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Biomedical subjects

R E Champlin

Publications and source records attributed to R E Champlin.

At least 127 records · Page 7Linked to original sources
PubMed1993

Genesis of human oncolytic natural killer cells from primitive CD34+CD33- bone marrow progenitors.

We have found that fully functional CD56+CD3- NK cells can be generated from highly enriched populations of CD34+ human bone marrow progenitors in long term bone marrow culture (LTBMC) with IL-2. Strong lytic activity against K-562 cells was observed after 2 to 3 weeks of culture and coincided with the appearance of CD56+CD3- large granular lymphocytes, which comprised 55 to 84% of cells. In contrast, lymphocytes generated from CD34- bone marrow cells were predominantly CD56-CD3+ T cells. The phenotypic profile of NK cells generated in LTBMC differed from that of IL-2-cultured peripheral blood NK cells. Specifically, a lower percentage of LTBMC-derived NK cells coexpressed CD16, CD2, CD7, and CD8 Ag. NK cells generated in LTMBC proliferated actively, with an expansion index ranging from two- to 200-fold. Furthermore, NK cells were generated from the CD34+CD33- hematopoietic subset, which had been depleted of the myeloid-committed progenitors (CD34+CD33+). Generation of cytotoxic NK cells in LTBMC was dependent on the dose of IL-2; although CD56+CD3- NK cells were generated in LTBMC supplemented with a broad range of doses (10 to 10(3) U/ml) of IL-2, the acquisition of full cytotoxic function required a high concentration of IL-2 (10(3) U/ml). These observations demonstrate the IL-2-driven differentiation of NK cells from early bone marrow progenitors and indicate that LTBMC may provide an excellent model for studies of NK cell lineage and differentiation in normal and pathologic conditions.

Antigens, CD↗
PubMed1993

Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?

Optimal prophylaxis of graft-versus-host disease (GVHD) is controversial. We compared efficacy of three posttransplant immune suppressive regimens in 2,286 recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia (ALL) in first remission, acute myelogenous leukemia (AML) in first remission, or chronic myelogenous leukemia (CML) in first chronic phase. Six hundred forty received methotrexate, 977 received cyclosporine, and 669 received combined cyclosporine and methotrexate. In children, the three regimens resulted in similar outcomes. In adults, cyclosporine and methotrexate had comparable risks of acute and chronic GVHD. Compared with methotrexate, cyclosporine was associated with less interstitial pneumonia (relative risk [RR] = 0.6; P < .001), less treatment-related mortality (RR = 0.6; P < .001), more relapses (RR = 1.6; P < .05), and less treatment failure (relapse or death from any cause; RR = 0.7; P < .001). Different effects were observed in different leukemias. In ALL, the rate of leukemia relapse was increased with cyclosporine versus methotrexate, with no effect on other outcomes. In AML and CML, interstitial pneumonia, treatment-related mortality, and treatment failures were decreased with cyclosporine, with no increase in relapse. Similar analyses comparing cyclosporine plus methotrexate with cyclosporine alone showed that adults receiving the combination had less acute GVHD (RR = 0.5; P < .001), less chronic GVHD (RR = 0.7; P < .01), and less interstitial pneumonia (RR = 0.7; P < .001). Treatment failure (RR = 0.8; P < .05) was marginally reduced. Separate analyses in ALL and AML showed less acute GVHD with combined therapy, but no significant effect on other outcomes. In CML, acute GVHD, interstitial pneumonia, treatment-related mortality, and treatment failure were decreased with combined therapy.

