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Biomedical subjects

S Jagannath

Publications and source records attributed to S Jagannath.

At least 55 records · Page 3Linked to original sources
PubMed1996

Differential mobilization of myeloma cells and normal hematopoietic stem cells in multiple myeloma after treatment with cyclophosphamide and granulocyte-macrophage colony-stimulating factor.

Peripheral blood stem cells (PBSCs) mobilized with high-dose chemotherapy and hematopoietic growth factors are now widely used to support myeloablative therapy of multiple myeloma and effect complete remissions in up to 50% of patients with apparent extension of event-free and overall survival. Because tumor cells are present not only in bone marrow, but also in virtually all PBSC harvests, it is conceivable that autografted myeloma cells contribute to relapse after autotransplants. In this study, the kinetics of mobilization of normal hematopoietic stem cells were compared with those of myeloma cells present in PBSC harvests of 12 patients after high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor administration. CD34+ and CD34+Lin-Thy+ stem cell contents were measured by multiparameter flow cytometry, and myeloma cells were quantitated by immunostaining for the relevant Ig light chain and by a quantitative polymerase chain reaction for the myeloma-specific CDRIII sequence. Results indicated marked heterogeneity in the percentages of mobilized stem cells among different patients (0.1% to 22.2% for CD34+ cells and 0.1% to 7.5% for CD34+Lin-Thy+ cells, respectively). The highest proportions of hematopoietic progenitor cells were observed early during apheresis, with 9 of 12 patients mobilizing adequate amounts of CD34+ cells for 2 autotransplants (> 4 x 10(6)/kg) within the first 2 days, whereas peak levels (percent and absolute numbers) of myeloma cells were present on days 5 and 6 (0.5% to 22.0%). During the last days of collection, mobilized tumor cells exhibited more frequently high labeling index values (1% to 10%; median, 4.4%) and an immature phenotype (CD19+). The differential mobilization observed between normal hematopoietic stem cells and myeloma cells can be exploited to reduce tumor cell contamination in PBSC harvests.

Biomarkers↗
PubMed1996

Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma.

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pretransplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy (P = 0.0001). All seven patients developing MDS post-transplantation belonged to group 2 (P = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38-86) and 24 months (range 9-39), respectively. Our findings provide evidence that prolonged standard-dose alkylating agent therapy prior to transplantation, rather than autotransplant-supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment-related MDS/AML.

Aged↗
PubMed1996

Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.

PURPOSE: To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS: We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, < 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS: The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION: HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.

Adolescent↗
PubMed1996

Hematopoietic stem cell transplants for multiple myeloma.

Standard chemotherapy with melphalan-prednisone or a combination of alkylating agents has not extended the overall survival of patients with multiple myeloma during the last 30 years and strictly defined complete remissions (CR) are exceedingly rare. The early mortality with conventional therapy varies between 2 and 10 percent. A substantial increase in the dose of melphalan (100-140 mg/m2) has resulted in a 30-45% CR rate in newly diagnosed patients and an overall survival advantage of approximately 1 year. However, treatment related morbidity and mortality, due to prolonged cytopenia was unacceptably high. Based on these findings the dose intensity was further increased by either escalating melphalan to 200 mg/m2 or by adding total body irradiation, while at the same time providing stem cell support to shorten the duration of cytopenia. Autologous transplants, especially with peripheral blood stem cells and hematopoietic growth factors, can now be performed safely up to the age of 70 with a low transplant-related mortality (2-10%). A CR is attained in approximately 50% of previously untreated patients and 10-20% of refractory cases. Overall survival of newly diagnosed and refractory patients treated with autotransplants appears superior to that of patients receiving conventional chemotherapy. Therefore, autotransplantation should be considered as a treatment option in all patients with multiple myeloma at least up to the age of 65. Despite these encouraging findings, most myeloma patients ultimately relapse and the survival curves do not suggest that autotransplantation as currently performed is a curative approach in a substantial proportion of patients. Further improvement with autotransplants should be achieved by providing tumor-free grafts and by introducing post-transplantation manipulations, aimed at eradicating minimal residual disease.

