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Biomedical subjects

J E Sanders

Publications and source records attributed to J E Sanders.

At least 145 records · Page 8Linked to original sources
PubMed1989

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma.

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.

Adolescent↗
PubMed1989

Busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study.

Thirty-six patients with advanced hematologic malignancy were entered into a phase I study designed to define a tolerable dose of busulfan (BU) and cyclophosphamide (CY) combined with 12 Gy of fractionated total body irradiation (TBI) as preparation for marrow transplantation from HLA-identical siblings, 0-1 locus HLA-non-identical family members or autologous cryopreserved marrow. Five of 18 evaluable patients prepared with 8.7 mg/kg of BU and 69 mg/kg CY + TBI developed severe regimen related toxicity (RRT) while none of 15 patients treated with 6.9 mg/kg of BU and 47 mg/kg of CY + TBI developed severe RRT. Ten of the 15 evaluable patients treated on the lower dose level are alive, nine disease-free, 262-737 days (median, 547) post-transplant with a 87% and 67% actuarial probability of survival at 3 and 18 months respectively. Six of the 18 patients treated on the higher dose level are alive disease-free 273-1039 days (median, 668) post-transplant with a 56% and 27% actuarial probability of survival at 3 and 18 months respectively. Eighteen patients were transplanted with allogeneic marrow for chronic myelogenous leukemia beyond chronic phase and acute non-lymphocytic leukemia beyond first remission or in relapse other than first untreated relapse and only one has relapsed posttransplant. It was concluded that a transplant preparative regimen combining 6.9 mg/kg of BU with 47 mg/kg of CY followed by 12 Gy fractionated TBI is well tolerated. The high probability of surviving this regimen and the low early relapse rate in patients with advanced myeloid malignancies is encouraging.

Adult↗
PubMed1988

Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923).

Thyroid hyperplasia and/or hepatomegaly were observed in a 14-week oral toxicity study with L-649,923, a leukotriene antagonist, at doses of 50 and 150 mg/kg/day. In a 16-day study, L-649,923 caused an increase in plasma TSH and hepatic enzyme induction, but did not affect plasma T3 and T4 levels. Light microscopy and ultrastructural examination of the liver and thyroid showed changes indicative of hepatic enzyme induction and increased stimulation of the thyroid by TSH. Because other hepatic enzyme inducers cause thyroid hyperplasia by increasing the turnover of plasma T3 and T4 it was hypothesized that L-649,923-induced thyroid hyperplasia might be occurring by the same mechanism. To examine this theory, rats were treated po with 300 mg/kg/day of L-649,923 for 17 days. On Day 15, all rats were dosed iv with [125I]thyroxine (33 microCi/rat). At various times after dosing, blood was collected and plasma levels of 125I were determined. The clearance and elimination rate constant were significantly larger in treated animals than in the control group (p less than 0.01). This work demonstrates that L-649,923 increases the plasma turnover of thyroxine which is associated with a stimulation of TSH and thyroid hyperplasia.

Animals↗
PubMed1988

Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation.

To determine the relation between the serum cyclosporine concentration and the risk of acute graft-versus-host disease (GVHD), we studied 179 recipients of bone marrow grafts from HLA-identical sibling donors who received prophylaxis with cyclosporine, either by itself or combined with methotrexate. Cyclosporine was given either orally or intravenously at full doses from the day before transplantation until day 50; it was then tapered off and discontinued on day 180. Trough concentrations of serum cyclosporine were measured by radioimmunoassay. The relation between patients' characteristics and the risk of acute GVHD was analyzed with a relative-risk regression model. In 66 patients (37 percent), grades II to IV of acute GVHD developed 7 to 66 days (median, 13) after transplantation. The trough cyclosporine concentration for a given week was significantly associated with the risk that acute GVHD would develop during the following week. The relative risks were 0.7 (i.e., there was a 30 percent reduction in risk) for every increase of 100 ng per milliliter in cyclosporine concentration and 1.0, 0.60, and 0.20 for concentrations of less than 100, 100 to 199, and 200 or more ng per milliliter, respectively (P less than 0.01). A patient's age, prophylaxis regimen, and year of transplantation also influenced the risk of acute GVHD significantly. These data indicate that low cyclosporine concentrations can be a cause of treatment failure and that concentrations should be monitored in recipients of marrow transplants.

Acute Disease↗
PubMed1988

Ovarian function following marrow transplantation for aplastic anemia or leukemia.

