secondary graft failure or impending graft rejection vs a state of tolerance and ongoing propensity for the establishment of a graft-vs-tumor effect is often difficult with currently available technologies and immunologic assays. The ability to understand the implication of mixed chimerism of multiple cell lineages and of varied lymphocyte subsets will remain important areas for future research to best harness the immunologic and other therapeutic benefits of allogeneic transplantation.


Subject(s)
Chromosomes, Human, Y , Graft Rejection/immunology , Graft vs Tumor Effect/immunology , Stem Cell Transplantation , Transplantation Chimera/immunology , Transplantation Tolerance , Bone Marrow Diseases/immunology , Bone Marrow Diseases/therapy , Female , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/therapy , Humans , Male , Neoplasms/immunology , Neoplasms/therapy , Transplantation, Homologous
11.
Ann Oncol ; 19(10): 1759-64, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18504251

ABSTRACT

BACKGROUND: Given the significant activity and tolerability of gemcitabine in patients with relapsed Hodgkin's lymphoma (HL), the critical role that nuclear factor kappa B (NF-kappaB) appears to play in the pathogenesis of this tumor, the ability of bortezomib to inhibit NF-kappaB activity, and laboratory studies suggesting synergistic antitumor effects of gemcitabine and bortezomib, we hypothesized that this combination would be efficacious in patients with relapsed or refractory HL. PATIENTS AND METHODS: A total of 18 patients participated. Patients received 3-week cycles of bortezomib 1 mg/m(2) on days 1, 4, 8, and 11 plus gemcitabine 800 mg/m(2) on days 1 and 8. RESULTS: The overall response rate for all patients was 22% (95% confidence interval 3% to 42%). Three patients developed grade III transaminase elevation: one was removed from the study and two had doses of gemcitabine held. Almost all patients exhibited inhibition of proteasome activity with treatment. CONCLUSIONS: The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Hodgkin Disease/enzymology , Humans , Male , Middle Aged , Proteasome Endopeptidase Complex/blood , Pyrazines/administration & dosage , Pyrazines/adverse effects , Gemcitabine
14.
Bone Marrow Transplant ; 36(9): 747-55, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16044140

ABSTRACT

ABO blood group antigens, of great importance in transplantation and transfusion, are present on virtually all cells, as well as in soluble form in plasma and body fluids. Naturally occurring plasma IgM and IgG antibodies against these antigens are ubiquitous. Nonetheless, the ABO blood group system is widely ignored by many transfusion services, except for purposes of red cell transfusion. We implemented a policy of transfusing only ABO identical platelets and red cells in patients undergoing stem cell transplantation or treatment for hematologic malignancies. Major bleeding episodes have occurred in about 5% of patients undergoing induction therapy for acute leukemia as compared with 15-20% in the literature. Overall survival times appear to be superior to that in historical cohorts. In 2002-2004, treatment-related mortality at 100 days in our Blood and Marrow Transplant Unit was 0.7% for autologous transplants (n=148), 13% for sibling allogeneic transplants (n=110), and 24% (n=62) for matched unrelated allogeneic transplants, suggesting that our approach is safe. We speculate that more rigorous efforts on the part of transfusion services to provide ABO identical blood components, and to remove incompatible supernatant plasma, when necessary, might yield reduced morbidity and mortality in patients undergoing stem cell transplantation.


Subject(s)
ABO Blood-Group System , Bone Marrow Transplantation , Erythrocyte Transfusion , Hemorrhage/therapy , Leukemia/therapy , Platelet Transfusion , Blood Grouping and Crossmatching/methods , Bone Marrow Transplantation/methods , Bone Marrow Transplantation/mortality , Erythrocyte Transfusion/methods , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/mortality , Hemorrhage/etiology , Hemorrhage/mortality , Histocompatibility Testing/methods , Humans , Leukemia/complications , Leukemia/mortality , Platelet Transfusion/methods , Transplantation, Homologous
15.
Bone Marrow Transplant ; 35(2): 171-7, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15531901

ABSTRACT

Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.