Adult↗
PubMed1996

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Adult↗
PubMed1995

Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.

Chromosomal abnormalities have major biologic and prognostic implications in leukemias. Cytogenetic information in typically hypoproliferative multiple myeloma (MM) is limited because of difficulties in obtaining analyzable metaphases. In this study, karyotypes and other known prognostic factors were analyzed in 155 newly diagnosed MM patients, entered on an intensive treatment program with two autotransplants. Complete remission (CR), event-free (EFS) and overall survival (OS) were analyzed using standard statistical methods. Abnormal cytogenetics were found in 39% of patients and were associated with a significantly lower CR rate (27% v 48%; P = .008). EFS and OS were inferior in patients with either partial or complete deletion of chromosome 13 or 11q abnormalities ("unfavorable" karyotype) when compared with the remaining patients (P < .001) who, as a group, had a similar prognosis irrespective of cytogenetic findings, ie, inevaluable, normal, or abnormal but without an "unfavorable" karyotype. The patients with abnormalities of both chromosomes 11 and 13 had a dismal prognosis with median EFS and OS of only 11 and 12 months, respectively. Significant associations were noted between an "unfavorable" karyotype and IgA isotype, elevated levels of beta-2 microglobulin (B2M, > or = 3 mg/L) and age > 60 years. On multivariate regression analysis, the absence of an "unfavorable" karyotype was the most significant variable associated with prolonged EFS and OS (P = .0001 and .0002, respectively). Other independent favorable variables were age less than 60 years, C-reactive protein (CRP) < or = 0.4 mg/dL and bone marrow plasmacytosis < or = 50% before treatment. On a multivariate analysis without cytogenetics, these same three standard parameters were identified as the only favorable variables. Patients not having all three standard favorable variables had a significantly lower CR rate (P = .03), EFS (P = .0001), and OS (P = .002) if an unfavorable karyotype was detected. We conclude that, in this program of uniformly treated MM patients, a poor prognosis was associated predominantly with abnormalities of chromosomes 11 and 13.

Chromosome Aberrations↗
PubMed1995

Cytogenetic findings in 200 patients with multiple myeloma.

Cytogenetic studies were performed in 200 consecutive patients with multiple myeloma and related disorders. Structurally or numerically abnormal clones were found in 63 patients (32%), including 8 of 45 untreated patients (18%), and 55 of 155 treated patients (35%). The abnormal karyotypes generally showed numerous numerical and structural aberrations and in some patients multiple abnormal clones. The most striking feature of patients with hyperdiploid karyotypes was the finding of consistent recurring trisomies for chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, cosegregating together in many cases. Monosomy for chromosome 13 was the most common chromosome loss, occurring in 18 abnormal patients (29%), while interstitial deletions involving band 13q14 occurred in an additional 9 patients, indicating a loss of all or part of chromosome 13 in a high percentage of patients with abnormal karyotypes (43%). Structural aberrations of chromosome 1 were most frequent, occurring in 30 of 63 patients (48%), and involved almost equally the short and long arms. The single most frequent chromosome breakpoint involved band 14q32 and was found in 21 patients (33%), including 11 patients with a 14q+ chromosome, 8 with t(11;14)(q13;q32), and 2 with t(8;14)(q24;132).

Adult↗
PubMed1995

Purified CD34+ Lin- Thy+ stem cells do not contain clonal myeloma cells.

