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Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 415 records · Page 23Linked to original sources
PubMed1986

Myasthenia gravis after allogeneic bone marrow transplantation: relationship to chronic graft-versus-host disease.

Three patients with chronic graft-versus-host disease (GVHD) developed myasthenia gravis (MG) 762 to 1,180 days after allogeneic bone marrow transplantation. Symptoms of MG were observed after taper or discontinuation of immunosuppressive treatment of chronic GVHD. All patients developed antibodies to acetylcholine receptor, and one had antibody formation to striated muscle. One patient died of complications of treatment of MG. The severity of disease underscores the importance of the differential diagnosis and the need for prompt therapy of this late complication after human bone marrow transplantation.

Acetylcholine↗
PubMed1986

Marrow transplantation for the treatment of chronic myelogenous leukemia.

One hundred ninety-eight patients with chronic myelogenous leukemia received marrow transplants after intensive chemotherapy and total body irradiation. Multivariate analysis showed disease status at time of transplantation to be the most powerful predictor of survival. The probability of long-term survival for allogeneic graft recipients was 49% for 67 patients in the first chronic phase, 58% for 12 in the second chronic phase, 15% for 46 in the accelerated phase, and 14% for 42 in the blastic phase. The major cause of death was interstitial pneumonia for patients in the chronic phase, and relapse for those in the blastic or accelerated phases. Factors favoring survival were early transplantation, age less than 30 years, and absence of severe graft-versus-host disease. Splenectomy or spleen size did not influence survival. For recipients of syngeneic grafts survival probability was 87% for 16 patients in the chronic phase, 27% for 7 in the accelerated phase, and 12% for 8 in the blastic phase. Of the 198 patients, 71 are alive without Philadelphia chromosomes 1 to 9 years after receiving their graft. All but 4 long-term disease-free survivors have Karnofsky performance scores of 80% or better.

Adult↗
PubMed1986

Marrow transplantation for severe aplastic anemia. Long-term outcome in fifty "untransfused" patients.

Fifty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. Of the 50, 42 are still alive 1 to 12 years after transplantation (median, 7 years). By actuarial standards, the 10-year probability of survival is 82%. Of the 42 surviving patients, 37 have Karnofsky performance status scores of 100% and 5 with chronic graft-versus-host disease have scores ranging from 50% to 90% (median, 80%). The 8 deaths were caused by early infection in 1, graft rejection in 1, acute graft-versus-host disease in 3, and chronic graft-versus-host disease in 3. All deaths occurred within two years after transplantation. The incidence of graft failure was 10%. Acute graft-versus-host disease developed in 14 of 44 patients at risk and chronic graft-versus-host disease, in 15 of 41. Risk factors for development of chronic graft-versus-host disease included increased age (p = 0.008) and presence of acute graft-versus-host disease (p = 0.001). The only factor associated with increased risk of death was development of acute graft-versus-host disease (p = 0.05). Results of this study extend our previous finding that patients with severe aplastic anemia who have transplants before the onset of transfusion-induced sensitization have an excellent probability of long-term survival and a normal life.

Acute Disease↗
PubMed1986

Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation.

Seventy-five patients with acute nonlymphoblastic leukemia (ANL) in first remission were treated with cyclophosphamide, 60 mg/kg on each of two consecutive days followed by total body irradiation (TBI) at an exposure rate of 4-6 cGy/min from two opposing 60Co sources. The first 22 patients were given 9.2 Gy of TBI as a single dose. Subsequently 53 patients were randomized to receive either 10 Gy single dose TBI (n = 27) or 6 x 2 Gy fractionated TBI (n = 26). All patients received marrow transplants from HLA-identical siblings and all had sustained engraftment. Patients given 10 Gy of TBI had more early toxicity, especially veno-occlusive disease of the liver, than patients given 9.2 or 6 x 2 Gy of TBI. Idiopathic interstitial pneumonitis appeared to be more frequent in patients given 9.2 or 10 Gy single-dose TBI than in patients given 6 x 2 Gy fractionated TBI. Patients have now been followed from 5 to 9 years. Survival (+/- 95% confidence limits) at 5 years is 54 +/- 31% among patients given 9.2 Gy single dose TBI, 33 +/- 31% among patients given 10 Gy single dose TBI, and 54 +/- 26% among patients given 6 x 2 Gy fractionated TBI (P = 0.04). These results indicate that about half the patients with ANL transplanted while in first chemotherapy-induced remission can be expected to become long-term survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Ultraviolet irradiation of blood prevents transfusion-induced sensitization and marrow graft rejection in dogs.