Subject(s)
Anemia, Sickle Cell/therapy , Hematopoietic Stem Cell Transplantation/methods , Thalassemia/therapy , Vidarabine/analogs & derivatives , Adolescent , Adult , Anemia, Sickle Cell/complications , Antilymphocyte Serum/administration & dosage , Child , Combined Modality Therapy/adverse effects , Female , Graft Rejection , Graft vs Host Disease , Hemoglobinopathies/therapy , Humans , Immunosuppressive Agents/therapeutic use , Infections , Male , Pancytopenia , Transfusion Reaction , Transplantation Chimera , Transplantation, Homologous , Vidarabine/administration & dosage , Whole-Body Irradiation
16.
Semin Oncol ; 31(6 Suppl 18): 59-61, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15726525

ABSTRACT

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.


Subject(s)
Amifostine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/therapeutic use , Cytarabine/therapeutic use , Etoposide/therapeutic use , Hematopoietic Stem Cell Transplantation , Lymphoma/therapy , Melphalan/therapeutic use , Adult , Amifostine/toxicity , Antineoplastic Combined Chemotherapy Protocols/toxicity , Carmustine/toxicity , Combined Modality Therapy , Cytarabine/toxicity , Cytoprotection , Etoposide/toxicity , Humans , Melphalan/toxicity , Middle Aged , Radiation-Protective Agents/adverse effects , Radiation-Protective Agents/therapeutic use , Transplantation, Autologous
17.
Leukemia ; 17(9): 1806-12, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12970780

ABSTRACT

Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hematopoiesis/drug effects , Leukemia/drug therapy , Quinolones/pharmacology , Animals , Antigens, CD34/metabolism , Apoptosis/drug effects , Caspase 3 , Caspases/metabolism , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cell Movement/drug effects , Colony-Forming Units Assay , Farnesyltranstransferase , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Poly(ADP-ribose) Polymerases/metabolism , Time Factors , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/transplantation
18.
Bone Marrow Transplant ; 32(3): 293-8, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12858201

ABSTRACT

The impact of peripheral blood stem cell transplantation (PBSCT) on survival relative to bone marrow transplantation (BMT) remains poorly defined. Several randomized controlled trials (RCTs) comparing HLA-matched related PBSC- and BMT for patients with hematologic malignancies have been published, yielding differing results. We conducted a meta-analysis of published RCTs to more precisely estimate the effect of PBSCT on survival. Seven trials that assessed survival were identified and included in our analysis. Using a fixed effects model, and combining the results of all seven trials, the summary odds ratio for mortality after PBSCT was 0.81 (95% CI, 0.62-1.05) when compared to BMT. Subgroup analysis revealed no association between the median PBSCT 34+ cell dose and relative risk for morality after PBSCT. However, there was an association between the proportion of patients enrolled with advanced-stage disease and the summary odds ratio for mortality. The pooled estimate was 0.64 for studies where patients with intermediate/advanced disease comprised at least 25% of enrollment, and was 1.07 for the studies enrolling a smaller proportion. This finding substantiates results from previously published studies that have demonstrated a survival advantage with PBSCT limited to patients with advanced disease.


Subject(s)
Bone Marrow Transplantation/mortality , Hematologic Neoplasms/therapy , Histocompatibility , Peripheral Blood Stem Cell Transplantation/mortality , Adult , Antigens, CD34 , Cell Count , Disease Progression , Female , HLA Antigens , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Odds Ratio , Randomized Controlled Trials as Topic/statistics & numerical data , Risk Factors , Survival Analysis , Transplantation, Homologous
19.
Blood Cells Mol Dis ; 28(3): 315-21, 2002.
Article in English | MEDLINE | ID: mdl-12367578

