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Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 253 records · Page 14Linked to original sources
PubMed1993

Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation.

The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.

Animals↗
PubMed1993

Studies of the use of L-leucyl-L-leucine methyl ester in canine allogeneic marrow transplantation.

L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) is a lysosomotropic agent that selectively kills cytotoxic T cells and their precursors, natural killer cells, and monocytes but not helper T cells or other cells of hematopoietic origin. In this study, the effects of treatment of bone marrow and peripheral blood buffy coat with Leu-Leu-OMe on the outcome of allogeneic marrow transplantation were studied in several canine models. Whereas incubation of autologous marrow with Leu-Leu-OMe had no adverse effects on subsequent engraftment, incubation of marrow from dog leukocyte antigen (DLA)-identical littermates resulted in a high rate of graft failure. Previous studies have demonstrated that the addition of peripheral blood buffy coat allows engraftment of unrelated DLA-nonidentical marrow, and in this study we found that incubation of buffy coat with Leu-Leu-OMe did not alter this graft promoting effect. In a final experiment it was demonstrated that incubation of both marrow and peripheral blood buffy coat did not prevent the development of graft-versus-host disease in recipients of marrow from DLA-haploidentical littermates. In considering the eventual application of Leu-Leu-OMe in the clinic, these results are less encouraging than those previously reported using murine models.

Animals↗
PubMed1993

FK-506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated dog leukocyte antigen-nonidentical donors.

FK-506 was evaluated either alone or combined with methotrexate (MTX) for prevention of graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and dog leukocyte antigen-nonidentical unrelated marrow grafts. Studies with marrow autografts showed gut toxicity and weight loss to be major side effects of FK-506. There was no hematopoietic toxicity with FK-506. In an initial allograft study, 5 dogs were given FK-506 intramuscularly at 0.3 mg/kg/day from days 0 to 8 and then orally at 0.5 mg/kg/day. All 5 died, 3 with intussusception most likely due to FK-506 toxicity, 1 with graft failure, and 1 with GVHD. Subsequently, the FK-506 dose was reduced and these drug schedules were used: FK-506 days 0-8 at 0.15 mg/kg/day i.m. and then orally at 0.5 mg/kg/day until day 90, with or without MTX intravenously at 0.4 mg/kg days 1, 3, 6, and 11. Twenty allografts were done, 10 with FK-506 alone, and 10 with MTX/FK-506. Results were compared with those in concurrent and historical controls given either no immunosuppression (n = 64), MTX (n = 114), CsA (n = 15), or MTX/CsA (n = 17). Five of 20 current dogs died with intussusception, too early to be evaluated for GVHD. The 10 dogs given FK-506 alone survived significantly better than those not given immunosuppression but not differently from those given short-term MTX or CsA alone. Three died from toxicity, 2 with graft failure, and 4 with GVHD. Only 1 dog became a long-term survivor, and this dog inadvertently received a single dose of MTX on day 7. Two of 10 dogs given MTX/FK-506 died from toxicity, 1 died with graft failure, 2 died with GVHD, and 5 became long-term survivors, a result that is significantly better than seen with either drug alone and similar to that seen with MTX/CsA. Four of the 5 survivors had no clinical GVHD. FK-506 blood levels were 15-35 ng/ml between days 8 and 15, when gut toxicity was most severe. Thereafter, levels were approximately 5 ng/ml. In conclusion, FK-506 prolonged survival of recipients of dog leukocyte antigen-nonidentical unrelated marrow grafts. When FK-506 was combined with MTX, graft-host tolerance was induced in 50% of dogs, even though FK-506 was stopped on day 90.

Animals↗
PubMed1993

Recombinant granulocyte-macrophage colony stimulating factor followed by immunosuppressive therapy for aplastic anaemia.

Seventeen patients with aplastic anaemia were treated with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) for 14 d. Nonresponding patients were then treated with anti-human thymocyte globulin (ATG), methylprednisolone and oxymetholone. Side-effects of rhGM-CSF included fever, nausea and vomiting, diarrhoea, bone pain, headache and chills. Two patients had sustained trilineage haemopoietic recovery after receiving only rhGM-CSF. Of 11 patients who received immunosuppressive therapy, there was one complete response, two partial responses, one minimal response, and seven nonresponses. Actuarial survival at 2 years is 64%. Early administration of rhGM-CSF had no apparent effect on subsequent response to immunosuppressive therapy.