In a canine model using DLA-identical littermate pairs, we have shown that a regimen of three transfusions of donor blood given 24, 17, and 10 days before transplant uniformly leads to marrow graft rejection, presumably due to sensitization to minor (non-DLA) histocompatibility antigens. Untransfused dogs uniformly achieve sustained engraftment. In the present study, we investigated whether the exposure of blood to ultraviolet (UV) light (220-300 nm) prior to transfusion prevented sensitization of the recipient and allowed for successful marrow engraftment. Ten dogs were each given three pretransplant transfusions from the marrow donor. Each transfusion consisted of 50 mL of whole blood exposed in vitro to UV light for a total of 1.35 J/cm2. All ten dogs achieved engraftment. In contrast, all four dogs that had received sham-exposed transfusions rejected their grafts. In vitro studies revealed that although cell viability was not affected, leukocytes contained in UV-exposed blood were unable to function as stimulator cells in mixed leukocyte cultures or as accessory cells in mitogen-stimulated cultures. These data are consistent with the hypothesis that accessory cells are involved in transfusion-induced sensitization. We conclude that in vitro exposure of blood to UV light before transfusion prevents sensitization and allows for subsequent marrow engraftment.

Animals↗
PubMed1986

Bone marrow transplantation experience for children with aplastic anemia.

From May 1971 through December 1981, 81 children (22 months to 17 years of age) received allogeneic bone marrow grafts for severe aplastic anemia. All donors were HLA-identical family members. Fifty-seven of the 81 (70%) are still alive. Twenty-three untransfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, and 19 (83%) have survived from 5 to 12 years. All 58 transfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, 11 received additional immunosuppression, and 19 received posttransplantation donor buffy coat cells. Thirty-eight (65%) have survived from 3 to 13 years (P = .1). In a multivariate analysis, the only factor significantly associated with increased survival among patients with sustained grafts was the absence of significant graft v host disease (P less than .0001). The factors significantly related to increased rejection were low bone marrow cell dose (P less than .05) and positive relative response in mixed leukocyte culture (P less than .0001), but the addition of buffy coat cells did not significantly influence graft rejection. The development of grades II to IV acute graft v host disease was associated with random donor platelet refractoriness (P less than .05) and donor/recipient sex differences (P less than .05). Patients at highest risk for chronic graft v host disease were those patients who developed significant acute graft v host disease (P less than .01) and who received buffy coat infusions (P less than .025). All patients who were untransfused had a negative relative response and were not refractory to random donor platelets.

Acute Disease↗
PubMed1986

Bone marrow transplantation in patients aged 45 years and older.