High-dose therapy with autologous marrow or peripheral blood stem cell (PBSC) rescue has been extensively applied in the treatment of multiple myeloma (MM) patients during the past 10 years resulting in improved event-free and overall survival when compared with standard chemotherapy. However, relapses are common and cure is unlikely in the majority of patients. Because both bone marrow and PBSCs are contaminated with myeloma cells it is conceivable that relapse after autotransplantation originates at least in part from autografted tumor cells. In this study, mobilized PBSCs were examined for the presence of myeloma cells based on immunophenotyping and sensitive polymerase chain reaction (PCR)-based techniques. In addition, CD34+ Lin- Thy+ stem cells were purified from mobilized PBSC harvests of 10 MM patients by sequentially using counterflow elutriation centrifugation, treatment with phenylalanine methylester, and flow sorting, using 5-parameter gating (propidium iodide, forward scatter, side scatter, CD34+ v Lin- and CD34+ v Thy+). Virtually all mobilized unsorted PBSC preparations contained myeloma cells in sufficient quantities (range, < 0.01 to > 10%) potentially causing a disease relapse. Stem cell purification led to an overall enrichment by about 50-fold in all 10 patients; approximately 90% of the final cell population expressed CD34+ Lin- Thy+ with no evidence of myeloma cell contamination based on flow cytometric analysis of CD38bright cells (< 0.1%). Quantitative PCR amplification of patient-specific complementarity determining region III (CDRIII) DNA sequences showed depletion of clonal B cells by 2.7 to 7.3 logs, with the highest log reduction noted in the samples initially containing the most tumor cells. Our results show that purification of CD34+ Lin- Thy+ cells depletes myeloma cells to undetectable levels from up to 10% present in unsorted PBSCs, thus offering a tool to investigate whether MM relapse after autotransplantation can be reduced markedly.

ADP-ribosyl Cyclase↗
PubMed1995

Enrichment of human hematopoietic stem cell activity in the CD34+Thy-1+Lin- subpopulation from mobilized peripheral blood.

The number of CD34+ cells in the peripheral blood of cancer patients is known to be increased following the administration of high dose chemotherapy and hematopoietic growth factors. These so-called peripheral blood stem cell grafts are now frequently used for autologous transplantation of patients with malignancies. In this report, we address the question of whether true long-term repopulating pluripotent hematopoietic stem cells (PHSC) are mobilized into peripheral blood following chemotherapy plus granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) mobilization. We have examined the presence of stem cells in mobilized peripheral blood (MPB) by using an antibody to the human Thy-1 molecule to stain the CD34+Lineage- (Lin-) population. The kinetics of mobilization of CD34+Thy-1+ Lin- cells into peripheral blood were studied, and the percentage of cells with this phenotype was found to vary widely depending on the day of leukapheresis. A CD34+Thy-1+Lin- cell population, potentially containing PHSCs, was isolated by fluorescence activated cell sorting (FACS) and analyzed for activity. The multilineage differentiative capacity of this candidate stem cell-containing population in MPB was determined using an in vitro long-term culture system, in which cobblestone area formation was used as a means of detecting PHSCs. We also measured repopulating capacity by using two in vivo models in which severe combined immunodeficiency (SCID)-hu mice were implanted with human fetal bone or thymus grafts. Using these assays, we show that the highest frequency of cobblestone area-forming cells (CAFC) after 7 weeks of culture was observed in a subpopulation of CD34+Lin- cells, which expressed low levels of Thy-1. This cell population was capable of producing both B and myeloid cells, and maintaining CD34+Lin- cells in these long term cultures. Moreover, the CD34+Thy-1+Lin- cell subset possessed a higher ability to engraft and to demonstrate multilineage differentiative potential at 8 weeks in the SCID-hu bone assay. However, in the SCID-hu thymus model, both Thy-1+ and Thy-1- subpopulations were capable of donor T-cell engraftment at 6 weeks, suggesting the presence of cells capable of initiating T lymphopoiesis in both populations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.

Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte-macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with > or = 2 x 10(6)/kg CD34 PBSCs infused and with < or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to < or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was > or = 2.0 x 10(6)/kg for patients with < or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and < or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might be candidates for autotransplantation. Alternatively, PBSCs should be collected early after diagnosis.