Adolescent↗
PubMed1993

Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience.

PURPOSE: To analyze results of 127 patients undergoing myeloablative therapy followed by marrow transplantation for relapsed or refractory Hodgkin's disease. PATIENTS AND METHODS: Twenty-three patients had primary refractory disease, 34 were in early first relapse or second complete remission (CR), and 70 had refractory first relapse or disease beyond second CR. Preparative regimens included total-body irradiation (TBI) and chemotherapy (n = 61) or chemotherapy only (n = 66). Sixty-eight patients received autologous marrow, six syngeneic marrow, and 53 allogeneic marrow. RESULTS: The 5-year actuarial probabilities of survival, event-free survival (EFS), relapse, and nonrelapse mortality for the entire group were 21%, 18%, 65%, and 49%, respectively. HLA-identical allogeneic marrow recipients had a statistically lower relapse rate compared with recipients of autologous marrow, but survival, EFS, and nonrelapse mortality rates were not significantly different. In the multivariate analysis, higher performance status and absence of bulky disease predicted for improved EFS and lower relapse rates, while fewer prior treatment regimens predicted for improved EFS and lower nonrelapse mortality rates. Additionally, the univariate analysis showed that patients who underwent transplantation with disease refractory to chemotherapy or beyond second CR had a worse outcome compared with those who had less advanced disease. CONCLUSION: Outcome with transplantation for patients with Hodgkin's disease is improved if transplantation is performed early after relapse when disease burden is less, tumor chemosensitivity is greater, and the patient is likely to have a better performance status. The use of HLA-matched sibling marrow results in a lower relapse rate and, thus, for some individuals, may be preferable to the use of autologous marrow.

Actuarial Analysis↗
PubMed1993

High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-limiting radiation therapy.

PURPOSE: To evaluate high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in patients with lymphoid malignancy who had received prior radiation therapy. PATIENTS AND METHODS: Fifty-seven patients with non-Hodgkin's lymphoma (NHL; n = 23), Hodgkin's disease (HD, n = 32), or acute lymphoblastic leukemia (ALL; n = 2) with a history of previous radiation therapy were treated with cyclophosphamide (Cy; 7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2) (CBV) followed by ABMT. RESULTS: The projected 2-year probabilities of survival, event-free survival (EFS), and relapse were .31, .24, and .76, respectively. For patients with intermediate- and high-grade lymphoma and HD the probabilities were .27, .10, and .14 for EFS and .57, .90, and .77 for relapse. The probability of nonrelapse mortality in the first 100 days post-ABMT was 33%. Idiopathic pneumonia syndrome (IPS) was observed in no patients who received carmustine 300 mg/m2 and 23% of patients who received carmustine 600 mg/m2 (P = .05). Eight-three percent of patients who received mediastinal radiation therapy less than 3 months before transplant developed IPS, compared with 13% who received radiation therapy more than 3 months before transplant (P = .001). CONCLUSION: ABMT following high-dose CBV resulted in long-term disease-free survival in 25% of patients with lymphoid malignancies who had previously received dose-limiting radiation therapy. Fatal IPS and a high relapse rate were major factors limiting successful outcome following ABMT. The morbidity and mortality rates associated with the administration of carmustine 600 mg/m2 were prohibitively high, especially in patients who received mediastinal radiation immediately before ABMT, and were not associated with a decrease in post-ABMT relapse.

Adolescent↗
PubMed1993

Autologous marrow transplantation for patients with acute myeloid leukemia in untreated first relapse or in second complete remission.