Adolescent↗
PubMed1993

Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of ganciclovir for prevention of cytomegalovirus (CMV) infection and disease. DESIGN: A randomized, placebo-controlled, double-blind trial. SETTING: University-affiliated bone marrow transplant center. PATIENTS: Cytomegalovirus-seropositive allogeneic bone marrow transplant recipients. INTERVENTIONS: Random assignment to receive either a placebo or ganciclovir at a dose of 2.5 mg/kg body weight every 8 hours for 1 week before transplant and then at a dose of 6 mg/kg once per day, Monday through Friday, after transplant when the post-transplant neutrophil count reached 1.0 x 10(9)/L. MEASUREMENTS: Cytomegalovirus infection (positive culture, seroconversion, positive histologic findings), CMV disease (pneumonia, gastroenteritis, the wasting syndrome), and study-drug toxicity. RESULTS: Cytomegalovirus infection developed in 25 of 45 placebo patients (56%) but in only 8 of 40 ganciclovir patients (20%) (P < 0.001). Cytomegalovirus disease may also have occurred less often in the ganciclovir patients (4 of 40 patients [10%] versus 11 of 45 patients [24%]; P = 0.09). The probability of CMV disease occurring within the first 120 days after transplantation was 0.29 among the placebo patients but only 0.12 among ganciclovir patients (P = 0.06). Reversible neutropenia was the only appreciable toxicity related to ganciclovir and required interruption of the study drug after transplant in 25 of 43 ganciclovir patients (58%) and in 13 of 47 placebo patients (28%) (P = 0.005). Overall survival was similar in both the placebo patients (29 of 45 [64%]) and ganciclovir patients (28 of 40 [70%]; P > 0.2). CONCLUSIONS: Prophylactic ganciclovir, started before transplant and continued after recovery of the post-transplant neutrophil count, reduces the incidence and severity of CMV infection in CMV-sero-positive bone marrow transplant recipients but is frequently associated with neutropenia.

Adolescent↗
PubMed1993

Parainfluenza virus infection in adult bone marrow transplant recipients.

The clinical course of parainfluenza virus infection occurring in 8 of 265 (3%) adult bone marrow transplant recipients during 1991 was reviewed. Parainfluenza virus type 3 was isolated from all eight patients. The clinical course ranged from self-limited upper respiratory tract infections (2 patients) to severe lower respiratory tract disease (6 patients) associated with a 50% mortality. This study highlights the important role of community respiratory viruses such as parainfluenza virus in the etiology of pneumonia in immunocompromised adults.

Adult↗
PubMed1993

Effectiveness of an oral triazole for opportunistic mold infections in patients with cancer: experience with SCH 39304.

Fungal infections are the most common infectious cause of death among patients with hematologic malignancies. Conventional antifungal agents have limited activity and a narrow therapeutic index. In an open-label study we assessed the activity of an oral triazole, SCH 39304, in the treatment of refractory life-threatening mold infections in 50 patients with cancer, most of whom had previously received amphotericin B and/or fluconazole. SCH 39304 was given at a daily dose of 200-400 mg for a median of 8 weeks. The overall rate of response was 79% among 34 evaluable patients, with a complete response in 22 instances and a partial response in 5. Some patients responded despite persistent, profound immunosuppression. Three patients developed relapses, and two developed fungal superinfections. SCH 39304 was well tolerated. We conclude that oral triazoles such as SCH 39304 may represent effective and safe treatment of mold infections in immunosuppressed patients, at least after standard antifungal chemotherapy. Unfortunately, the carcinogenic potential of SCH 39304 in animals has precluded its development. Our hope is that analogues with similar efficacy but without carcinogenic potential can be developed.

Administration, Oral↗
PubMed1993

Leptomeningeal toxoplasmosis after allogeneic marrow transplantation. Case report and review of the literature.

A 37-year-old woman with chronic myelogenous leukemia underwent allogeneic bone marrow transplantation with CD8-depleted marrow from an HLA-identical sister. On day 43 post-transplant, the patient developed a headache and became lethargic and tremulous. Magnetic resonance imaging (MRI) of the brain showed abnormal meningeal and superficial parenchymal enhancement anteriorly. The spinal fluid had an elevated protein level with normal glucose and a neutrophilic pleocytosis. At autopsy, Toxoplasma meningoencephalitis was seen. On review of the literature, headache and confusion at 1-2 months post-transplant are common presenting signs of central nervous system toxoplasmosis. The predominance of neutrophils in the spinal fluid in this patient probably reflects the meningeal component of the infection and is an unusual finding. The presentation of toxoplasmosis in marrow transplant recipients is quite pleomorphic, and a definite diagnosis is difficult to obtain antemortem. Empiric therapy with pyrimethamine and sulfadiazine should be considered for marrow transplant recipients with neurologic deficits for which there is no other apparent etiology.

