15 results on '"Uday Popat"'
Search Results
2. Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis
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David R. Beers, Jenny S. Henkel, Ericka Simpson, George Carrum, Helen E. Heslop, József I. Engelhardt, László Siklós, Albert A. Yen, Y. Luo, Stanley H. Appel, Uday Popat, and Malcolm K. Brenner
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Genetic enhancement ,Pilot Projects ,Hematopoietic stem cell transplantation ,medicine ,Humans ,Prospective Studies ,Amyotrophic lateral sclerosis ,Neuroinflammation ,business.industry ,Amyotrophic Lateral Sclerosis ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Total body irradiation ,medicine.disease ,Transplantation ,Haematopoiesis ,Immunology ,Neurology (clinical) ,Stem cell ,business - Abstract
Background: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both. Objective: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment. Methods: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism. Results: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS. Conclusions: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.
- Published
- 2008
3. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab
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Malcolm K. Brenner, Robert A. Krance, Catherine M. Bollard, Helen E. Heslop, R. Lamba, Uday Popat, George Carrum, and G.D. Myers
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Adult ,Male ,Ganciclovir ,Foscarnet ,Cellular immunity ,Transplantation Conditioning ,Antibodies, Neoplasm ,Congenital cytomegalovirus infection ,Graft vs Host Disease ,Antibodies, Monoclonal, Humanized ,Betaherpesvirinae ,medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Alemtuzumab ,Antigens, Viral ,Aged ,Transplantation ,biology ,business.industry ,Antibodies, Monoclonal ,virus diseases ,Recovery of Function ,Hematology ,Middle Aged ,biology.organism_classification ,medicine.disease ,Virology ,Hematologic Neoplasms ,Cytomegalovirus Infections ,Immunology ,Female ,Virus Activation ,business ,Stem Cell Transplantation ,T-Lymphocytes, Cytotoxic ,medicine.drug - Abstract
We studied the incidence and recurrence of Cytomegalovirus (CMV) infection and reactivation in 38 recipients of Alemtuzumab reduced intensity conditioning-stem cell transplantation, and used CMV-HLA tetramer studies to discover if these events correlated with recovery of circulating CMV-specific CD8+ T cells (cytotoxic T lymphocyte (CTLs)). The cumulative incidence of CMV infection was 60% at 1 year (95% CI, 45-78%) with a median reactivation time of 24 days (range 5-95 days). All patients with CMV reactivation received Ganciclovir or Foscarnet, and only one developed CMV disease. More strikingly, only 8/21 patients had relapse of CMV antigenemia. Tetramer analysis in 13 patients showed that 11 reconstituted CMV CTLs (7/11 by day 30 and 10/11 by day 90). The development of CMV infection was accompanied by a >5-fold rise of CMV CTLs. Recurrence of CMV infection occurred only in the patients who failed to generate a CTL response to the virus. Hence, recipients of SCT using Alemtuzumab-RIC are initially profoundly immunosuppressed and have a high incidence of early CMV reactivation. However, in the majority of patients, infection is transient, and antiviral T cell reconstitution is rapid. Monitoring with CMV-specific CTLs may help identify the subset of patients at risk from recurrent infection or disease.