Increasing age has been reported to be a poor prognostic factor for survival after bone marrow transplantation. We evaluated causes of death and frequency and type of complications after marrow grafting in 24 syngeneic and 39 allogeneic recipients who were 45 to 68 years old at the time of transplant. Most patients were in an advanced stage of hematologic malignancy. Among patients given syngeneic transplants, actuarial disease-free survival at 7 years is 20%. The major causes of death were relapse of leukemia and idiopathic interstitial pneumonia. Among allogeneic recipients, 9 (23%) are currently alive, and actuarial disease-free survival at 7 years is 11%. Cytomegalovirus pneumonia and septicemia were the most frequent causes of death. Patients over 50 years of age had the poorest survival rate (1/13), but many of these were transplanted in an advanced stage of their disease. However, among 12 patients transplanted while in remission or at an early stage of their disease, 5 are surviving 65 to 1,160 days after transplantation, with an actuarial survival rate of 22% at 3 years. This is in contrast to those who received their transplant in relapse: 2 out of 20 patients (10%) became long-term survivors, with a probability of survival of 15% at 3 years. The actuarial incidence of grade II through IV acute graft-v-host disease (GVHD) was 30% for allogeneic recipients 45 to 50 years of age. This was not significantly different from the incidence in younger patients. In patients 51 to 62 years of age, the actuarial incidence of acute GVHD was 79%; however, this group included three partially HLA-mismatched transplants. Ten of 15 patients surviving at least 3 months developed chronic GVHD. These results suggest that marrow transplantation is feasible and should be considered in patients over 45 years, especially if recipients are in good clinical condition and are at an early stage of their disease, such as the chronic phase of chronic myelogenous leukemia and preleukemia. For patients more than 50 years of age, allogeneic marrow grafting cannot presently be considered first-line therapy.

Adult↗
PubMed1986

Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease.

Ninety-six patients with severe aplastic anemia who received a sex-mismatched, HLA-identical allogeneic sibling marrow transplant had sequential cytogenetic analyses performed to determine the incidence and implications of posttransplant mixed hematologic chimerism. Of the 96 patients, 56 (58.3%) became mixed chimeras with coexisting host and donor cells detected in peripheral blood or marrow 14 days or later after transplant, and 40 patients (41.7%) were complete chimeras with 100% donor-type hematopoietic cells. The incidence of mixed chimerism was independent of prior blood production transfusions and infusion of donor buffy coat. The rejection rate was significantly increased in the mixed chimeric group, particularly in patients not receiving buffy coat (14 of 36 rejecting), although overall, the majority (69.7%) retained their first graft. Rejection was seen almost exclusively in patients exposed to multiple transfusions before transplantation. If patients who reject their first graft are censored, the overall incidence of grades II through IV acute graft-v-host disease (GVHD) was significantly reduced in those with mixed chimerism. Transfused patients with mixed chimerism in particular were less likely to develop grades II through IV acute GVHD. The incidence of chronic GVHD was similar in the two groups and did not significantly influence survival. In this study, mixed chimerism persisted for up to 395 days posttransplant, either the first graft being rejected or, more commonly, hematopoiesis reverting to 100% donor-type cells. Mixed lymphohematopoietic chimerism may persist in patients with aplastic anemia who have received matched allogeneic marrow transplants for significant periods before hematopoiesis reverts to donor cell type.

Adolescent↗
PubMed1986

Growth and development following marrow transplantation for leukemia.

One hundred forty-two patients between the ages of 1 and 17 years who survived disease-free more than 1 year after marrow transplantation for hematologic malignancy had growth and development evaluations from one to 14 years posttransplant (median 4 years). Prior to transplant all children received multiagent chemotherapy and 55 also received central nervous system irradiation, but none had growth and development evaluations. Marrow transplant preparation included high-dose chemotherapy and total body irradiation (TBI) given as a single dose of 9.2 to 10.0 Gy (79 patients) or as fractionated doses of 2.0 to 2.25 Gy/d for six to seven days (63 patients). After transplant abnormal thyroid function was present in 39%. Stimulated 11-desoxycortisol levels were subnormal in 24% of patients evaluated. Growth hormone (GH) deficiency was present in 17 of 25 children who received previous cranial irradiation. Partial GH deficiency was present in 4 of 25 who received previous cranial irradiation and in 6 of 18 who had not received cranial irradiation. Height velocity was decreased in all patients. After transplant, height was significantly influenced by chronic graft-v-host disease and single-dose TBI. Sixty-eight percent had delayed development of secondary sexual characteristics. Gonadal failure occurred in nearly all who were postpubertal at transplant. While it is not possible to determine how many of these endocrine abnormalities occurred as a result of treatment administered prior to transplantation, these data do demonstrate that children who become long-term survivors after marrow transplantation for hematologic malignancy have endocrine abnormalities that adversely affect growth and development.

