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Biomedical subjects

F Appelbaum

Publications and source records attributed to F Appelbaum.

At least 55 records · Page 3Linked to original sources
PubMed1989

Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial.

Patients with acute nonlymphoblastic leukemia (ANL) in first remission (n = 38) or chronic myelocytic leukemia (CML) (n = 55) were given cyclophosphamide and total body irradiation, followed by marrow infusion from HLA-identical siblings. To evaluate postgrafting prophylaxis for acute graft-versus-host disease (GVHD), the patients were randomized to receive either methotrexate and cyclosporine (n = 43) or cyclosporine alone (n = 50). Methotrexate/cyclosporine significantly reduced the incidence and severity of acute GVHD, and improved early survival. This report updates the results with a 3.0 to 4.5 year follow-up. Methotrexate/cyclosporine did not interfere with sustained hematopoietic engraftment, although granulocyte recovery to 1,000/microL was delayed by five days on the average. The incidence of chronic GVHD was identical in the two groups (26% v 24%). Disease-free 3-year survival was slightly better in the methotrexate/cyclosporine group (65% v 54%), but this benefit was restricted to patients with CML (73% v 54%), while no improvement was seen in patients with ANL (41% v 41%). In contrast to patients with CML (relapse rates 8% v 9%), the early survival benefit among patients with ANL given methotrexate/cyclosporine was offset by an increase in leukemic relapses (29% v 16%).

Acute Disease↗
PubMed1989

Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial.

Forty-six patients with aplastic anaemia (median age 23 years) were given cyclophosphamide followed by infusion of marrow from an HLA-identical family member. To evaluate postgrafting prophylaxis for graft-versus-host disease (GVHD), the patients were entered into a randomized prospective trial comparing a combination of methotrexate and cyclosporin (n = 22) to methotrexate alone (n = 24). Methotrexate/cyclosporin significantly reduced the incidence and severity of acute GVHD and improved early survival. This report updates the results of the randomized trial with followup ranging from 3 to more than 6 years. The methotrexate/cyclosporin regimen did not interfere with sustained engraftment, and there were no significant differences in the incidence of early or late graft rejection among the two treatment groups (10% v 4%). The incidence of chronic GVHD was higher among methotrexate/cyclosporin-treated patients (58% v 36%; P = 0.18). Two patients in each treatment group still require treatment for chronic GVHD, while treatment is no longer needed in the other patients. Projected 4-year survival is 73% in patients given methotrexate/cyclosporin compared to 58% in patients given methotrexate alone (P = 0.16). Having achieved a reduction in the incidence of acute GVHD and associated early mortality without impairing engraftment, it is clear that future progress in marrow grafting for aplastic anaemia must come in the area of chronic GVHD.

Adolescent↗
PubMed1989

Specific marrow localization of an 131I-labeled anti-myeloid antibody in normal dogs: effects of a "cold" antibody pretreatment dose on marrow localization.

Tumor recurrence and regimen-related toxicity remain major obstacles in the successful use of marrow transplantation as therapy for hematologic malignancies. By attaching radionuclides to monoclonal antibodies (MoAbs) targeted at myeloid-associated antigenic determinants, a more effective and directed delivery of therapy may be possible without increasing toxicity. We investigated the biodistribution over time of an anti-myeloid antibody (DM-5) labeled with trace amounts of 131I in normal dogs. This study demonstrates the ability to target marrow with a high degree of selectivity, achieving marrow/blood ratios of 25-30:1 with the greatest concentration in any other organ being a tissue/blood ratio of 1.4:1 for stomach at 48 h. A pretreatment dose of unlabeled antibody effectively reduced early hepatic uptake by 80%, resulting in improved marrow localization with an estimated 58.6% of the injected dose localized in marrow within 2 h following infusion, compared to 32.8% without pretreatment. The marrow concentration clearance curve for the radioimmunoconjugate revealed an initial short half-life (4.75 h), suggesting rapid internalization, digestion, and release of free iodine (dehalogenation). This view was supported by a corresponding rise in trichloroacetic acid-non-precipitable activity during this period. Methods aimed at decreasing dehalogenation may result in longer residence time of the radionuclide within the marrow space, resulting in more effective tumor cell kill. This approach may provide a way to improve upon the current results obtained with marrow transplantation as treatment for patients with leukemia and other hematologic malignancies.