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- 2005
4. Bystander Transfer of Functional Human CD40 Ligand from Gene-Modified Fibroblasts to B-Chronic Lymphocytic Leukemia Cells
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Michael Andreeff, Raphael Rousseau, Frank C. Marini, Satoshi Takahashi, Malcolm K. Brenner, Ettore Biagi, Gianpietro Dotti, Persis Amrolia, Eric Yvon, Uday Popat, Biagi, E, Yvon, E, Dotti, G, Amrolia, P, Takahashi, S, Popat, U, Marini, F, Andreeff, M, Brenner, M, and Rousseau, R
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medicine.medical_treatment ,Genetic Vectors ,CD40 Ligand ,Biology ,Cancer Vaccines ,Adenoviridae ,Cell Line ,Viral vector ,Immunoenzyme Techniques ,Antigen ,Transduction, Genetic ,Antigens, CD ,Tumor Cells, Cultured ,Genetics ,medicine ,Humans ,Coculture Technique ,Molecular Biology ,B cell ,CD40 ,Histocompatibility Antigens Class I ,Bystander Effect ,Immunotherapy ,Fibroblasts ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Embryonic stem cell ,Molecular biology ,Coculture Techniques ,Cell biology ,Leukemia ,medicine.anatomical_structure ,Cell culture ,biology.protein ,Fibroblast ,Molecular Medicine ,Genetic Vector ,Cancer Vaccine ,Human - Abstract
CD40 ligand (CD40L) is a good candidate molecule for the immunotherapy of B cell malignancies including B-chronic lymphocytic leukemia (B-CLL), because it may increase the capacity of the malignant cells to present tumor antigens. However, efforts to manipulate expression of the human CD40L (hCD40L) molecule have foundered on problems associated with lack of consistent gene transfer into the malignant target cells. We now describe a new, highly reproducible method for inducing hCD40L surface expression on malignant B cells, which is dependent on intercellular transfer of the hCD40L protein from donor gene-modified fibroblasts to patient tumor cells. Ten B-CLL samples were cocultured with MRC-5 fibroblasts (a human embryonic lung cell line) previously transduced with an adenoviral vector encoding the hCD40L gene. The malignant cells expressed high levels of surface hCD40L, B7-1, B7-2, and ICAM-1 after coculture. Upregulation of B7-1 and B7-2 was cycloheximide inhibitable and was a consequence of CD40 activation. However, inhibition of protein synthesis had no effect on the ability of B-CLL cells to acquire surface expression of hCD40L. hCD40L surface expression required cell-to-cell contact, but was independent of CD40 engagement. hCD40L transfer was not mediated by membrane fusion. The transferred hCD40L was functionally intact and B-CLL cells expressing this molecule induced increased interferon-gamma production from autologous peripheral blood T lymphocytes. This approach does not use any direct gene transfer to primary leukemia cells and can readily be scaled up for production of clinical B-CLL vaccines.
- Published
- 2003
5. New onset of myelofibrosis in association with pulmonary arterial hypertension
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Romelia May, Vishnu Reddy, Enli Liu, Uday Popat, Josef T. Prchal, Adaani Frost, and Remzi Bag
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Adult ,medicine.medical_specialty ,business.industry ,Extramural ,Hypertension, Pulmonary ,MEDLINE ,General Medicine ,Middle Aged ,medicine.disease ,New onset ,Primary Myelofibrosis ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Female ,Myelofibrosis ,business - Published
- 2005
6. CD52 and CD45 monoclonal antibodies for reduced intensity hemopoietic stem cell transplantation from HLA matched and one antigen mismatched unrelated donors
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Helen E. Heslop, George Carrum, R. Lamba, Uday Popat, Romelia May, Robert A. Krance, and Malcolm K. Brenner
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,CD52 ,Antibodies, Neoplasm ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Antibodies, Monoclonal, Humanized ,Lymphocyte Depletion ,Age Distribution ,Antigens, CD ,Antigens, Neoplasm ,Internal medicine ,medicine ,Humans ,Alemtuzumab ,Survival analysis ,Aged ,Glycoproteins ,Transplantation ,business.industry ,Histocompatibility Testing ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Combined Modality Therapy ,Survival Analysis ,Histocompatibility ,Fludarabine ,CD52 Antigen ,Hematologic Neoplasms ,Immunology ,Leukocyte Common Antigens ,Female ,business ,Vidarabine ,Whole-Body Irradiation ,medicine.drug - Abstract
Allogeneic hemopoietic stem cell transplantation (HSCT) is the only curative option for many patients with hematological malignancies. Since many of these patients lack HLA-identical sibling donors and are older or have comorbidity, a fully ablative HSCT is not feasible and an alternative approach is required. We studied 22 consecutive patients who could not have myeloablative conditioning because of comorbidity or age - 21/22 being over the age of 50 years (median 58 years range 20-70 years). A conditioning regimen consisting of fludarabine, total body radiation 450 cGy and alemtuzumab (CD52 mAb) was used for 15 patients. A second group of seven patients received CD45 monoclonal antibodies in addition. Unrelated donor stem cells were HLA matched (15 patients - 68%) or one locus mismatched (seven patients - 32%). In all, 16 patients had high-risk disease, including 12 with active malignancy at the time of transplant. With a median follow-up of 715 (216-1470) days, nonrelapse mortality, actuarial event-free and overall survival is 27, 45 and 45%, respectively. Hence the outcome of reduced intensity HSCT with lymphodepleting antibodies in older patients with intermediate/high-risk hematological malignancies appears comparable to that obtained with fully ablative transplantation in younger patients, even when these older recipients lack HLA-identical sibling donors.