PURPOSE: This study compares outcomes of autologous bone marrow transplantation (ABMT) in patients with acute myeloid leukemia (AML) in untreated first relapse (REL1) or in second complete remission (REM2). PATIENTS AND METHODS: Forty-seven patients with AML in REL1 (n = 21) or in REM2 (n = 26) were treated with busulfan (BU) and cyclophosphamide (CY) with or without total-body irradiation (TBI) followed by ABMT. All REL1 patients and four REM2 patients had marrow stored during first remission (REM1). Twenty-seven had marrow stored with and 20 without treatment in vitro with 4-hydroperoxycyclophosphamide (4-HC). Eighteen patients received BU and CY and 29 received BU, CY, and TBI. REL1 patients relapsed within a median of 9 months (range, 2 to 26) after marrow harvest and were transplanted a median of 30 days (range, 9 to 87) from detection of relapse. RESULTS: With a median follow-up of 2.1 years (range, 0.4 to 5.3), 19 patients survive in remission (10 of 21 in REL1; nine of 26 in REM2). The actuarial probabilities of relapse-free survival at 2 years for patients transplanted in REL1 and REM2 were 45% +/- 22% and 32% +/- 18%, respectively (P = .33). The corresponding probabilities of relapse were 30% +/- 26% and 44% +/- 23%, respectively (P = .45). No conclusions could be drawn about the benefits of adding TBI to BU plus CY. There were no significant differences in neutrophil or platelet recovery or in posttransplant probabilities of relapse and nonrelapse mortality between patients who received marrow treated or not treated with 4-HC. CONCLUSION: These results suggest that ABMT may produce long-term leukemia-free survival in approximately one third of patients with AML in REL1 or in REM2. There is no apparent clinical advantage in attempting to obtain second remissions in relapsed patients before ABMT if marrow has been cryopreserved during REM1. Although a strategy of transplantation in REL1 has advantages for the patient, such an approach involves the storage of marrow, which may not be used, and is impractical without the coordinated support of the treating physician, the patient, and the marrow transplant center.

Acute Disease↗
PubMed1993

A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study.

Fludarabine monophosphate is a new antimetabolite with demonstrated activity in chronic lymphocytic leukemia (CLL). We have investigated the practicality of utilizing fludarabine in combination with chlorambucil in a disease-specific phase I trial. Twenty-one patients with advanced and previously treated, relapsed or refractory CLL were treated with chlorambucil plus fludarabine. Chlorambucil was given day 1 at 15 or 20 mg/m2 per os and fludarabine days 1-5 at 10, 15, or 20 mg/m2 intravenously, every 28 days. We concluded that with chlorambucil 15 mg/m2, the maximum tolerated dose for fludarabine was 20 mg/m2 in this patient population with this scheduling. Dose-limiting toxicity was thrombocytopenia. A low incidence of peripheral neuropathy, rash, pulmonary fungal infection, and acute tumor lysis syndrome was also encountered. Although responses were observed, it was impossible from this study to determine whether the combination was better than fludarabine alone in this heavily pretreated population. This study does, however, demonstrate the feasibility of exploring the utility of such a combination in previously untreated patients. An intergroup phase III trial utilizing this combination has been initiated.

Administration, Oral↗
PubMed1993

Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial.

Samarium-153-ethylenediaminetetramethylene phosphoric acid (EDTMP), a bone-seeking radiopharmaceutical, was given to prostate cancer patients in a dose escalation protocol for pain palliation to determine the maximally tolerated dose. Fifty-two patients with hormone refractory prostate cancer with bony metastases were treated with doses beginning at 0.5 mCi/kg (18.5 MBq/kg), escalating in 0.5-mCi (18.5 MBq) increments to 3.0 mCi/kg (111 MBq/kg). Pain response after treatment was assessed as well as hematologic and serum chemistry parameters. Pain palliation with a mean duration of 2.6 mo was present in 74% of the patients. Toxicity was exclusively hematologic at the highest dose levels. No infectious or bleeding complications occurred, with 45 of the 52 (86%) patients demonstrating complete hematologic recovery. Patients receiving higher doses had significantly greater reductions in serum prostate specific antigen and serum prostatic acid phosphatase levels. The patients receiving greater doses also showed a trend toward improved survival.

Aged↗
PubMed1993

Autologous bone marrow transplantation for acute lymphoblastic leukemia.

Between December 1979 and February 1991, 89 patients with ALL received autologous BMT. Median patient age was 18.4 years. Ten patients were in first remission, 52 were in second or greater remission and 27 were in relapse at the time of transplant. Conditioning regimens utilized chemotherapy alone (5 patients) or in combination with 10-15.75 Gy total body irradiation (84 patients). Disease-free survival at 1 year is 50% for patients transplanted in first remission, 27% for those in > or = second remission and 8% for patients in relapse. Pre- and post-transplant variables were evaluated in univariate and multivariate analyses for their effect on survival and relapse. Factors significantly associated with improved survival were being transplanted in first remission and achieving a self-sustained platelet count > or = 20 x 10(9)/l in a shorter period of time. A decreased relapse rate after transplant was associated with a lower white blood count at diagnosis, being transplanted in first remission and not being transplanted in relapse.