Adrenal Cortex↗
PubMed1986

Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors.

Patients with severe aplastic anemia were conditioned with cyclophosphamide (200 mg/kg) and given marrow grafts from HLA-identical family members. Among 233 patients transplanted, 225 survived greater than or equal to 14 days and could be evaluated for engraftment. Forty-four of the 225 rejected their graft; 33 of these died and 11 survive. One hundred eighty-one patients had sustained engraftment; of these, 46 died and 135 survived. Binary logistic regression analyses revealed five risk factors for graft rejection: year of transplant, a large number of platelet transfusions, a positive relative response in mixed leukocyte culture, a low marrow cell dose, and omission of donor buffy coat cell infusion for transfused patients. These data show that patients transplanted recently had a lower likelihood of graft rejection than did patients transplanted in earlier years. Conceivably, this was related to changes in transfusion practices, but other factors as yet unidentified are likely to be involved. The data confirm that the largest possible number of marrow cells should be transplanted. Although the difference in the incidence of graft rejection between untransfused and transfused patients was not significant, it should be noted that transfused patients were given buffy coat cells. Because the addition of buffy coat cells results in a higher incidence of chronic graft-v-host disease (GVHD), it is still desirable to transplant patients with marrow alone early in their course before they have been transfused.

Anemia, Aplastic↗
PubMed1985

Treatment of acute leukemia in adults with chemoradiotherapy and bone marrow transplantation.

The use of supralethal chemoradiotherapy followed by marrow transplantation has progressed from being an experimental approach applied only to a limited number of end-stage patients to an important therapeutic option appropriate for many adults with a variety of hematologic malignancies. With the use of transplantation, 10% to 30% of patients with relapsed leukemia and approximately 50% of patients with acute nonlymphoblastic leukemia in first remission can be cured. Cures have also been seen in a variety of other hematologic malignancies, including chronic granulocytic leukemia, preleukemia, hairy cell leukemia, and malignant lymphoma. Transplantation is currently limited by the need for a suitable marrow donor; by the complications of the transplant procedure, including infection, graft-versus-host disease, and the toxicities of intensive chemoradiotherapy; and by the risk of recurrent disease. Some of these limitations will likely be overcome as a result of current research. The use of partially matched family members and matched unrelated donors will make transplantation available to more patients. Some forms of posttransplant infection, including those associated with herpes simplex and cytomegalovirus, can now be prevented or treated. Improved methods of controlling graft-versus-host disease including T-cell depletion of marrow and the use of more effective immunosuppressive agents, as well as a better understanding of the toxicities of the preparative regimens, are making the transplant procedure safer and more tolerable. Finally, the development of better preparative regimens and transplantation earlier in the patient's disease course will likely allow for a larger percentage of patients to be cured.

Acute Disease↗
PubMed1985

Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graft-versus-host disease.

One hundred fourteen children with acute lymphoblastic leukemia were treated with allogeneic marrow transplantation from HLA-identical siblings after conditioning with cyclophosphamide and total body irradiation. Methotrexate was given posttransplantation for prophylaxis of graft-versus-host disease. The minimum follow-up after transplantation was 2 years. Sixteen of 51 patients transplanted in marrow remission survive from 2.1 to 8.9 years (median 2.7), 13 in continuous remission, one in remission following testicular relapse, and two after marrow relapse. Sixty-three were transplanted in relapse and eight survived 3-10 years (median 5.7), five in continuous remission, and three in remission following testicular relapse. In a multivariate analysis, factors significantly related to increased survival were marrow remission at transplant (p less than 0.007) and chronic graft-versus-host disease (p less than 0.005). Factors associated with increased relapse were marrow relapse at transplant (p less than 0.002) and absence of significant graft-versus-host disease (p less than 0.004). The development of acute graft-versus-host disease was associated with high marrow cell doses (p less than 0.04). These data suggest that some children with acute lymphoblastic leukemia and a poor prognosis with conventional chemotherapy may be cured with marrow transplantation.