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- 2005
7. Double Cord Blood Transplantation (CBT) with and without Ex-Vivo Expansion (EXP): A Randomized, Controlled Study
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Elizabeth Shpall, Richard E Champlin, Krishna Komanduri, Stefan Ciurea, Yago Nieto, Borje S. Andersson, Gabriela Rondon, Amin Alousi, Martin Korbling, Chitra Hosing, Issa Khouri, Simon Robinson, Peter Thall, Susan Kelly, Dean Lee, Demetrios Petropoulos, Lawrence Cooper, Leandro de Padua Silva, Sergio Giralt, Roy Jones, Muzaffar Qazilbash, Uday Popat, Partow Kebriaei, Laura Worth, Rima Saliba, Jonh D. McMannis, and Marcos De Lima
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Melphalan ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,ThioTEPA ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Granulocyte colony-stimulating factor ,Regimen ,Median follow-up ,Internal medicine ,medicine ,Cumulative incidence ,business ,Busulfan ,medicine.drug - Abstract
CBT is frequently complicated by delayed and failed engraftment when compared to other sources of hematopoietic stem cell support. Strategies to improve engraftment include double CBT and ex-vivo expansion. We are comparing these approaches in a randomized, prospective fashion. Patients (N=71) were randomized to receive either two unmanipulated (UNM) CB units (N=36) or one UNM unit and one unit which was EXP ex-vivo (N=35). The majority of CB units were 4/6 HLA matches. Methods: Diagnoses were AML/MDS (N=25; 35%), ALL(N=17; 24%), NHL(N=10; 14%), HD(N=7; 10%), CML (N=5; 7%), and CLL(N=7; 10%). Patients (Table 1) had primarily advanced disease, with a median of 3 (1–8) prior regimens including autotransplants in 22%. Preparative regimens included ATG and either myeloablative fludarabine plus dose-adjusted busulfan (N=13; myeloid diseases), or melphalan and thiotepa (N=28); patients not eligible for high-dose therapy received non-myeloablative fludarabine plus cyclophosphamide and 200 Gy TBI (=27) or melphalan (n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day −14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×107/Kg was 3.5 and 3.6, and median CD34×105/Kg was 1.8 and 1.1, respectively for EXP and UNM pts. Median TNC fold-expansion was 23 (0.44–275) and for CD34+ cells, 2.3 (0–957). The median ex-vivo fold expansion of patients that engrafted platelets was higher than patients that did not engraft (23 (range, 0.4–275) versus 9.3 (range, 1.1–63), P=0.4). Patients that received EXP cells and a reduced-intensity regimen engrafted neutrophils in a median of 7 days (range, 4–15 days; n=14) versus 14 days (range, 5–32 days; n=12) in the UNM arm (P=0.05). Thirty-four patients are alive (48%) with a median follow up of 11.3 mo (range, 2–49 months). Twenty-four patients have relapsed (34%). Chimerism analysis showed that ultimately one CB unit dominated in all patients, on both the UNM and EXP arms of the trial. For the EXP arm the majority of patients had evidence of expanded CB chimerism posttransplant ranging from 7–82%. In half of those patients, the expanded CB unit predominated over the unmanipulated unit for 2–12 months posttransplant (52–87%), followed by gradual predominance of the unmanipulated CB unit by 14 months in all patients. Conclusion: Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues and we are focusing on strategies which improve CB expansion. | | Expanded | Unmanipulated | P | |:----------------------------------:| -------------- | ------------- | ---- | | Complete remission at UCBT | 41% | 59% | 0.09 | | Median weight | 85 (20–168) | 76 (15–144) | 0.18 | | Median age | 43 (4–70) | 38.1 (2–73) | 0.4 | | Ablative preparative regimen | 47% | 68% | 0.09 | | GVHD prophylaxis with methotrexate | 32% | 30% | NS | | Time to ANC500 (median/95%CI) | 14 days (4–32) | 17 (5–45) | | | | | | 0.2 | | Proportion engrafting ANC500 | 80% | 86% | | | | | | NS | | Time to PLT20K (median/95%CI) | 34 (4–70) | 34 (27–134) | NS | | Proportion engrafting PLT | 69% | 55% | 0.2 | | 1-year survival | 60% (40–75) | 46% (27–63) | 0.2 | | 2-year survival | 55% | 20% | 0.1 | | aGVHD gd II–IV/III–IV | 43%/7% | 43%/17% | NS | | C.Incid. cGVHD | 45% (28–78) | 25% (15–65) | 0.1 | | C.Incid.: cumulative incidence | | |