Adult↗
PubMed1993

Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia.

PURPOSE: To determine whether prior interferon alfa (IFN-A) treatment affects the outcome of allogeneic bone marrow transplantation. PATIENTS AND METHODS: We analyzed the outcome of 77 patients with chronic myelogenous leukemia (CML) who received transplants from an HLA-identical donor using a total-body irradiation-containing preparative regimen. Engraftment, acute and chronic graft-versus-host disease (GVHD), survival, and disease-free survival were compared between patients who had previously received interferon (IFN+) to those who had not (IFN-). Forty-one patients were transplanted in chronic phase and 36 had more advanced CML. The IFN+ group had received IFN-A in doses of 3 to 5 x 10(6) U/m2 three times a week or more for at least 4 weeks anytime before transplantation. RESULTS: For patients in chronic phase, there were no significant differences between the IFN+ group and the IFN- group in regard to neutrophils recovery more than 1.0 x 10(9)/L (29 v 24), platelet recovery more than 50 x 10(9)/L (33 v 36), incidence of grade II to IV GVHD (23% v 28%), incidence of chronic GVHD (39% v 47%), disease-free survival (46% +/- 11% v 59% +/- 13%), relapse (9% v 11%), or 100-day transplant-related mortality (22% v 16%). In patients with more advanced stage disease, there was also no significant differences between the IFN+ group and the IFN- group in regard to these outcomes. CONCLUSION: Prior treatment with IFN-A did not adversely affect transplant outcome. Further studies are required to better understand the complementary roles of IFN-A and allogeneic bone marrow transplantation for the treatment of CML.

Adolescent↗
PubMed1993

Low-dose non-glycosylated rhGM-CSF is effective for the treatment of delayed hematopoietic recovery after autologous marrow or peripheral blood stem cell transplantation.

Twenty-six patients with hematologic malignancies (20) or solid tumors (six) were treated with non-glycosylated rhGM-CSF (E. coli) for delayed hematopoietic recovery (granulocytes < 0.1 x 10(9)/l on day 21 or < 0.5 x 10(9)/l on day 28) after autologous marrow or peripheral blood stem cell transplantation. Median pretreatment granulocytes were 0.1 x 10(9)/l (range 0-0.4 x 10(9)/l). Treatment with rhGM-CSF was initiated at 60-250 micrograms/m2 subcutaneously daily with dose escalation every 7 days if there was no response. Within 14 days, 21 (84%) of the 25 evaluable patients achieved granulocytes > 0.5 x 10(9)/l and 17 (68%) had granulocytes > 1.0 x 10(9)/l. For those who responded within 14 days, granulocytes were > 0.5 x 10(9)/l at a median of 3 days (range 1-13) and > 1.0 x 10(9)/l at 6 days (range 2-12). Sixteen of the 23 patients receiving an initial rhGM-CSF dose of 60-125 micrograms/m2 achieved granulocytes > 1.0 x 10(9)/l. Three patients discontinued use of rhGM-CSF because of toxicity, and four patients never recovered despite use of rhGM-CSF doses as high as 1000 micrograms/m2. Graft failure-related mortality was 16% at 4 months after transplantation. These results demonstrate that relatively low doses of non-glycosylated rhGM-CSF administered subcutaneously daily can be used to promote granulocyte recovery in patients with delayed engraftment after autologous transplantation. No beneficial effects were seen on red cell or platelet recovery.

Adolescent↗
PubMed1993

Intravenous immunoglobulin and CMV-seronegative blood products for prevention of CMV infection and disease in bone marrow transplant recipients.