Animals↗
PubMed1988

A prospective randomized trial of HLA-matched versus mismatched single-donor platelet transfusions in cancer patients.

The use of histocompatability antigen (HLA)-matched platelets has been advocated for the support of thrombocytopenic cancer patients. We randomized 78 newly diagnosed cancer patients prospectively (before thrombocytopenia) to receive either HLA-matched or mismatched single-donor platelet transfusions. Three hundred forty-one platelet transfusions were given for 80 separate episodes of therapy-induced thrombocytopenia in 33 patients. Forty-five patients receiving intensive chemotherapy did not develop significant (less than 20,000 platelets/mm3) thrombocytopenia and did not receive a platelet transfusion. No marked difference was observed between the matched and mismatched groups in regard to number of total platelet transfusions per patient (median, 3 vs. 5, respectively; P = 0.076), number of platelet transfusions per episode (median, 3.0 vs. 3.5, respectively; P = 0.28), or days between transfusions (median, 2 vs. 2, respectively, P greater than 0.4). Bleeding episodes, although rare, tended to be of increased severity in the mismatched group. Febrile patients receiving mismatched platelets tended to have a lower posttransfusion increment increase than their nonfebrile counterparts (P = 0.068), although a similar trend could not be demonstrated between febrile and nonfebrile patients who received matched platelets (P = 0.22). Patients treated as outpatients had significantly higher posttransfusion increments than when transfused as inpatients when they were given mismatched platelets (P less than 0.0005). Development of antiplatelet antibody did not appear to affect response to platelet transfusions. Only one patient developed sustained high-level antibody titers. In patients where thrombocytopenia was significant, the transfusion of HLA-matched platelets did not appear to offer a significant advantage. However, HLA-matched platelet transfusions tended to be associated with higher posttransfusion increments in febrile patients and a trend toward fewer severe bleeding episodes. A multi-institution trial containing a large number of patients is needed to evaluate trends observed in this study.

Adolescent↗
PubMed1988

Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size, and fractionation interval on acute and delayed toxicity.

Dogs were given single dose or fractionated total body irradiation (TBI) and autologous marrow grafts to prevent death from myelosuppression. Acute and delayed non-marrow toxicities were compared. Fifty-six dogs were given single dose TBI at 2.1 (n = 13), 5 (n = 12), 10 (n = 15), or 20 (n = 16) cGy/min. Acute radiation toxicity and mortality was related to the exposure rate; radiation doses resulting in 50% mortality at 7 days (LD 50/7) at 2.1, 5, 10 and 20 cGy/min were 1,692, 1,499, 1,261, and 1,056 cGy respectively. Fifty-three dogs were given fractionated TBI, 200 cGy three times a day with 6-hour intervals at 2.1 (n = 13), 5 (n = 9), 10 (n = 13), or 20 (n = 18) cGy/min. The LD 50/7 at the four exposure rates were 1,628, 1,470, 1,184, and 1,320 respectively. Thus, for exposure rates of 2.1, 5, and 10 cGy/min, the tolerated doses were comparable for single dose and fractionated TBI. At 20 cGy/min dose fractionation appeared to offer some advantage, although this fractionation effect in part may have been due to random variation with small numbers of dog treated. Following recovery from the immediate TBI-related toxicity, eight dogs given single dose and four dogs given fractionated TBI died, generally from infections, 8-30 days following transplantation. There was a striking difference in regards to long-term survival dependent upon the TBI regimen. Among dogs given greater than or equal to 1,000 cGy of TBI and alive 30 days after transplant only 1 of 18 given single dose TBI became a long-term survivor compared to 19 of 22 given fractionated TBI. Causes of death included pancreatic fibrosis, malnutrition, hepatic failure, and a generalized wasting syndrome. All 5 dogs given a single dose of 800 cGy (at 20 cGy/min) became long-term survivors. Fourteen dogs were given increments of 150 cGy at 7 cGy/min every 3 hours for total doses of 1,500-2,400 cGy. The LD 50/7 was approximately 1,900 cGy. All 6 dogs alive at 30 days became healthy long-term survivors. Four dogs were given increments of 600 cGy at 2.1 cGy/min every 48 hours for a total dose of 1,800 cGy. All 4 dogs became long-term survivors. In conclusion, exposure rate and total dose are the most important parameters for acute toxicity associated with TBI. The effect of dose fractionation is minimal at low exposure rates and appears to be dependent also upon increment size and fractionation interval.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
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

Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials.