Adolescent↗
PubMed1993

The influence of total dose, fractionation, dose rate, and distribution of total body irradiation on bone marrow transplantation.

Total body irradiation (TBI) is a common component of many preparative regimens used prior to bone marrow transplantation. The biologic effects of TBI are influenced by a number of factors, including total dose, dose fractionation, dose rate, and dose distribution. Higher doses of TBI result in greater antileukemic activity, but this effect may be offset by concomitant increases in treatment-related toxicities. Increased doses of TBI also produce a greater degree of immunosuppression. Fractionated TBI results in decreased late toxicities and immunosuppressive effects when compared with single-dose TBI, yet the extent of marrow ablation seems to be similar. For both single-dose and fractionated TBI, higher dose rates produce increased treatment-related toxicities. Dose rates also may affect marrow ablation and immunosuppression. By targeting radiation to leukemic or immunocompetent cells, alterations in dose distribution have the potential to significantly improve the clinical benefits of TBI. Directed external beam irradiation is one approach to achieving the goal of targeted therapy. Other approaches involve the conjugation of radionuclides to antibodies that recognize specific cell-surface antigens or to aminophosphonic acid compounds that bind to bone. Such specific targeting of radiation could lead to significant increases in the intensity of therapy without resulting in greater treatment-related toxicities.

Animals↗
PubMed1993

Use of granulocyte-macrophage colony-stimulating factor and erythropoietin in combination after autologous marrow transplantation.

The toxicities and possible utility of the combination of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant human erythropoietin (rHuEPO) given after autologous BMT were evaluated in this pilot trial. Eighteen patients received the combination and were compared with six concurrent control and 65 historical control patients treated with rhGM-CSF alone. Patients treated with the combination tended to have more rapid recovery to an absolute neutrophil count of 500 x 10(6)/l (median = 12.5 vs 18 days for concurrent and 19 days for historical control patients). There was no apparent impact on red cell transfusion requirements, platelet recovery or duration of hospitalization. Patients treated in the current study with rhGM-CSF plus either rHuEPO or with placebo had a higher incidence of rash than seen in our historical experience using rhGM-CSF. This difference may reflect changes in the source of rhGM-CSF or in the infusion schedule. Erythropoietin can be combined safely with rhGM-CSF after autologous transplantation. Larger controlled trials will be necessary to detect possible therapeutic effects.

Adolescent↗
PubMed1993

Consequences of cryopreserving first remission autologous marrow for use after relapse in patients with acute myeloid leukemia.

Ninety-eight patients with AML had marrow harvested and cryopreserved at a median of 6 months (range 1-36 months) after achieving first CR with the intent of performing an ABMT at the first sign of relapse. Thirty-three of the 98 patients have not relapsed and 32 survive at a median of 64 months (range 10-105 months) after marrow storage. Sixty-five of the 98 patients relapsed at a median of 7 months (range 1-53 months) after marrow storage. The survival at 2 and 4 years for the 65 patients who relapsed was 22% and 8% respectively. Sixteen of 24 patients treated initially with chemotherapy were ultimately transplanted and two are surviving 21 and 41 months following ABMT and allogeneic marrow transplant respectively. There were no survivors among the eight patients treated with chemotherapy who were not transplanted. Thirty-eight of the 65 patients who relapsed proceeded directly to ABMT without attempts at remission induction, and eight survive disease-free 15-114 months following ABMT. One of the first 17 patients treated with cyclophosphamide and total body irradiation survives without relapse. The probabilities of relapse-free survival, non-relapse mortality, and relapse for the 17 most recent patients prepared with busulfan-containing regimens were 41%, 39% and 32% respectively. Surviving patients had longer first remissions (p = 0.08) and lower peripheral blood blast counts at the time of transplant (p = 0.02) when compared with patients who died. These data suggest that ABMT in untreated first relapse is a reasonable approach for the treatment of patients with AML who relapse.

Adolescent↗