Search PubMed⌕ Search

Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 379 records · Page 21Linked to original sources
PubMed1988

Functional dendritic cells are required for transfusion-induced sensitization in canine marrow graft recipients.

Untransfused dogs given 9.2 Gy total-body irradiation and hematopoietic grafts from DLA-identical littermate donors uniformly achieve sustained engraftment, whereas dogs given three transfusions (Tx) of whole blood from the intended marrow donor 24, 17 and 10 days pretransplant uniformly reject their graft. Sensitization appears to be mediated by peripheral blood mononuclear cells and can be prevented by prior irradiation of the Tx product with UV light, known to inactivate leukocytes, in particular, cells with accessory function. In the present study we investigated which leukocyte population was responsible for Tx-induced sensitization and subsequent marrow graft rejection. Surprisingly, neither monocytes nor macrophages or dendritic cells induced sensitization, and all dogs so treated achieved engraftment; however, all four evaluable dogs transfused with UV-exposed blood to which small numbers of normal dendritic cells (12.5 x 10(3)/kg) were added rejected their marrow graft. Among five dogs given UV-exposed blood and normal monocytes (12.5 x 10(3)/kg) only one rejected its graft, and four achieved sustained engraftment. We conclude that donor dendritic cells are necessary, albeit not sufficient for in vivo sensitization. Sensitization is prevented by elimination or inactivation of dendritic cell.

Animals↗
PubMed1988

Chemotherapy v marrow transplantation for adults with acute nonlymphocytic leukemia: a five-year follow-up.

We previously published the results of a prospective comparison of continued chemotherapy or marrow transplantation for adults with acute nonlymphocytic leukemia (ANL) who had achieved a first remission. This report updates that study now that greater than 5 years have passed since the last patient was entered. Among 86 patients eligible for comparison, 43 had no donors and were treated with continued chemotherapy, 43 had donors, but 10 declined transplantation and 33 were transplanted. Five-year disease-free survivals are 21% for the chemotherapy group, 48% for the transplant group, and 10% for the group with matched siblings who declined transplantation.

Acute Disease↗
PubMed1987

Engraftment of DLA-nonidentical bone marrow facilitated by recipient treatment with anti-class II monoclonal antibody and methotrexate.

Marrow transplants were carried out between unrelated DLA-nonidentical dogs. Recipients were prepared for transplantation by 9.2 Gy single-dose total-body irradiation (TBI) administered at 7 cGy/min. All recipient dogs received marrow, 4 X 10(8) cells/kg, and no buffy coat cells. In addition to TBI, 19 dogs were given anti-class II monoclonal antibody (mAb) 7.2, either alone or combined with a second anti-class II mAb, HB10a, at doses of 0.2 or 0.4 mg/kg/day on days -5 to 0 or -1 to +3. Seven had hemopoietic engraftment. Ten dogs were given, in addition to TBI, methotrexate (MTX), 0.4 mg/kg/day on days 1, 3, 6, and 11 after grafting, and six had engraftment. Ten dogs were given a combination of mAb 7.2 pregrafting and MTX after grafting, and 9 had evidence of engraftment. Among 7 dogs treated with the irrelevant mAb 31E6.4, only one had engraftment. Thus the administration of anti-class II mAb pregrafting and MTX postgrafting had a beneficial effect in overcoming resistance to histoincompatible marrow grafts. Possibly this effect is more pronounced when both approaches are combined.

Animals↗
PubMed1987

Allogeneic bone marrow transplantation in irradiated adult rabbits.