Adolescent↗
PubMed1985

Treatment of acute graft-versus-host disease after allogeneic marrow transplantation. Randomized study comparing corticosteroids and cyclosporine.

Seventy-seven patients (age 12 to 46 years) who underwent allogeneic marrow transplantation for hematologic malignancy or aplastic anemia and who had grade II to IV acute graft-versus-host disease despite methotrexate prophylaxis were randomly assigned to receive methylprednisolone 2 mg/kg per day intravenously (n = 39) or cyclosporine (n = 38) either 12 to 15 mg/kg per day orally or 3 to 5 mg/kg per day intravenously. In both groups, clinical and histologic evidence of graft-versus-host disease was detected at medians of 16 and 25 days, respectively. Drugs were given for a minimum of 14 days unless significant deterioration occurred. If graft-versus-host disease did not improve with this therapy, treatment with a second agent was initiated. Treatment responses were scored after reviewing clinical and laboratory data collected before, during, and after the 14-day treatment period. Possible scores were as follows: -1, worse; 0, no change; + 1, improvement in one organ system (skin, liver, gut) with no deterioration in the other two; +2, complete resolution of all involved systems. The median response score among 39 methylprednisolone-treated patients was 0. Sixteen patients (41 percent) showed response to treatment, 11 with partial and five with complete response. The median response score among 38 cyclosporine-treated patients was +1. Twenty-three patients (61 percent) showed response to treatment, 15 with partial and eight with complete response (p = 0.039). Twenty patients receiving methylprednisolone and 18 receiving cyclosporine required additional therapy. The incidence of chronic graft-versus-host disease was similar in both groups. It developed in all nonresponding patients at risk who had received secondary therapy. Among responding patients (scores +1 or +2) who were not given additional treatment, chronic graft-versus-host disease developed in eight of 11 (72 percent) receiving methylprednisolone and five of ten (50 percent) receiving cyclosporine. Survival beyond 17 months was similar in the two groups (28 percent and 24 percent, respectively). These data suggest that cyclosporine is a useful agent for the treatment of acute graft-versus-host disease, comparable in its efficacy to methylprednisolone.

Acute Disease↗
PubMed1985

Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine.

Fifty-six patients, 30-47 yr of age, with leukemia in relapse received allogeneic marrow transplants from HLA-identical siblings. All patients were treated with cyclophosphamide (120 mg/kg) and 7 daily fractions of 2.25 Gy of total body irradiation (TBI) for seven consecutive days. Nine patients (16%) are currently alive and free of disease 324-845 days from transplantation. The actuarial relapse and survival rates at 2 yr were 56% and 9.5% respectively. These data were not remarkably different from those in previous studies using 10 Gy of TBI administered as a single dose. Thirty patients were randomized to receive methotrexate (MTX) and 26 to receive cyclosporine (CSP) as postgrafting prophylaxis for acute graft-versus-host disease (GVHD). The probability of developing significant acute GVHD by day 100 post-transplant was 71% for patients in the MTX group and 45% for patients in the CSP group (p less than 0.05). The probability of relapse was 37% for patients in the MTX group and 70% for patients in the CSP group (p less than 0.05). Transplant-related deaths were more frequent in the MTX group and leukemic deaths were more frequent in the CSP group although this may have been related to an uneven distribution of high-risk patients. Long-term disease-free survival was comparable. Patients in the MTX group had more severe mucositis, more alveolar pneumonias and possibly more deaths due to complications of acute and chronic GVHD. Patients in the CSP group had a higher incidence of hypertension, neurological complications and renal dysfunction.