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- 2008
8. High Circulating CD34 Cells, Dacrocytes, Clonal Hematopoiesis, and JAK 2 Mutation Differentiate Secondary Myelofibrosis Associated with Pulmonary Hypertension from Myelofibrosis with Myeloid Metaplasia
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Enli Liu, Josef T. Prchal, Yongli Guan, and Uday Popat
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Janus kinase 2 ,Myeloid ,biology ,business.industry ,Essential thrombocythemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dacrocyte ,medicine.anatomical_structure ,Polycythemia vera ,Myeloproliferative Disorders ,medicine ,biology.protein ,Bone marrow ,Myelofibrosis ,business - Abstract
Myelofibrosis with myeloid metaplasia (MMM) is a clonal myeloproliferative disorder, characterized by splenomegaly and myelofibrosis. Like all myeloproliferative disorders, it is due to an acquired somatic mutation of a hematopoietic progenitor resulting in clonal erythrocytes, platelets, and granulocytes. A single acquired point mutation of JAK2 1849G>T (V617F), a tyrosine kinase with a key role in signal transduction from growth factor receptors, occurs in 50%–97% of patients with MMM, essential thrombocythemia (ET) and polycythemia vera (PV). We studied 25 myelofibrosis patients with myeloid metaplasia and myelofibrosis complicating PV or ET. These were compared to 19 patients with secondary myelofibrosis of equivalent severity associated with pulmonary hypertension (PH) treated by epoprostenol. In these two groups we compared peripheral blood CD34 counts, clonality of granulocytes and platelets in peripheral blood, mutational status of JAK 2 kinase gene, and morphology of peripheral blood and bone marrow. Heterozygosity for JAK 2 1849G>T somatic mutation was seen in 17 of 23 (74%) patients with MMM including 10 of 15 patients (67%) with idiopathic myelofibrosis and 7 of 8 patients (88%) with myelofibrosis complicating PV or ET, but was absent in all 19 patients with myelofibrosis associated with PH (P We conclude that a high circulating CD34 count, clonal platelets and granulocytes, presence of dacrocytes, and JAK2 1849G>T (V617F) mutation of clonal progenitors are the intrinsic features present in patients with myelofibrosis due to myeloproliferative disorders and that these features are not due to the abnormal marrow architecture that is seen in secondary myelofibrosis.
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- 2005
9. Immunotherapy of Chronic Lymphocytic Leukemia using CD40L and IL2 Expressing Autologous Tumor Cells
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Ettore Biagi, Rousseau Raphael, Michael Andreef, Malcolm K. Brenner, Rice Lawrence, Yvon Eric, Dotti Giampietro, and Uday Popat
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CD40 ,biology ,business.industry ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,Immunotherapy ,medicine.disease ,Biochemistry ,Tumor antigen ,Leukemia ,Immune system ,Antigen ,Aldesleukin ,medicine ,Cancer research ,biology.protein ,business - Abstract
Transgenic human CD40 ligand (hCD40L) activates B-Chronic Lymphocytic Leukemia (B-CLL) cells by CD40 stimulation and may thereby enhance their capacity to present tumor antigens. Pre-clinical models show that co-expression of IL-2 further potentiates the immunogenicity of CD40L-expressing tumor cells. To discover whether these promising pre-clinical data could usefully be applied to patients with B-CLL, we used adenovectors to prepare hIL2- and hCD40L-expressing autologous tumor vaccines. Within these vaccines, a mean of 92% B-CLL cells were CD40L positive (versus 1/1500 post vaccination) and of Granzyme-B expressing T-cells (1/2500 post). This reactivity is mediated at least in part by CD8-positive T cells with specificity to survivin, a known B-CLL associated tumor antigen. Although these immunologic effects have as yet been accompanied by only transient disease responses, our continuing accrual of additional patients who will receive immunomodulatory doses of vaccine should indicate whether the approach could contribute to the management of early or advanced B-CLL.