In an effort to produce stable, long-term, complete hematopoietic chimerism in unrelated RLA-matched adult rabbits, the maximum dose of total-body irradiation (TBI) tolerated both with and without autologous marrow support was defined, and it was then determined whether the maximum tolerated dose was sufficiently immunosuppressive and myeloablative to allow engraftment of allogeneic marrow. Forty rabbits received TBI at 4.8 cGy/min at doses from 525-925 cGy. All rabbits receiving 525, 625, 725 and 825 cGy survived without marrow transplantation. At 875 cGy 50% of animals died and at 925 cGy all animals died within 96 hr of TBI. Survival was not changed with autologous marrow support, with all animals receiving 825 cGy surviving, while 50% survived at 875 cGy, and none at 925 cGy. Two RLA-matched, sex and immunoglobulin allotype-mismatched pairs were transplanted following 825 cGy and were given posttransplant cyclosporine. Both recipients survived beyond 200 days posttransplant, with cytogenetic and immunoglobulin allotype evidence of complete, or nearly complete, hematopoietic engraftment. Thus, stable, long-term complete chimerism can be achieved in adult RLA-matched unrelated rabbits prepared by TBI, and this animal model can be used for bone marrow transplantation studies.

Animals↗
PubMed1987

Facilitation of engraftment of DLA-nonidentical marrow by treatment of recipients with monoclonal antibody directed against marrow cells surviving radiation.

Past studies in dogs have suggested that marrow graft rejection was mediated by major histocompatibility complex (MHC) class II antigen-positive non-T cells that survived standard doses of total-body irradiation (TBI). We have now raised 4 monoclonal antibodies (mAbs) against marrow cells harvested 6 days after TBI. The mAbs are highly reactive (greater than 70%) with marrow cells surviving radiation and also bind strongly (greater than 50%) to normal marrow cells, lymphocytes, monocytes, and granulocytes. One of the mAbs (34-S3) reacted strongly with NK-like cells. In vitro treatment of marrow with mAb and rabbit complement (C') did not affect erythroid colony-forming unit (CFU-E) growth, whereas 2 of the 4 mAbs inhibited granulocyte-macrophage colony-forming unit (CFU-GM) growth, and all 3 mAbs tested suppressed autologous marrow engraftment. One of the mAbs, 69-S5 (IgG1), bound to a 95,000 dalton antigen. It crossreacted with human cells, but not with cells from Rhesus monkeys, baboons, and cats. We administered this mAb intravenously at 0.2 mg/kg/day on days -5 to 0 to dogs given 9.2 Gy TBI on day 0 followed by marrow grafts (less than or equal to 4 x 10(8) cells/kg) from DLA-nonidentical unrelated donors. Three of five dogs had sustained grafts. Increasing the dose of mAb ten-fold (2 mg/kg/day) resulted in graft failure (2 of 2 dogs). Treatment with a dose of 0.2 mg/kg/day from day -7 to -2 showed sustained engraftment in 7 of 10 dogs. This result is in contrast to sustained grafts in 3 of 36 dogs not given mAb, and in 1 of 7 dogs treated with an irrelevant mAb (P = 0.0002 and 0.04, respectively). We conclude that treatment of recipients with a mAb raised against marrow cells surviving radiation and not directed at major histocompatibility complex (MHC) class II antigens and NK-like cells can also facilitate engraftment of DLA-nonidentical canine marrow. These results may be relevant for the transplantation of HLA-incompatible marrow in man, particularly after in vivo T cell depletion, where graft failure is frequent.

Animals↗
PubMed1987

Does histologic grading of inflammation in bone marrow predict the response of aplastic anaemia patients to antithymocyte globulin therapy?

We tested the hypothesis of teVelde and Haak that the degree of bone marrow inflammation in aplastic anaemia might correlate with an immunological process responsive to immunosuppressive therapy. 120 patients with aplastic anaemia but no suitable marrow donor were treated with horse antithymocyte globulin (ATG) and 53 who had matched sibling donors with bone marrow transplants. Pretreatment bone marrow histology in methacrylate and paraffin specimens was graded by degree of inflammatory infiltrate in a four-tiered system. High grade (II-III) was compared to low (O-I) as a correlate of response to ATG. Complete and partial response to ATG was seen in 50% of patients with high grade marrow and 31% of patients with low grade marrow (P = 0.099). Only one of four patients with grade III inflammation responded significantly to ATG treatment. Median survival following ATG therapy was similar in both groups as well. There was a significantly lower median age in the patients with low grade (24.5 years) versus high grade (37.5 years) inflammation (P = 0.016). Grade also had no prognostic value in the marrow transplant group.

Adolescent↗
PubMed1987

The detection of bone marrow involvement by lymphoma using magnetic resonance imaging.