The efficacy of i.v. immunoglobulin plus CMV-seronegative blood products or CMV-seronegative blood products alone for prevention of CMV infection, symptomatic CMV disease, other infections and GVHD after BMT was evaluated in a randomized, controlled trial. Fifty-one CMV-seronegative allogeneic BMTs with a CMV-seronegative or CMV-seropositive marrow donor were randomly assigned to receive either i.v. immunoglobulin (1.0 g/kg once weekly for 120 days after transplant) plus CMV-seronegative blood products or CMV-seronegative blood products alone. CMV infection occurred in 2 of 25 patients (7%) receiving i.v. immunoglobulin plus CMV-seronegative blood and in 2 of 23 patients (9%) receiving CMV-seronegative blood alone. All CMV infections were asymptomatic and characterized by viral excretion with or without CMV seroconversion. There were no cases of CMV-related interstitial pneumonia. Grade > or = II GVHD was less frequent in patients given i.v. immunoglobulin (5 of 25 patients (20%) vs. 11 of 23 patients (48%), p = 0.04). The number of bacterial and fungal infections was similar in both groups. Fewer non-CMV viral infections (9 of 27 patients (33%) vs. 15 of 24 patients (63%), p = 0.03) and fewer deaths associated with infection (1 of 27 patients (4%) vs. 5 of 24 patients (21%), p = 0.07) occurred in recipients of immunoglobulin. Neither survival nor risk of leukemia relapse was changed by the immunoglobulin. The high doses of i.v. immunoglobulin were well tolerated. These results suggest that CMV-seronegative blood products alone prevent most CMV infections and CMV disease in CMV-seronegative allogeneic BMT recipients, even when the marrow donor is CMV-seropositive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

B cell reconstitution after human bone marrow transplantation: recapitulation of ontogeny?

Patients undergoing BMT have a long-lasting defect of B cell-mediated immunity, especially if chronic GVHD ensues. It has been postulated that the post-transplant B cell abnormalities can be explained by the recapitulation of B cell ontogeny. To test this hypothesis, we studied the quantitative and phenotypic reconstitution of circulating B cells in 24 transplant recipients and compared it with normal ontogeny. The results confirm that a second round of ontogeny occurs in transplant recipients without chronic GVHD. This was evidenced by the pattern of quantitative B cell reconstitution (low-->high-->normal B cell counts), large B cell size and a high proportion of B cells overexpressing CD38, membrane IgM (mIgM) and membrane IgD (mIgD). The recapitulation of ontogeny was blunted in most patients with chronic GVHD, as evidenced by the absence of the overshoot of total B cells and by the relative lack of CD38high, mIgMhigh and mIgDhigh B cells. We conclude the post-transplant B cell development in patients without chronic GVHD parallels ontogeny. The limited ability of patients with chronic GVHD to re-enact B cell ontogeny may contribute to their longer-lasting and more severe humoral immunodeficiency.

Adult↗
PubMed1993

Acute lymphoid leukemia molecular phenotype in a patient with benign-phase chronic myelogenous leukemia.

The benign phase of chronic myelogenous leukemia (CML) typically is characterized by an overproduction of myeloid cells that eventually progresses to a more acute stage termed blast crisis. This latter stage can exhibit either myeloid or lymphoid blast clones. Our recent results have demonstrated the presence of the P210 BCR-ABL protein in blood cells from benign phase CML patients (Guo et al., Cancer Research 51:3048, 1991). This protein is the product of an 8.5 kb chimeric RNA encoded by fused BCR-ABL genes produced by the formation of the Philadelphia (Ph) chromosome. Using this new assay we have identified a patient with benign-phase CML who produces P190 BCR-ABL, the form of the BCR-ABL protein found in about 50% of cases of acute lymphocytic leukemia (ALL). This patient lacked detectable P210 BCR-ABL protein and did not contain a DNA rearrangement in the major breakpoint cluster region of the BCR gene. Consistent with this result, polymerase chain reaction (PCR) analyses detected a BCR-ABL mRNA with BCR exon 1 fused to ABL exon 2. No BCR-ABL mRNAs with 2'- or 3'-bcr exon to ABL exon 2 fusions were detected in these analyses. Blood cells from this patient lost P190 BCR-ABL after the patient underwent an allogeneic bone marrow transplant, but regained this protein although the patient was still in chronic phase after a subsequent autologous transplant as treatment for graft failure. These findings indicate that P190 BCR-ABL alone is not sufficient to induce a blast crisis phenotype in leukemia patients who are Ph chromosome-positive.