- Published
- 2004
10. High Incidence but Low Morbitiy of Early Cytomegalovirus (CMV) Infections Following Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation with Alemtuzumab and Ganciclovir Prophylaxis
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Malcolm K. Brenner, Renu Lamba, Helen E. Heslop, Robert A. Krance, George Carrum, and Uday Popat
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Ganciclovir ,medicine.medical_specialty ,CD52 ,business.industry ,medicine.medical_treatment ,Immunology ,Immunosuppression ,Cell Biology ,Hematology ,Total body irradiation ,Biochemistry ,Gastroenterology ,Fludarabine ,Transplantation ,Internal medicine ,medicine ,Alemtuzumab ,Cumulative incidence ,business ,medicine.drug - Abstract
Background : IThe CD52 monoclonal antibody Alemtuzumab appears to be of great promise when incorporated as a lymphocyte depleting agent in RIC stem cell transplants. However the degree of functional immunosuppression produced by this antibody in this application has not yet been well characterized. As a surrogate functional marker, we have studied the incidence and pattern of CMV infection following RIC transplantation regimens with a regimen incorporating this antibody. Methods : We analyzed CMV infections and risk factors in 49 patients who underwent allogeneic stem cell transplantation with a RIC regimen consisting of Fludarabine (120mg/m2), total body irradiation (450 cGy), antithymocyte globulin (40mg/kg), (n=11) or Alemtuzumab (40mg), (n=38) with or without CD45 monoclonal antibodies for various malignant disorders. Donors were HLA identical (related, n=20; unrelated, n=20) or one antigen mismatched (n=9). Ganciclovir was used as prophylaxis starting at engraftment or on recovery from cytopenias. CMV antigenemia and polymerase chain reaction based assays were performed on peripheral blood twice a week till day 100 and then on each clinic visit. Results : The cumulative incidence of CMV reactivation at 1 year post-transplant with Alemtuzumab, in patients at risk, was 60% (95% CI, 45%–78%). Median time to reactivation of 24 days (range, 5– 95 days). Fifty seven percent (12/21) of the reactivations occurred before day 30. Recurrence of CMV reactivation occurred in 38% (8/21) of patients with a median number of recurrences of 2 (range, 1–6) and they extended beyond day 100. Only one patient developed CMV colitis and fully recovered with treatment. There was no CMV related mortality. The overall non-relapse mortality was 16% and overall survival in CMV reactivators and non-reactivators was not statistically different. Risk factors for CMV reactivation analyzed were patients age, sex, acute graft vs host disease, Alemtuzumab use, Ganciclovir use before day 30 and absolute lymphocyte count at day 30. In univariate analysis, use of Alemtuzumab (P= 0.001) and starting Ganciclovir after day 30 (P= 0.002) were significantly associated with CMV reactivation but in multivariate analysis only starting Ganciclovir after day 30 was statistically significant, P= 0.009 (95% CI, 1.5%–17%). Conclusions : RIC stem cell transplantation using Alemtuzumab is associated with a particularly high incidence of early CMV reactivation, and is also associated with recurrent reactivation extending beyond day 100. Although the incidence of CMV disease was low, the high frequency of viral reactivation with Alemtuzumab is likely an indicator of profound post transplant immune suppression, suggesting that despite the “reduced intensity” of the conditioning, these patients require early, comprehensive and prolonged pre-emptive/prophylactic therapy for opportunistic infections.
- Published
- 2004
11. Rasburicase Improves Renal Function and Uric Acid Nephropathy in Patients Developing Acute Renal Failure after Conditioning for Hematopoetic Stem Cell Transplant (HSCT)
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Donovan Strader, Michael S. Oholendt, Uday Popat, George Carrum, and Helen E. Heslop
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medicine.medical_specialty ,Creatinine ,business.industry ,medicine.medical_treatment ,Immunology ,Urology ,Renal function ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Nephropathy ,Surgery ,Tumor lysis syndrome ,chemistry.chemical_compound ,chemistry ,medicine ,Rasburicase ,Hyperuricemia ,Renal replacement therapy ,business ,Blood urea nitrogen ,medicine.drug - Abstract
Significant reduction in renal function secondary to protein deposition in the renal tubules is a common occurrence among patients with plasma cell dyscrasias such as Multiple Myeloma (MM) and Amyloidosis undergoing HSCT. Conditioning chemotherapy and uric acid release following cellular lysis may worsen already compromised renal function, leading to acute renal failure. Rasburicase, a recombinant urate oxidase enzyme, has been approved by the U.S. Food and Drug Administration for the treatment and prevention of hyperuricemia associated with tumor lysis syndrome in pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing chemotherapy. We hypothesized that prompt treatment of hyperuricemia with rasburicase may prevent uric acid nephropathy and improve renal function, obviating the need for dialysis and improving the eventual outcome. Six adults, four with MM and two with amyloidosis, with rising uric acid levels after high dose Melphalan (200mg/m2) were given a single dose of rasburicase (0.15 mg/kg). At baseline, all patients had rising serum creatinine [mean: 2.1 mg/dL (range: 0.9–4.5 mg/dL)], rising BUN [mean: 27.6 mg/dL (range: 1.3–70 mg/dL)], and declining creatinine clearance (CrCL) [mean: 50.5 ml/min (range: 16–75 ml/min)]. After one dose of rasburicase, renal function significantly improved according to CrCL at 48 hours [mean: 55.2 ml/min (range: 17–82 ml/min)] and continued to improve at five days [mean: 68.2 ml/min (range: 18–109 mg/dL)]. Baseline uric acid was elevated [mean: 8.61 mg/dL (range: 7–9.9 mg/dL)] and improved 24 hours after treatment with rasburicase [mean: 0.2 mg/dL (range: 0–0.6 mg/dL)]. None of the patients required renal replacement therapy. There were no serious adverse events associated with rasburicase therapy. We therefore conclude that a single dose of rasburicase is promising in improving deteriorating renal function post high dose chemotherapy in patients with compromised renal function; further controlled studies are warranted.