We used magnetic resonance (MR) to image the bone marrow of 31 patients with lymphoma. Images were obtained of the femoral, pelvic, and vertebral marrow with a 0.15 tesla imaging system using a T1-weighted spin echo sequence (TR600/TE 40). With this pulse sequence, normal marrow produces a high intensity signal that reflects the presence of marrow fat (short T1 relaxation time). We previously reported MR imaging of patients with leukemia in relapse and found a diffusely and symmetrically decreased marrow signal intensity due to the replacement of normal marrow fat by cellular material with a long T1. Unlike leukemia, patients with lymphomatous marrow involvement often had patchy, often discrete, areas of low signal intensity, representing focal marrow infiltration. Five of six patients in this study with lymphoma detected by histologic examination also had marrow lesions seen on MR. An additional four patients had marrow lesions detected by MR that were not detected on initial marrow biopsies; two of these had marrow involvement proven on subsequent biopsies, one had disease isolated to the vertebrae that was never pathologically documented, and one had progression of disease in the marrow documented by MR without biopsy confirmation. These results indicate that marrow involvement with lymphoma can be detected by MR imaging and that MR can complement bone marrow biopsy.

Adult↗
PubMed1987

Marrow transplantation for acute nonlymphocytic leukemia following therapy for Hodgkin's disease.

Seven patients with acute nonlymphocytic leukemia (ANL) following therapy for Hodgkin's disease (HD) were treated with cyclophosphamide (Cy) alone or combined with 10.00 to 15.75 Gy total body irradiation (TBI) and marrow transplantation. Five patients were transplanted without an attempt at prior remission induction, one patient following failure of remission induction and one patient in first remission following successful induction. Four patients died of multiorgan failure, 15 to 70 days after transplant. Three patients died of progressive or recurrent leukemia 56, 120, and 280 days after transplant. These results illustrate the difficulty of treating patients for secondary leukemia with marrow transplantation and suggest that transplantation in the preleukemic phase should be studied.

Acute Disease↗
PubMed1987

Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide.

In order to test the toxicity and efficacy of intensive postremission therapy with high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide in adults with acute nonlymphocytic leukemia (ANL), 100 adults (ages 19 to 75) with previously untreated ANL were entered into a study using six sequential cycles of chemotherapy. Cycles 1 (induction), 3, and 5 included conventional doses of daunomycin, cytosine arabinoside, 6-thioguanine, vincristine (VCR), and prednisone. Cycle 2 was cytosine arabinoside 3 g/m2 intravenously (IV) every 12 hours for four doses, followed by L-asparaginase 10,000 U intramuscularly (IM) at hour 42; this combination was repeated 1 week later. Cycle 4 included amsacrine 120 mg/m2/d and etoposide 100 mg/m2/d, both IV for five days, and cycle 6 was three monthly courses of VCR on day 1, and prednisone, mercaptopurine, and methotrexate each for five days. Seventy-four patients (74%) achieved complete remission (CR) (51 with cycle 1 and 23 after cycle 2). The overall disease-free survival (DFS) for patients achieving CR is 27% at 3 years by Kaplan-Meier analysis, while for patients achieving CR with cycle 1 it is 34%. The actuarial probability of being free from relapse at 3 years for patients achieving CR is 34%. Sixteen of the 74 CR patients (22%) died in CR while continuing to receive intensive chemotherapy, including 12 (18%) who succumbed to infection (nine bacterial, three fungal). After a median follow-up of 20 months, 36 patients have relapsed and 21 remain alive in CR. Intensive consolidation with high-dose cytosine arabinoside, amsacrine, and etoposide can modestly prolong DFS compared with historical controls. However, relapse continued to be a major problem and, in addition, with more aggressive consolidation therapy, infection during marrow aplasia resulted in a significant number of deaths.

Acute Disease↗
PubMed1987

Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation.