Base Sequence↗
PubMed1992

Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s.

OBJECTIVE: To identify changes in practice and outcome of bone marrow transplants for leukemia in the 1980s. DESIGN: Comparison of key explanatory and outcome variables in five 2-year cohorts, from 1980 through 1981 to 1988 through 1989, using a large database of detailed clinical information. PATIENTS: Recipients (7788) of bone marrow transplants for acute lymphoblastic, acute myelogenous, or chronic myelogenous leukemia reported to the International Bone Marrow Transplant Registry, Milwaukee, Wis, by 185 transplant teams worldwide. RESULTS: Linear increases occurred during the periods 1980 through 1981 to 1988 through 1989 as follows with 95% confidence intervals: (1) transplants for chronic myelogenous leukemia from 14% +/- 2% to 35% +/- 2%; (2) transplants from unrelated donors from 1% +/- 1% to 7% +/- 1%; (3) preparative regimens without radiation from 3% +/- 1% to 30% +/- 2%; and (4) use of methotrexate plus cyclosporine to prevent graft-vs-host disease from 2% +/- 1% to 55% +/- 2%. Among recipients of human lymphocyte antigen-identical sibling bone marrow, the 2-year probability of treatment-related mortality decreased by 6% to 22%. The probability of relapse decreased from 46% +/- 6% to 38% +/- 6% in intermediate leukemia but did not change appreciably in early or advanced leukemia. Probabilities of leukemia-free survival improved from 51% +/- 4% to 57% +/- 3% in early leukemia, from 28% +/- 4% to 36% +/- 5% in intermediate leukemia, and from 12% +/- 4% to 18% +/- 5% in advanced leukemia. A separate analysis of a homogenous population of patients indicated that improvements in outcome in the 1980s were due to improvements in transplant practice rather than improved patient selection. CONCLUSIONS: Modest increases in leukemia-free survival rates occurred after human lymphocyte antigen-identical sibling bone marrow transplants in the 1980s. Improvements were due primarily to reductions in treatment-related mortality with little or no change in relapse risk. More effective antileukemia strategies and continued reductions in treatment-related toxic effects are needed.

Adult↗
PubMed1992

Hemolysis of transfused group O red blood cells in minor ABO-incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate.

Hemolysis most commonly occurs following bone marrow transplant when there is "minor" ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti-B antibody produced from "passenger" immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO-incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.

ABO Blood-Group System↗
PubMed1992

Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers?

There is substantial evidence that the volume of medical procedures in a hospital has an inverse relationship with mortality. We analyzed data for 1313 recipients of HLA-identical sibling bone marrow transplants for early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in first chronic phase) to determine whether transplant outcome differed in small and large centers. Transplants were performed in 86 bone marrow transplant centers active between the years 1983 and 1988, which participated in the International Bone Marrow Transplant Registry. Twenty-one (24%) centers performed five or fewer allogeneic transplants per year during the study period; five (6%) performed more than 40 per year. After adjustment for differences in patient and disease characteristics, the relative risks of treatment-related mortality (1.53, P less than .01) and treatment failure (1.38, P less than .04) were higher among patients who received transplants at centers doing five or fewer transplants per year than among those at larger centers. Among patients receiving transplants in centers performing more than five transplants a year, there was no statistically significant correlation between number of transplants and outcome.

Adult↗
PubMed1992

Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome.

Data for 595 patients with severe aplastic anemia receiving HLA-identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

Adolescent↗
PubMed1992

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

PURPOSE: Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS: The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS: After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS: Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

Actuarial Analysis↗