- Published
- 2004
12. Quantitative Analysis of Flow Cytometry Immunophenotyping Data for Aiding in the Diagnosis of Myelodysplastic Syndromes (MDS)
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Kelty R. Baker, Ha T. Nishino, Gordon Zeng, Youli Zu, George Carrum, Uday Popat, Larry Rice, John J. McCarthy, and Chung-Che Chang
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Pathology ,medicine.medical_specialty ,Myeloid ,Myelodysplastic syndromes ,medicine.medical_treatment ,Immunology ,CD34 ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biology ,CD38 ,medicine.disease ,Biochemistry ,Transplantation ,medicine.anatomical_structure ,Immunophenotyping ,hemic and lymphatic diseases ,medicine ,Bone marrow - Abstract
Recent studies have shown that flow cytometry immunophenotyping is a promising tool aiding in the diagnosis of myelodysplastic syndromes (MDS). However, the majority of these studies apply only qualitative pattern analysis in their interpretation of immunophenotypic data. The goal of this study was to analyze immunophenotyping results quantitatively, investigating the potential of this approach for providing additional information useful diagnosing MDS. Using flow cytometry immunophenotyping, we studied 56 bone marrow specimens from 13 patients with well-defined MDS by morphologic, clinical, and/or cytogenetic findings (5 RA, 3 RARS, 2 RAEB grade 1, 2 RAEB grade 2 and 1 secondary to chemotherapy), 15 cytopenic patients (controls, age-matched with MDS patients) with non-MDS/non-clonal hematologic disorders receiving marrow evaluation for other reason (ITP, fever of unknown origin, or lymphoma staging), 8 patients with AML transformed from MDS (t-AML), 6 patients with de novo AML, and 7 patients (14 specimens) with regenerating marrow after stem cell transplantation. These samples were analyzed qualitatively as reported in the literature as well as quantitatively for percentages of T-cells (CD3+), B-cells (CD20+), NK cells (CD3−/CD56+), granulocytes (moderate CD45 intensity and high side scatter characteristics), monocytes (CD14+/CD11c+), blasts (defined by dim CD45 and low side scatter, CD34+ or CD117+), erythroid precursors (CD71+/CD45−) and plasma cells (bright CD38), CD4/CD8 ratio, percentages of granulocyte subsets (CD10+, CD10−, CD36+/CD64+, CD36−/CD64+, CD11b−/CD16−, CD11b+/CD16− or CD11b+/CD16+ granulocytes per total granulocytes), percentage of CD56+ monocytes, and percentages of erythorid precursors subset (glycophorin A+ or glycophorin A- erythroid precursors per total erythroid precursors). In agreement with previous studies, qualitative analysis of these data demonstrated abnormal patterns of expression in myeloid and erythroid lineages in patients with MDS and t-AML. However, these patterns are also observed in age-matched controls and patients with de novo AML or with regenerating marrow. The quantitative analysis showed significantly increased T-cells and a significantly decreased granulocyte subset of CD11b+/CD16− in MDS patients when compared to age-matched controls (9.0 +/− 6.7% vs. 4.4 +/− 3.0 %, p = 0.023 and 28.1 +/− 14.9% vs. 44.5 +/−12.9%, p = 0.004, student t-test). There were also trends for increased NK cells and CD4:CD8 ratios and decreased total granulocytes in MDS patients as compared to the age-matched controls (p = 0.097, 0.094 and 0.059, respectively, student t-test). Other immunophenotypic parameters demonstrated no significant differences between these two groups. Furthermore, the changes observed in MDS patients were also seen in patients with t-AML. Patients with de novo AML or regenerating marrow post stem cell transplantation showed a quantitative immunophenotypic pattern between that of MDS patients and age-matched controls. These findings suggest that quantitative analysis of flow cytometry immunophenotyping data can aid in the diagnosis in MDS as well as the identification of AML arising from background MDS. The latter is clinically significant since these patients carry worse prognosis than those with de novo AML and may require novel therapies.