Between July 1970 and January 1985, 100 patients with malignant lymphoma were treated with high-dose chemoradiotherapy and bone marrow transplantation. Twenty-eight of the 100 are alive and the actuarial probability of disease-free survival 5 years from transplantation is 22%. The most common reason for treatment failure was disease recurrence, with an actuarial probability of 60%. A proportional hazards regression analysis showed that the likelihood of disease-free survival was less in those patients transplanted in resistant relapse and in those previously treated with chest radiotherapy. Neither disease histology (Hodgkin's disease, high-grade lymphoma or intermediate-grade lymphoma), nor source of marrow (syngeneic, allogeneic, or autologous) significantly influenced either disease-free survival or probability of relapse. The use of high-dose chemoradiotherapy and marrow transplantation appears to offer a better chance for long-term survival than any other form of therapy for young patients with disseminated malignant lymphoma whose disease has progressed after initial combination chemotherapy. The best results with marrow transplantation were obtained in patients transplanted in early relapse or second remission who had not received prior chest radiotherapy.

Adolescent↗
PubMed1987

Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation.

STUDY OBJECTIVE: To determine the efficacy of prophylactic interferon for prevention of cytomegalovirus infection and relapse of leukemia after allogeneic marrow transplantation. DESIGN: Randomized trial with intermittent interferon administration to day 80 after transplantation. SETTING: Marrow transplantation units of a cancer research center. PATIENTS: Consecutive patients with acute lymphocytic leukemia in remission at the time of transplantation. Thirty-nine patients received interferon, and 40 were control patients. INTERVENTIONS: Partially purified human leukocyte interferon given every 3 days beginning after marrow engraftment and continuing to day 80 after transplantation. After initial safety testing, the starting and minimum dose was 6 X 10(4) units/kg of body weight, with dose escalations determined by the circulating neutrophil count. Transplant conditioning and post-transplantation prophylaxis of graft-versus-host disease with methotrexate followed standard procedures. MEASUREMENTS AND MAIN RESULTS: No difference was observed in the probability or severity of cytomegalovirus infection or in the probability or severity of graft-versus-host disease. Relapse of leukemia occurred in 9 interferon recipients and 21 control patients, with a minimum follow-up of 4 years among surviving patients. The probability of relapse among all interferon recipients was 0.36 (95% confidence interval [Cl], 0.56 to 0.17) and among all control patients was 0.74 (95% Cl, 0.91 to 0.58) (p = 0.04 by log-rank test). Among patients who received transplants in first or second remission, the probability of relapse among interferon recipients was 0.19 (95% Cl, 0.37 to 0.02) compared with 0.71 (95% Cl, 0.97 to 0.51) among control patients (p = 0.008 by log-rank test). Survival rates did not differ between interferon recipients and control patients. Transient decreases in leukocyte count and anorexia and nausea occurred among interferon recipients. Six interferon recipients, all of whom had received chemoradiotherapy of the central nervous system before transplantation, developed leukoencephalopathy after transplantation. CONCLUSIONS: These data suggest that interferon given after transplantation reduces the risk for subsequent relapse of leukemia. The effect of longer administration and of administration in patients with other underlying diseases will require additional trials. No effect was observed on cytomegalovirus infection, either because interferon was not initiated until a median of 18 days after transplantation or because of a lesser effect among marrow allograft recipients.

Adolescent↗
PubMed1987

Management of the myelodysplastic syndromes.

It is important to make the correct diagnosis of MDS and to exclude very carefully all other disorders that may induce dysplastic features in the bone marrow. In patients without excess of bone marrow blasts, cytogenetics and in vitro bone marrow cultures may aid in making the correct diagnosis. MDS patients without excess of bone marrow blasts or symptomatic cytopenia or cytogenetic abnormalities associated with poor prognosis should be followed on a regular basis with sequential examinations of blood counts and bone marrow specimens. In the absence of obvious disease progression, ie, increasing cytopenia or increasing percentage of marrow blasts, patients should only receive supportive care. An increase in RBC requirements alone is insufficient reason to start cytotoxic therapy. Once progression of the disease has been well documented, cytotoxic treatment is indicated. There is no reason to delay treatment until these patients have progressed to overt AML. In patients over the age of 50, the best available therapy is low-dose cytarabine with a 30% probability of a good response; this therapy requires careful supervision and the availability of intensive supportive care. In patients under 50 years with progressive disease, or with clear evidence of a poor prognosis, allogeneic BMT is the therapy of choice if a HLA-identical sibling can be identified. In those patients who lack a HLA-identical sibling, intensive combination therapy is the treatment of choice and should preferably include high-dose cytarabine. Intensive consolidation therapy will be necessary for a durable remission. Trials with inducers of differentiation remain experimental. Results to date have been disappointing.