Adult↗
PubMed1995

Cytokine-mobilized peripheral blood CD34+Thy-1+Lin- human hematopoietic stem cells as target cells for transplantation-based gene therapy.

Gene-therapy of blood-borne disorders may be best achieved using hematopoietic stem cells (HSC) which have extensive self renewal potential as well as multilineage repopulating potential as a cellular target. The human HSC, which is CD34+Thy-1+Lin- has been isolated from fetal, adult bone marrow and cytokine-mobilized peripheral blood (MPB) (1-3). Results presented in this study show that the degree of mobilization of HSC into peripheral blood of cancer patients is highly variable and that the combined use of high dose chemotherapy and GM-CSF as a mobilization strategy is superior to the use of G-CSF with regard to the mobilization of true HSC. A multistep cell isolation procedure has been developed which utilizes high speed flow-cytometric cell sorting and allows the isolation of sufficient numbers of HSC from MPB to permit their use as an hematopoietic graft for clinical transplantation. Hematopoietic stem cells isolated from MPB are capable of self-renewal and differentiation into multiple hematopoietic lineages as shown by their behavior in both in vitro and in vivo assays. Mobilized PB mononuclear cells isolated from cancer patients are frequently contaminated with tumor cells. Using this cell isolation procedure, HSC preparations from patients with multiple myeloma have been created with greatly reduced tumor cell burdens. These CD34+Thy-1+Lin- cells are capable of being stably transduced at high efficiency (32-75%) by co-culture on a cell line producing recombinant retroviruses containing the neomycin-resistant gene. These HSC cell populations are likely ideal targets for hematopoietic cell-based gene therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy.

Owing to lack of progress with standard chemotherapy and the presence of a dose response effect for alkylating agents, autotransplantation is performed with increasing frequency for multiple myeloma (MM). However, sustained relapse-free survival is still infrequent. We studied 94 patients who had relapsed following autotransplantation, in order to evaluate the efficacy of further therapy. Post-transplant salvage treatment consisted of either standard dose therapy (53) or transplantation with an intensive preparative regimen (with autograft support in 31 and allogeneic transplantation in 10). Complete remission (CR) rate, event-free and overall survival were assessed and prognostic variables identified in a multivariate regression analysis. With a median follow-up of 11 months, the projected overall survival at 18 months for all patients is 59%. A multivariate analysis identified pre-salvage beta-2-microglobulin (B2M) < or = 2.5 mg/l (P = 0.0002) and late relapse after the preceding transplant ( > 12 months; (P = 0.02) as independent significant favorable variables for overall survival. By combining pre-salvage B2M and the time to relapse, 2 risk groups of patients could be identified with significantly different overall survival: those with at least one favorable variable had a projected survival at 18 months of 79%, compared to 38% for patients with no favorable variable. Transplantation performed as primary salvage therapy was associated with a significantly prolonged survival (P = 0.009), although this may be more a reflection of the way salvage therapy was selected.

Follow-Up Studies↗
PubMed1994

High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants.

One hundred and thirty-five patients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 to 100 mg/m2 (MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m2 or thiotepa 750 mg/m2 and autologous bone marrow transplant (ABMT) (< or = 30% plasma cells; 21 patients); melphalan 200 mg/m2 (MEL 200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as a double-transplant program (67 patients; 42 have completed and 3 are still awaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (< 500/microL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy. Low beta 2-microglobulin (beta 2M) levels < or = 2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these two parameters, three risk groups were defined: 29 good-risk patients with low beta 2M receiving MEL 200 had the best outcome, with median durations of EFS of 37 months and projected OS of > or = 43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high beta 2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (all P < .0001). Further analysis that excluded treatment as a variable identified high beta 2M and resistant relapse as the two major adverse prognostic factors, one of which was present in 80% of the 135 patients. Among these 108 high-risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy using the double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease.

Age Factors↗
PubMed1994

Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation.

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty-one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno-occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI.

Adolescent↗