One hundred seventy-nine patients with acute nonlymphoblastic leukemia in first remission (n = 75), chronic myelocytic leukemia in chronic or accelerated phase (n = 48) or leukemia in advanced stage (n = 56) were given HLA-identical marrow grafts and randomized to receive methotrexate or cyclosporine for prevention of graft-v-host disease (GVHD). The current report updates the three prospective trials with follow-ups ranging from 3.2 to 6.2 years after marrow grafting. Results were analyzed separately for each individual study and for all three studies combined. Overall, 40% of patients given cyclosporine and 55% of those given methotrexate developed acute GVHD (P = .13); the incidence of chronic GVHD was 42% and 48%, respectively (P = .67). Twenty-two percent of cyclosporine-treated patients and 30% of methotrexate-treated patients developed interstitial pneumonia of any etiology (P = .25), and the figures for cytomegalovirus pneumonia were 18% and 20%, respectively (P = .41). The overall incidence of leukemic relapse was 31% in cyclosporine-treated patients and 36% in methotrexate-treated patients (P = .75). The probabilities of survival for cyclosporine-v methotrexate-treated patients were comparable for all three study groups: 52% v 48% in patients with acute nonlymphoblastic leukemia (P = .42), 55% v 60% for those with chronic myelocytic leukemia (P = .61), 12% and 12% for those with advanced leukemia (P = .93), and 39% v 38% overall (P = .72). We conclude that cyclosporine and methotrexate are comparable regarding the likelihood of acute/chronic GVHD, interstitial pneumonia, leukemic relapse, and long-term survival.

Acute Disease↗
PubMed1988

Phenotypic characterization of canine lymphoma, using monoclonal antibodies and a microlymphocytotoxicity assay.

Cells acquired from lymph node biopsy specimens obtained from 58 dogs scheduled to undergo chemotherapy for lymphoma were immunophenotyped, using a microlymphocytotoxicity (MLCT) assay comprising a panel of well-characterized monoclonal antibodies (MAB) specific for canine cell surface antigens. Cells from 54 of the dogs concurrently were tested cytofluorometrically, using surface immunoglobulin (SIg) as a marker for B cells and the MAB DT2 specific for peripheral blood T cells. The MLCT results indicated frequent coexpression of antigens identified by DT2 antibody and, to a lesser extent, by 1A1 antibody on SIg-positive cells, suggesting that these antigens may be associated with other types of less-differentiated lymphoid cells, in addition to being associated with mature T cells. Class-II major histocompatibility antigens, as recognized by MAB H81.98.71, HB10a, and H40.315.7, were detected on most SIg-positive cells, but generally were lacking on SIg-negative, DT2-negative cells. The MAB Wig4, reactive with canine monocytes, recognized relatively few cells (11 of 58). Response to chemotherapy was not correlated with reactivity to MAB DLy6 specific for resting lymphocytes or to MAB W3G10 specific for a polymorphic antigen associated with the canine major histocompatibility complex. The MLCT assay appears to be efficient, rapid, and inexpensive for immunophenotyping cells from lymphoma biopsy specimens.

Animals↗
PubMed1987

Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas.

Four patients with refractory malignant B cell lymphomas were treated with continuous intravenous (IV) infusions of murine monoclonal antibody (MoAb) 1F5 (anti-CD20) over five to ten days. Dose-dependent levels of free serum 1F5 were detected in all patients. Two patients had circulating tumor cells and in both cases 90% of malignant cells were eliminated from the blood stream within four hours of initiation of serotherapy. Antigenic modulation did not occur, and sustained reduction of circulating tumor cells was observed throughout the duration of the infusions. Serial bone marrow aspirations and lymph node biopsies were examined by immunoperoxidase and immunofluorescence techniques to ascertain MoAb penetration into extravascular sites. High doses (100 to 800 mg/m2/d and high serum 1F5 levels (13 to 190 micrograms/mL) were required to coat tumor cells in these compartments in contrast to the low doses that were adequate for depletion of circulating cells. Clinical response appeared to correlate with dose of MoAb administered with progressive disease (52 mg), stable disease (104 mg), minor response (1,032 mg), and partial response (2,380 mg) observed in consecutive patients. The patient treated with the highest 1F5 dose achieved a 90% reduction in evaluable lymph node disease, but the duration of this remission was brief (six weeks). This study demonstrates that high doses of 1F5 can be administered to patients with negligible toxicity by continuous infusion and that clinical responses can be obtained in patients given greater than 1 g of unmodified antibody over a ten-day period.