Adult↗
PubMed1985

Marrow transplant studies in dogs with malignant lymphoma.

Ninety-five dogs with spontaneous malignant lymphoma in chemotherapy-induced remission were treated with total-body irradiation (TBI) and bone marrow transplantation. Among 38 dogs treated with 8.4 Gy delivered at 4 cGy/min, 9 (24%) became long-term disease-free survivors. Ten of the 38 (26%) died of transplant-related complications and the actuarial relapse rate was approximately 65%. Forty animals were treated with higher-dose TBI (13.5 Gy). The higher-dose TBI led to an increased incidence of transplant-related deaths (55% vs. 26%) and did not reduce the actuarial relapse rate. Eight animals were treated with 8.4 Gy at 4 cGy/min, allogeneic marrow from unrelated donors, and posttransplant immunosuppression with methotrexate and cyclosporine. Of 8 animals, 6 died within 2 weeks of transplant of infection and 2 died later of graft-versus-host disease. Finally, 9 dogs were treated with 8.4 Gy at 4 cGy/min, autologous marrow, and posttransplant methotrexate and cyclosporine. Six of these animals died within 2 weeks of transplant. These studies thus demonstrated that dogs with malignant lymphoma in remission can be cured with high-dose TBI and autologous marrow transplantation, that increasing the total dose of TBI led to increased toxicity without a decrease in the relapse rate, and that post-transplant therapy with methotrexate and cyclosporine was poorly tolerated in these animals.

Animals↗
PubMed1985

Treatment of human acute graft-versus-host disease with antithymocyte globulin and cyclosporine with or without methylprednisolone.

Forty-eight patients with hematologic malignancies treated by allogeneic marrow transplantation developed acute graft-versus-host disease (GVHD), grades II-IV, despite prophylaxis with methotrexate. They were treated with a combination of antithymocyte globulin (ATG) and cyclosporine (CsA), with or without the addition of methylprednisolone (MP). Thirty patients had received HLA-identical and 18 HLA-nonidentical transplants. Median onset of GVHD was day 13 (range 8-60) for patients with HLA-nonidentical grafts and day 18 (range 7-48) for patients given HLA-identical grafts (P = 0.01). Forty-five patients could be evaluated for response on day 7 of therapy. Among these, 13 of 27 given ATG/CSP and 6 of 18 given ATG/CSP/MP improved. Among 33 patients evaluable on day 14 of therapy 13 of 19 given ATG/CSP and 5 of 14 given ATG/CSP/MP showed improvement of GVHD. Patients given HLA-nonidentical grafts responded somewhat (although not significantly) less frequently than patients given HLA-identical grafts. Chronic GVHD developed in 16 of 18 evaluable patients given ATG/CSP and in 5 of 6 given ATG/CSP/MP. Viral, bacterial, and fungal infections were the major cause of death in both groups. Interstitial pneumonitis was more frequent among patients given ATG/CSP/MP. Survival beyond 6 months was 67% among patients treated with ATG/CSP and 25% with ATG/CSP/MP. These data indicate that a regimen of ATG/CSP is of value in the treatment of acute GVHD. The addition of MP was not beneficial and resulted in decreased survival--presumably because of excessive immunosuppression and associated complications.

Adolescent↗
PubMed1985

Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin's disease.

Eight patients with disseminated Hodgkin's disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy were treated with high-dose chemoradiotherapy and marrow transplantation from an HLA-identical sibling. Two patients remain alive in unmaintained complete remission (CR) at 38 and 39 months after transplant. In the other six patients, reasons for failure included relapse of lymphoma (two patients), or death due to complications of the transplant procedure, including Legionnaire's disease, disseminated zoster, graft-v-host disease, and aspiration pneumonia secondary to severe mucositis. These results demonstrate that some patients with MOPP-resistant Hodgkin's disease can obtain prolonged CR following intensive chemoradiotherapy and allogeneic marrow transplantation.

Adult↗