- Published
- 2004
13. Evaluation of Aprepitant for Treatment of Acute and Delayed Chemotherapy-Induced Nausea and Vomiting in Patients Undergoing Autologous Stem Cell Transplantation
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Chad M. Barnett, Michael S. Oholendt, Uday Popat, George Carrum, and Helen E. Heslop
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Melphalan ,Chemotherapy ,business.industry ,Nausea ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Autologous stem-cell transplantation ,Anesthesia ,Clinical endpoint ,Medicine ,medicine.symptom ,business ,Aprepitant ,Etoposide ,medicine.drug ,Chemotherapy-induced nausea and vomiting - Abstract
Autologous stem cell transplant (ASCT) requires therapy with very highly emetogenic chemotherapy regimens. Nausea and emesis are a major issue for patients undergoing ASCT. Aprepitant, a selective substance-P/neurokinin 1 (NK1) receptor antagonist, has been approved by the U.S. Food and Drug Administration for treatment of acute and delayed CINV in combination with a corticosteroid and 5-HT3 receptor antagonist. Due to little patient data in this area, a retrospective chart review was performed which evaluated 41 ASCT patients that had received standard therapy (control group, n=25) compared to aprepitant in addition to standard therapy (aprepitant group, n=16). Patients who underwent an ASCT and were greater than 18 years of age were eligible for inclusion in the study. Patients who underwent an allogeneic stem cell transplant were excluded. All data was collected from the hospital’s computerized nurse charting system. Episodes of nausea and emesis were collected from nursing notes while data for rescue medications was collected from the charted medications. Conditioning regimens given during the study included high dose (HD) melphalan, BEAM (carmustine, etoposide, cytarabine, and melphalan) or R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). All patients evaluated in the aprepitant group had received aprepitant 125 mg orally once daily on the first day of chemotherapy administration and 80 mg orally once daily the following 2 days in the HD melphalan group (Day -1 through Day 0) and the following 5 days in the BEAM group (Day-6 through Day -1). Although aprepitant dosing was consistent, dosing was determined by the individual physician and prescribed on a patient-specific basis. The primary endpoint was the number of episodes of nausea and emesis after chemotherapy, while the secondary endpoint was the number of rescue medications that were used for nausea and emesis. For the primary endpoint of the study, the mean number of nausea episodes per patient was reduced in the aprepitant group compared to the control group in the acute phase (1.7 versus 2.2, p=0.51) and delayed phase (5.3 versus 5.6, p=0.83). Emetic episodes per patient were decreased in the aprepitant group compared to the control group in both the acute (0.06 versus 0.9, p=0.21) and delayed phases (0.9 versus 2.4, p=0.17). Use of rescue medication per patient was decreased in the aprepitant group compared to the control group in the acute phase (2.3 versus 3.6, p=0.40) but not in the delayed phases (8.1 versus 8.1, p=0.99). None of the results of this study were statistically significant, although the reduced number of emetic episodes with aprepitant may be clinically significant. The results of this study warrant consideration for a prospective evaluation of this therapy in ASCT patients to greater clarify the use of aprepitant in these patients.