Adult↗
PubMed1986

Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.

We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.

Acute Disease↗
PubMed1986

Prevention of graft-versus-host disease by immunosuppressive agents after transplantation of DLA-nonidentical canine marrow.

Dogs given 9.2 Gy of total body irradiation (TBI) followed by hematopoietic grafts from DLA-nonidentical unrelated or littermate donors and no postgrafting immunosuppression all develop acute graft-versus host disease (GVHD) and die within 3 weeks of grafting. Over a period of 10 years, the present study evaluated various immunosuppressive drugs either alone or in combination and compared their effectiveness to that of methotrexate (MTX) in preventing acute GVHD and prolonging survival. Among the single agents tested, 6-mercaptopurine and azathioprine resulted in a slight but significant prolongation of survival compared to controls, but they were less effective than MTX. Procarbazine and cytosine arabinoside were ineffective. Drugs tested in combination included MTX, cyclophosphamide, 6-mercaptopurine, azathioprine, cyclosporin, procarbazine, prednisone and antithymocyte globulin. Drug combinations, while effective in delaying the onset of GVHD, were associated with hematopoietic and other toxicities, which made their use impractical. Administration of MTX twice weekly proved to be no better than once weekly administration. Prednisone administered for the first 4 days after grafting in addition to MTX resulted in a modest improvement in survival. High-dose MTX (200 mg/kg) followed by leukovorin rescue resulted in severe early toxicity, both gastrointestinal and hematopoietic; however, some of those dogs which survived the early postgrafting period became stable long-term survivors. Most single agents tested in the present study proved to be either ineffective or were inferior to MTX in their ability to prevent GVHD. None of the drug combinations tested was as effective as the one involving MTX/cyclosporin reported previously.

Acute Disease↗
PubMed1986

Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation.

Sixteen patients with leukemia in relapse or second to third remission, 5 to 27 years old (median, 17), were given cyclophosphamide (60 mg/kg X 2) and total body irradiation (2.25 Gy for each of seven days) followed by unmodified marrow grafts from HLA-identical siblings. Patients did not receive posttransplant immunosuppression and were followed a median of nine months (range, 5-17). Prompt engraftment was sustained in 12 patients with a median time of 16 days (range, 10 to 63) to achieve 500 neutrophils/mm3. One patient failed to engraft, one had delayed engraftment, and two had late poor graft function. All 15 with engraftment developed moderate to life-threatening graft-v-host disease (GVHD, eight grade II and seven grade III-IV). This syndrome was hyperacute (median onset eight days [range, 7 to 29] posttransplant) and manifest by severe skin disease (14 patients at stage 3 and one at stage 4), fever (ten patients), and liver (four patients, stage 3-4) or gut (four patients, stage 3-4) involvement. Serial tissue biopsies confirmed acute GVHD in 13 of 15 patients. Ten were treated with antithymocyte globulin and cyclosporine (four survive), and four with corticosteroids (two survive). Actuarial survival to 17 months was 37%. Causes of death included interstitial pneumonia (four), infection (three), graft failure (one), venocclusive disease (one), and relapse of leukemia (one). Age-matched controls receiving standard methotrexate after transplant had comparable relapse-free survival but only a 25% incidence of grade II-IV acute GVHD (P less than .0001). We conclude that deleting posttransplant immunosuppression is associated with frequent and severe hyperacute GVHD, infectious complications, and occasional poor graft function.

Acute Disease↗
PubMed1986

Adverse effect of severe marrow fibrosis on hematologic recovery after chemoradiotherapy and allogeneic bone marrow transplantation.

We reviewed the records and marrow biopsy specimens of 75 patients with leukemic, myelodysplastic, or myeloproliferative disorders to determine whether the presence of marrow fibrosis affected engraftment after allogeneic marrow transplantation. While 28 control patients without fibrosis achieved prompt engraftment, two of 32 patients (6%) with mild and five of 15 patients (33%) with severe fibrosis failed. The rate of myeloid recovery was significantly slower and the dependence on platelet and red blood cell transfusions was significantly longer in patients with severe fibrosis than in patients with no fibrosis. A finding of severe marrow fibrosis should therefore be taken into account when evaluating the risks and benefits of marrow transplantation.

Adolescent↗