Bone Marrow Transplantation↗
PubMed1987

Venocclusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation.

We determined the incidence of venocclusive disease of the liver (VOD) in 96 recipients of autologous bone marrow transplants (BMT) to be 9.4%, a figure less than that reported for allogeneic transplantation. The development of VOD was compared in a cohort of 21 autologous BMT recipients and in 56 randomly chosen, comparably conditioned, concurrent allogeneic BMT recipients. One of these 21 (4.8%) autologous recipients developed VOD, versus 14 of 56 (25%) allogeneic recipients (P less than 0.05). Logistic regression analysis confirmed pretransplant hepatocellular dysfunction as a risk factor for VOD, and suggested that the use of methotrexate and/or cyclosporine contributes to the development of VOD after chemoradiation therapy. However, a graft-versus-host reaction cannot be excluded as a cause of the higher incidence of VOD in allogeneic recipients.

Adolescent↗
PubMed1987

Second marrow transplants in patients with aplastic anemia rejecting the first graft: use of a conditioning regimen including cyclophosphamide and antithymocyte globulin.

Sixteen (11%) of 146 consecutive patients with severe aplastic anemia prepared for engraftment with cyclophosphamide (200 mg/kg) rejected marrow grafts from their HLA-identical siblings. They were given a second marrow transplant from either the same (n = 13) or a second (n = 3) HLA-identical sibling between 23 and 743 (median 86) days after the first transplant. The preparation for the second transplant included cyclophosphamide, 50 mg/kg, on each of four successive days. Twelve hours after each of the first three doses of cyclophosphamide, antithymocyte globulin, 30 mg/kg/dose, was infused. One of the 16 patients died from infection too early after the second transplant to be evaluated, two had failure of engraftment and died with infection, one rejected the second graft and is surviving almost 5 years later with full autologous marrow recovery, and 12 had successful and sustained second grafts. Of these 12, six are surviving between 11 months and 7 3/4 years. Four of the six have no graft-v-host disease (GVHD), while two have chronic GVHD requiring treatment. Five have Karnofsky scores of 100% and one of 90%. Six of the 12 patients with sustained grafts died between 63 days and 38 months after transplantation, four with infections (related in two patients to chronic GVHD), one with acute GVHD, and one with hemorrhage. The average interval from first to second transplant was 308 days during the past five years, compared to 61 days in earlier patients. Five of seven recent patients are surviving, compared to two of nine earlier patients. In conclusion, successful second transplants after cyclophosphamide and antithymocyte globulin are possible in most patients with aplastic anemia who have rejected their first marrow grafts; however, mortality remains high, with only 40% of the patients becoming long-term survivors.

Adolescent↗
PubMed1987

Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia.

Between June 1981 and August 1986, 183 patients with the referring diagnosis of aplastic anemia were evaluated with cytogenetic studies and marrow biopsies. Seven patients (4%) on biopsy were found to have myelodysplasia. Seven of the 176 patients (4%) with marrow biopsies that confirmed the pathologic diagnosis of severe aplastic anemia were found to have clonal cytogenetic abnormalities in unstimulated marrow samples. Among the 169 patients with typical aplastic anemia and no cytogenetic abnormalities, 5 (3%) subsequently developed either myelodysplasia or leukemia. Two of three patients with pathologically confirmed aplastic anemia and clonal cytogenetic abnormalities, who were not transplanted, developed myelodysplasia. These results demonstrate that approximately 4% of patients with aplastic anemia have clonal cytogenetic abnormalities of marrow cells, and that while all patients with aplastic anemia may have some risk of developing leukemia, those with a cytogenetic abnormality have an especially high risk.

Adolescent↗