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- 2004
14. Stem Cell Transplantation in Patients with Preexisting Coronary Artery Disease
- Author
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Uday Popat, George Chen, and George Carrum
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medicine.medical_specialty ,Ejection fraction ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Angina ,Coronary artery disease ,Internal medicine ,medicine ,Cardiology ,Sinus rhythm ,Myocardial infarction ,business ,Multiple myeloma - Abstract
Patients with preexisting coronary artery disease (CAD) have traditionally not undergone stem cell transplantation because of the perceived cardiac risk of the procedure. With the advent of reduced intensity stem cell transplantation and increased numbers of elderly patients, the question of whether or not it is safe to transplant patients with CAD is increasingly pertinent. We reviewed the outcomes of eight transplants performed in patients with clinically significant CAD. We also assessed the contribution of anthracycline/cyclophosphamide use and mediastinal radiation to cardiac toxicity. Clinically significant CAD was defined as that associated with myocardial infarction or that requiring percutaneous intervention/coronary artery bypass grafting (see chart for individual details). All patients were clinically stable at the time of transplant although two had experienced transient angina within three months. For all patients, baseline echocardiogram demonstrated ejection fractions greater than 50%, and baseline EKG demonstrated sinus rhythm although Q waves, T wave inversions, diffuse T wave abnormalities, and first-degree AV block were present. One fully ablative allogeneic, three subablative allogeneic, and four autologous transplants were performed. Conditioning regimens are presented below. All transplants used peripheral blood stem cells. Transplants were performed for multiple myeloma, ALL, AML, and CML. None of the patients were exposed to mediastinal radiation or cardiac toxic doses of anthracyclines or cyclophosphamide. Median survival after transplant was 496.9 days (range 58 – 1367 days). Two patients have died; one from disease progression and the other from pneumonia related complications. One patient was retransplanted on day 721. No ischemic events have been reported on follow up which has included myocardial perfusion scanning in three transplants. We conclude that cardiac risk is minimal and acceptable in patients with stable CAD who undergo transplant. Baseline Cardiac History and Transplantation Characteristics Cardiac History Transplant Conditioning Follow up 1v stent Autologous Melphalan 200 mg/m2 Retransplanted day 721, no ischemic events, normal myocardial perfusion scan 7v CABG Autologous Melphalan 200 mg/m2 Alive day 579, no ischemic events 3v CABG Autologous Melphalan 200 mg/m2 Alive day 1367, no ischemic events 1v stent Autologous Melphalan 200 mg/m2 Alive day 877, no ischemic events 1v stent Haploidentical 4/6 TBI 450 cGy (single dose), campath 40 mg, fludarabine 120 mg/m2 Alive day 58, no ischemic events, normal myocardial perfusion scan 1v stent Matched related Busulfan 6.4 mg/kg, fludarabine 120 mg/m2 Alive day 86, no ischemic events, normal myocardial perfusion scan 3v CABG, 1v angioplasty Matched related TBI 450 cGy (single dose), campath 30 mg, anti-CD45 antibody 1.6 mg/kg, fludarabine 120 mg/m2 Dead day 68 from disease progression Small vessel disease with myocardial infarction Mismatched related 5/6 TBI 800 cGy, cyclophosphamide 120 mg/kg Dead day 219 from pulmonary complications
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- 2004
15. High Peripheral Blood CD34 Count in Patients with Idiopathic Myelofibrosis (IF) Is Not Due to Fibrosis and Altered Marrow Microenvironment
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Romelia May, Uday Popat, April G. Durett, Adaani E. Frost, Josef T. Prchal, Vishnu Reddy, and Enli Liu
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Pathology ,medicine.medical_specialty ,Myeloid ,medicine.diagnostic_test ,business.industry ,Immunology ,CD34 ,Hematopoietic stem cell ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,Megakaryocyte ,Fibrosis ,Biopsy ,medicine ,Bone marrow ,business - Abstract
Idiopathic myelofibrosis (IF) is due to an acquired somatic mutation(s) of a single hematopoietic multipotent progenitor and thus circulating myeloid, erythroid, megakaryocyte, B and T cells (Reeder et al Blood. 2003;101: 1981–1983) are clonal. It has been suggested that fibrosis may occur secondary to cytokines secreted by the malignant clone. Although marked elevation of circulating CD34 cells occurs in patients with IF, it is not known whether it is a consequence of the primary defect of the hematopoietic stem cell, or secondary to fibrosis and impaired marrow microenvironment. To answer this question, we studied CD34 count in peripheral blood of patients with IF and secondary myelofibrosis due to pulmonary hypertension. Nineteen patients with either primary or secondary pulmonary hypertension due to connective tissue disease and 11 patients with IF were studied. Bone marrow biopsy revealed fibrosis in all 19 patients with PH: 11 severe, 3 moderate, and 5 mild. All eleven patients with IF had severe fibrosis. Clonality studies in 13/14 informative patients with PH showed polyclonal platelets and granulocytes in contrast to monoclonal platelets and granulocytes in patients with IF. Peripheral blood was assayed for CD34+ cells using a three-color direct immunofluorescent staining method. Mean absolute CD34 count was significantly (P=0.02) lower - 6/ul (range: 1–18/ul) in patients with PH compared to 142 /ul (range 4–833/ul) in patients with IF. We therefore conclude that high CD34 count is not seen in patients with PH with secondary myelofibrosis; furthermore, elevated CD34 in patients with IF is not due to marrow fibrosis and altered microenvironment.
- Published
- 2004
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