One hundred eighty-seven women between 13 and 49 years of age had ovarian function evaluated from 1 to 15 years (median, 4) after marrow transplant for aplastic anemia or leukemia. Among 43 women transplanted for aplastic anemia following 200 mg/kg cyclophosphamide (CY), all 27 less than 26 years of age, but only five of 16 greater than 26 years of age recovered normal ovarian function. Nine of the 43 have had 12 pregnancies, resulting in eight live births, and two elective and two spontaneous abortions. All eight children are normal. Nine of 144 women transplanted for leukemia following 120 mg/kg CY and 9.20 to 15.75 Gy total body irradiation (TBI) recovered ovarian function. Two of these nine have had three pregnancies, resulting in two spontaneous and one elective abortion. The probability of having ovarian failure was 0.35 by 7 years for patients receiving CY alone and was 1.00 at 1 year for patients receiving CY plus TBI (P less than .0001). By 7 years after transplant the probabilities of having normal ovarian function were 0.92 after CY alone and 0.24 after CY plus TBI (P less than .0001). Multivariate analysis showed that TBI was the only factor significantly influencing ovarian failure and that both TBI and greater patient age at transplant were significantly associated with a decreased probability of recovering normal ovarian function. These data demonstrate that after high-dose CY, recovery of ovarian function occurs in younger women and in a minority of older women, but after CY and TBI, recovery occurs in only a few younger women and none of the older women.

Adolescent↗
PubMed1988

Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.

We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III). All three groups received identical doses of prednisone (1 mg/kg every other day) and one double-strength trimethoprim-sulfamethoxazole (TMP-SMX) tablet twice daily. Between January 1980 and December 1983, 179 previously untreated patients were enrolled and 164 were evaluable. Patients randomized to group I (n = 63) and group II (n = 63) were well matched for prognostic factors; those placed into group III (n = 38) had more frequent acute GVHD and progressive onset of chronic GVHD. Median duration of therapy was 2 years. Complications included diabetes (5%), aseptic necrosis (5%) and infection. For groups I, II, and III, the respective incidence of infection was disseminated varicella, 11%, 24%, 34%; bacteremia, 6%, 11%, 34%; and interstitial pneumonia, 5%, 14%, 18%. Recurrent malignancy was the most frequent cause of death and did not differ significantly across the groups. Nonrelapse mortality, however, did differ: 21% in group I, 40% in group II, and 58% in group III (I v II, P = .003; I v III, P = .001). Forty patients in group I, 30 in group II, and 10 in group III survive with a minimum follow-up of 3.8 years. Karnofsky performance scores for 68 survivors are 90% to 100%, scores for seven survivors are 70% to 89% and scores for five survivors are less than 70%. Actuarial survival at 5 years after transplant is 61% in group I, 47% in group II, and 26% in group III (I v II, P = .03; I v III, P = .0001). Treatment with prednisone alone results in fewer infections and better survival than prednisone and azathioprine in standard-risk chronic GVHD. Treatment with prednisone alone is less effective in high-risk patients with thrombocytopenia, and other strategies are required.

Adolescent↗
PubMed1988

Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease.

Therapy of chronic graft-v-host disease (GVHD) has been unsatisfactory in patients with platelet counts less than 100,000/microL. Survival at 5 years after marrow transplant is only 26% in such patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) and every other day with prednisone. Since October 1982, 61 patients with high-risk extensive chronic GVHD were treated with a new alternating-day regimen of prednisone (1 mg/kg every other day) and oral cyclosporine (6 mg/kg every 12 hours every other day) with one double-strength TMP-SMX tablet twice daily. Forty patients (group I) received primary treatment of thrombocytopenic chronic GVHD (median platelet count 35 [range 7 to 87] x 10(3)/microL). Twenty-one patients (group II) received salvage treatment after failing initial prednisone +/- azathioprine. Twenty-one patients in group I and 15 in group II survive with a minimum of 2 years and a median of 3.7 years follow-up. At 4 years after transplant, actuarial survival is 51% (group I) and 67% (group II). Causes of death included interstitial pneumonia (six), relapse (five), GVHD without infection (five), infection (four), organ failure (three), and hemorrhage (two). Mortality increased with the progressive type onset of chronic GVHD and treatment failure. Toxicity included hypertension (13), nephrotoxicity (nine), nausea (seven), aseptic necrosis (five), neurologic abnormalities (four), and diabetes (three). Median cyclosporine levels at four and 36 hours were 296 and 64 ng/mL, respectively. Four patients required permanent discontinuation of cyclosporine, but none required renal dialysis. Karnofsky performance scores for 25 survivors are 90% to 100%, scores for six survivors are 70% to 89%, and scores for five survivors are less than 70%. Alternating-day cyclosporine and prednisone has acceptable toxicity and appears to improve survival in patients with high-risk chronic GVHD.

Adolescent↗
PubMed1988

Second marrow transplants in patients with leukemia who relapse after allogeneic marrow transplantation.

