Search PubMed⌕ Search

Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 343 records · Page 19Linked to original sources
PubMed1989

Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.

Adolescent↗
PubMed1989

Marrow transplantation for malignant plasma cell disorders: summary of the Seattle experience.

28 patients with plasma cell malignancies received marrow transplants from identical twins (N = 8), HLA-identical family members (N = 15), HLA partially-matched relatives (N = 3) or cryopreserved autologous marrow (N = 2). Treatment regimens included cyclophosphamide (CY) and total body irradiation (TBI) for 15 patients and busulphan (BU) and CY for 13 patients. 3 of 8 twins are alive, 2 without disease at 24 and 34 months, and 1 is alive and well at 116 months without evidence of disease except for at small residual monoclonal protein spike. 12 of the 18 allografted patients died of transplant-related causes and 2 died of progressive disease. 4 of 18 allograft recipients are alive; 2 are free of disease at 16 and 15 months, 1 is alive at 6 months without disease except for persistent monoclonal Kappa protein. 1 patient is alive with residual marrow involvement and a persistent IGA lambda monoclonal protein at 7 months. 1 of the 2 autograft recipients is alive 2 months after transplant and is not yet evaluable for tumor response and the other patient died early of transplant-related complications. Both CY + TBI and BU + CY resulted in remissions in patients with advanced plasma cell malignancies. However, the optimal treatment regimen and timing of transplantation remain to be determined.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Relapse of acute leukemia after marrow transplantation: natural history and results of subsequent therapy.

Of 455 acute nonlymphocytic leukemia (ANL) patients who underwent marrow transplantation, 95 (21%) relapsed a median of 6.5 months posttransplantation and 62 received further treatment. Twenty achieved remission. Success of therapy was related to the length of time from marrow transplant to relapse and to the use of cytarabine (Ara-C) and daunomycin. Aggressive chemotherapy for patients relapsing within 100 days of marrow transplant was associated with a high incidence of early death (six of 14 patients) and a low probability of remission (one of 14). Of 23 patients who relapsed in excess of 1 year from marrow transplant, 15 achieved a complete remission. The median disease-free survival is 6 months (range, 0.4 to 53+ months). Acute lymphocytic leukemia (ALL) recurred in 130 of 366 patients (36%), and 94 received further therapy. Fifty-two achieved a remission. Remissions were more common in late relapse patients (greater than 1 year from transplantation): 65% v 7% for those relapsing within 100 days from transplant (P less than .05). Testicular relapse occurred in 11 patients and was the sole site of relapse in seven. Three are alive and free of disease 58 to 109+ months after relapse. The median survival for the treated patients is 10.5 months (range, 5 to 109+ months). We propose that reinduction be attempted in all patients relapsing greater than 1 year from marrow transplantation. Ara-C and daunomycin should be employed in the treatment of ANL. The decision for treatment of patients relapsing earlier than 1 year should be made on an individual basis.

Adult↗
PubMed1989

Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission.

To test whether variables at diagnosis can identify patients with acute nonlymphoblastic leukemia (ANL) for whom bone marrow transplantation (BMT) is more likely to be of benefit and those for whom continued chemotherapy is a better approach, the association of 15 clinical and laboratory factors with outcome was investigated among 220 patients (ages 1 to 53 years) treated with cyclophosphamide and total body irradiation (TBI) followed by allogeneic BMT, and among 392 patients (ages 13 to 50) administered intensive chemotherapy. In the BMT group, female sex, younger age, the absence of hepatitis during induction, a larger percentage of circulating blasts, and a shorter duration of symptoms were associated with longer survival, whereas only female sex and younger age favorably influenced disease-free survival (DFS). In the chemotherapy group, younger age, lower WBC at diagnosis, a single successful induction course, and the absence of circulating promyelocytes were associated with longer survival, whereas only a lower WBC and a lower percentage of peripheral neutrophils were associated with longer DFS. Estimated regression coefficients for treatment-by-prognostic-factor interactions were used to characterize subgroups of patients in which one treatment or the other produced better outcomes. BMT and chemotherapy produced similar durations of survival in a subset of patients characterized by many or all of the following: older age, male sex, achievement of complete remission (CR) after one induction, and absence of circulating blast cells at presentation. These data suggest that, using pretreatment variables, subgroups of patients can be identified for whom either BMT or continued chemotherapy is most likely to be beneficial.

Adolescent↗
PubMed1989

Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody.

The biodistribution, toxicity, and therapeutic potential of anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 (131I) was evaluated in ten patients with advanced-, low- or intermediate-grade non-Hodgkin's lymphomas who failed conventional treatment. Sequential dosimetric studies were performed with escalating amounts of antibody MB-1 (0.5, 2.5, 10 mg/kg) trace-labeled with 5 to 10 mCi 131I. Serial tumor biopsies and gamma camera imaging showed that the 10 mg/kg MoAb dose yielded the best MoAb biodistribution in the ten patients studied. Biodistribution studies in the five patients with splenomegaly and tumor burdens greater than 1 kg indicated that not all tumor sites would receive more radiation than normal organs, and these patients were therefore not treated with high-dose radioimmunotherapy. The other five patients did not have splenomegaly and had tumor burdens less than 0.5 kg; all five patients in this group showed preferential localization and retention of MoAb at tumor sites. Four of these patients have been treated with 131I (232 to 608 mCi) conjugated to anti-CD37 MoAb MB-1, delivering 850 to 4,260 Gy to tumor sites. Each of these four patients attained a complete tumor remission (lasting 4, 6, 11+, and 8+ months). A fifth patient, whose tumor did not express the CD37 antigen, was treated with 131I-labeled anti-CD20 MoAb 1F5 and achieved a partial response. Myelosuppression occurred 3 to 5 weeks after treatment in all cases, but there were no other significant acute toxicities. Normal B cells were transiently depleted from the bloodstream, but immunoglobulin (Ig) levels were not affected, and no serious infections occurred. Two patients required reinfusion of previously stored autologous, purged bone marrow. Two patients developed asymptomatic hypothyroidism 1 year after therapy. The tolerable toxicity and encouraging efficacy warrant further dose escalation in this phase I trial.