ABSTRACT

To find a parameter to predict the quality of collected mobilized CD34+ blood as hemopoietic reconstituting cells, the ratio of CFU-GM to CD34+ cells was examined. One hundred six consecutive patients who underwent blood stem cell transplantation at the University of Rochester from 01/01/99 to 12/31/99 were examined retrospectively for the number of days to reach an absolute neutrophil count of 500 or 1000 cells/microl and an absolute platelet count of 20,000 or 50,000 cells/microl without transfusion support as measures of engraftment. Linear regression analyses were conducted to determine factors influencing engraftment. The number of CD34+ cells/kg and CFU-GM/kg correlated highly with the number of nucleated blood cells/kg. In this population, in which 90% of patients received >2 x 10(6) CD34+ cells/kg, neither the number of CD34+ cells/kg nor the number of CFU-GM/kg correlated with the time to engraftment as judged by neutrophil or platelet levels. In contrast, the lower the ratio of CFU-GM to CD34+ cells, the more rapid the reconstitution of platelets to 20,000/microl (P = 0.03) and 50,000/microl (P = 0.02). Thus, a lower ratio of the CFU-GM/CD34+ appended to reflect a greater number of hematopoietic reconstituting cells in the blood cell collection. The CFU-GM/CD34+ ratio is an apparent predictor of earlier platelet engraftment, suggesting that the ratio reflects the engraftment potential of mobilized donor progenitor cells.


Subject(s)
Graft Survival , Hematopoietic Stem Cell Mobilization/standards , Hematopoietic Stem Cells/cytology , Peripheral Blood Stem Cell Transplantation/standards , Adolescent , Adult , Aged , Antigens, CD34/analysis , Blood Cell Count , Child , Child, Preschool , Cohort Studies , Hematopoiesis , Humans , Infant , Kinetics , Middle Aged , Neoplasms/therapy , Prognosis , Regression Analysis , Retrospective Studies
20.
J Hematother Stem Cell Res ; 10(5): 643-55, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11672510

ABSTRACT

Ultrastructural studies of marrow and examination of the in vivo processes of stem cell homing and mobilization show that multipotential hematopoietic progenitors are able to traverse endothelial cells. The regulation of this process by various classes of chemokines was studied in this report, using an in vitro model of transendothelial migration. Human umbilical vein endothelial cells (HUVECs) or bone marrow-derived endothelial cells (BMECs) were grown to confluence on 3-microm microporous membrane inserts and placed in 24-well culture plates. CD34(+) cells isolated from normal volunteer donor marrow by immunoadsorption or magnetic bead selection techniques were added to the inserts and various individual chemokines were added to the lower chamber of the culture plates in serum-free conditions. After 24 h, the percentage of transmigrated cells was determined. A mean of 8.5% of unfractionated marrow CD34(+) populations migrated, and all chemokines tested, with the exception of macrophage inflammatory protein-1alpha (MIP-1alpha), had some positive effect on this migration. The greatest effects were seen with stroma-derived factor-1alpha (SDF-1alpha) and stroma-derived factor-1beta (SDF-1beta), with lesser effects noted for other chemokines and cytokines. When the CD34(+) population was subselected for expression of CD38, a greater fraction of the CD38(-) cells migrated as compared to the CD38(+) fraction. CD34(+) cells isolated from mobilized peripheral blood and cord blood also migrated in response to chemokines. Chemokines of the CC, CXC, and CX(3)C classes as well as other hematopoietic cytokines may modulate the process of stem cell transmigration of endothelial cells. Further understanding of this process may help elucidate the mechanism of stem cell mobilization and homing.


Subject(s)
Antigens, CD34/analysis , Chemokines/pharmacology , Hematopoietic Stem Cells/drug effects , Antibodies/pharmacology , Calcium/metabolism , Cell Movement/drug effects , Cells, Cultured , Chemokines, CC/pharmacology , Chemokines, CX3C/pharmacology , Chemokines, CXC/pharmacology , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/immunology , Humans , Interleukin-8/pharmacology , Receptors, CXCR4/immunology
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