Twenty-six patients with recurrent leukemia following allogeneic marrow transplantation received a second marrow transplant between 1.5 and 78 months (median 26) after the initial transplant. Preparative regimens for second transplant included multi-agent chemotherapy with total body irradiation, 2.0-10.0 Gy (five patients), dimethylbusulfan alone (one patient), and dimethylbusulfan or busulfan plus cyclophosphamide (20 patients). One patient died before engraftment of infection and 18 died after engraftment from veno-occlusive disease (4), infection (2), idiopathic pneumonia (3), cytomegalovirus pneumonia (3), leukemia (5) and encephalopathy (1). Seven patients (27%) survive 12-38 months (median 26); five (19%) are disease-free and two have recurrent leukemia. Two of the five disease-free survivors have chronic graft-versus-host disease. All of the surviving patients received dimethylbusulfan or busulfan plus cyclophosphamide and six of the seven surviving patients were among 11 patients transplanted more than 2 years after the first transplant whereas only one was among the 15 transplanted in less than 2 years. Those who have second marrow transplants one or more years after their initial transplant are more likely to benefit, while those who are less than 1 year from initial transplant appear to benefit the least.

Adolescent↗
PubMed1988

Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up.

Thymus tissue implants, thymic epithelial cells obtained from third party donors sharing one HLA-A and -B locus with the recipient, or the thymic hormones thymosin fraction 5 and thymopentin were given to recipients of HLA-identical sibling bone marrow to prevent chronic graft-versus-host disease (GVHD) and accelerate immunologic reconstitution. The clinical courses of 17 patients receiving thymus tissue and 18 patients receiving thymic hormones were reported initially 5 years ago and showed no difference in the incidence of chronic GVHD or immunologic recovery from those of concurrent or historical controls. We report here for the first time nine new patients who received thymus tissue implants with modifications of the culture method to lower the number of lymphocytes in the transplanted tissue with the intent of reducing rejection of the thymus tissue grafts. The clinical outcomes and immunologic functions of these nine patients were similar to those of the recipients of the earlier thymus tissue implants. With follow-up now ranging from 2.2 to 12.3 years (median 6.7) for the total group, 16 patients are alive. Seven never developed chronic GVHD. Nine were treated for chronic GVHD, seven of whom recovered and are leading normal lives, one has chronic pulmonary insufficiency, and one is disabled from chronic GVHD. We conclude that thymus tissue grafts or thymic epithelial cells partially HLA-matched to the recipient, thymosin fraction 5, or thymopentin used as described were not effective in reducing the incidence of chronic GVHD, improving immunologic recovery, or altering long-term survival.

Adolescent↗
PubMed1988

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy.

Nine patients with advanced hematological malignancy were entered into a phase I study to determine the maximum tolerated doses of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) combined with a standard dose of total body irradiation (TBI). Ara-C was administered continuously over 36 h and two doses of CY were given at 24-h intervals during Ara-C administration. TBI was given as 2.0 Gy fractions on each of 6 consecutive days followed by bone marrow transplantation. The initial three patients received a total dose of 6048 mg/m2 of Ara-C and 84 mg/kg of CY, with two of three patients experiencing fatal toxicity. The next two patients received a total dose of 5040 mg/m2 of Ara-C and 70 mg/kg of CY and both experienced fatal toxicity. The next four patients received a total dose of 3024 mg/m2 of Ara-C, 56 mg/kg of CY; two patients had no toxicity but two had grade 4 (fatal) toxicity. Four of the six patients with fatal toxicity did not complete the TBI regimen and two of these did not receive marrow infusion. One patient is alive (greater than 547 days post-transplant) but has relapsed (day 305). It is concluded that phase I trials of regimens containing concurrent administration of Ara-C and CY may not be appropriate due to severe dose-independent toxicity as demonstrated in this study.

Adolescent↗
PubMed1988

Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia.

Fourteen children between the ages of 2 and 5 years with juvenile chronic myelogenous leukemia were given cyclophosphamide, total-body irradiation, and marrow transplants. Unmodified marrow was given to six patients who received marrow from HLA-identical siblings and eight patients who received marrow from family members HLA identical for one haplotype but mismatched for one to three loci on the nonshared haplotype. Five patients died of transplant-related complications, and three relapsed at 48, 81, and 1,670 days posttransplant and died of leukemia. Six patients survive in continuous remission from 0.5 to 11.5 years posttransplant.

Bone Marrow Transplantation↗
PubMed1988

Bone marrow transplantation for the treatment of acute nonlymphoblastic leukemia in children aged less than 2 years.

Eleven children with acute nonlymphoblastic leukemia in first remission who were less than 2 years of age at diagnosis were treated with 120 mg/kg of cyclophosphamide, 12-Gy fractionated total-body irradiation, and marrow transplantation. Seven patients remain in complete remission from 3.5 to 13.8 years posttransplant, four for more than 6.75 years. The immediate posttransplant course was relatively uncomplicated in surviving patients. No child developed severe graft-v-host disease. The major long-term side effect has been a slowing in growth. Although the prognosis for such children with conventional chemotherapy remains poor, intensive cytotoxic therapy and marrow transplantation offers an alternative therapy with a chance for cure.

Antineoplastic Combined Chemotherapy Protocols↗