Adult↗
PubMed1989

Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma.

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .008), and was more common in patients with advanced disease conditioned with cytarabine (Ara-C)/total body irradiation (TBI) versus those prepared with cyclophosphamide (CY)/TBI (P = .033). There was no significant difference in the incidence of grade 3 or 4 toxicity in autologous, histocompatibility locus antigen (HLA)-identical, or HLA-mismatched marrow recipients. Grade 3 or 4 RRT tended to be more common and 100-day survival worse in patients with a Karnofsky performance status of less than 90 (P = .063 and .0002, respectively). Patients receiving 20 Gy or more of mediastinal irradiation before coming to transplant had more idiopathic or cytomegalovirus (CMV) interstitial pneumonitis than those who received less than 20 Gy (30% v 9%, P = .027). The probability of survival decreased with the number of organs in which toxicity was observed (P = .0001). Severe or fatal toxicities directly related to the preparative regimen are a significant problem in the treatment of patients with advanced malignant lymphoma and can be reduced by carrying out transplantation earlier in the course of the disease.

Actuarial Analysis↗
PubMed1989

Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation.

This study was designed to test whether recombinant human G-CSF (rh G-CSF) affects hematopoiesis in normal dogs and, if so, to test the effects of G-CSF in dogs given otherwise lethal total body irradiation (TBI). Rh G-CSF given subcutaneously at 10 or 100 micrograms/kg/d for 14 days to two normal dogs increased peripheral blood neutrophils eight to tenfold and monocytes four to sixfold above controls. Lymphocyte counts remained unchanged at the lower dose and increased threefold at the higher dose of rh G-CSF. No significant changes were observed in eosinophil, platelet, reticulocyte, or hematocrit levels. After 2 weeks of treatment with rh G-CSF, bone marrow displayed myeloid hyperplasia and left-shifted granulocytopoiesis. After discontinuation of rh G-CSF, peripheral leukocyte counts returned to control levels within three days. Five dogs administered 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow infusion or growth factor, all developed profound pancytopenia and died between 17 and 23 days after TBI with infections secondary to marrow aplasia. Four of five dogs treated within two hours after 400 cGy TBI with 100 micrograms rh G-CSF/kg/d subcutaneously twice a day for 21 days showed complete and sustained endogenous hematopoietic recovery. In contrast, five dogs irradiated with 400 cGy TBI and treated with 100 micrograms rh G-CSF/kg/d starting on day 7 after TBI, all died between days 17 and 20 after TBI with infections secondary to marrow aplasia. Rh G-CSF, if administered shortly after irradiation, can reverse the otherwise lethal myelosuppressive effect of radiation exposure.

Animals↗
PubMed1989

The clinical use of hematopoietic growth factors.

Recombinant DNA technology has allowed for the production of large quantities of several hematopoietic growth factors as cloned gene products. Three of these factors--recombinant human erythropoietin (r-HuEPO), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF)--are currently undergoing clinical trials and appear to offer considerable promise for the treatment of a variety of hematopoietic abnormalities. Therapy with r-HuEPO can raise the hematocrit levels of patients with end-stage renal disease. Therapy with GM-CSF in patients undergoing marrow transplantation results in acceleration of granulocyte and platelet recovery by 1 to 2 weeks, leading to fewer infections and earlier discharge from the hospital. Other demonstrated uses of GM-CSF include treatment for aplastic anemia, myelodysplastic syndromes, chemotherapy-induced neutropenia, and neutropenia associated with the acquired immunodeficiency syndrome (AIDS). Similar beneficial effects have been reported with G-CSF. Other hematopoietic growth factors, including the interleukins (IL)-1, -3, and -6, will soon be entering clinical trials. For the first time, the availability of a large number of hematopoietic growth factors may allow physicians to regulate closely the entire hematopoietic system of their patients.

Clinical Trials as Topic↗
PubMed1989

Use of trimetrexate for the prevention of graft-versus-host disease.

The effects of trimetrexate following marrow transplantation were studied in a dog model. Four animals were given 9.2 Gy total body irradiation (TBI), autologous marrow, and either trimetrexate alone (0.4 mg/kg on days 1, 3, 6, and 11) or combined with cyclosporine (CSP) (15 mg/kg per day i.m. on days 1-7, then orally until day 25, then taper). All four animals engrafted normally, demonstrating that trimetrexate at this dose is tolerable. Ten additional animals were given a similar dose of TBI followed by marrow and buffy coat cells from littermate donors differing for one DLA haplotype. Trimetrexate and CSP were given as noted above. Four of the 10 animals died, one with septicemia prior to engraftment (day 14), one with intussusception (day 28), one with graft failure (day 32) and one with a tracheal abscess without graft-versus-host disease (GVHD) (day 67). Six dogs survived in excess of 100 days; one of the six developed chronic GVHD. These results are superior to those previously achieved with either methotrexate or CSP as single agents and are roughly equivalent to results achieved with a combination of methotrexate and CSP in similarly mismatched donor-recipient pairs.

Animals↗
PubMed1989

Engraftment in 86 with patients lymphoid malignancy after autologous marrow transplantation.

The kinetics of marrow engraftment was retrospectively analysed in 55 patients with malignant lymphoma (ML) and 31 patients with acute lymphoblastic leukemia (ALL) after marrow-ablative therapy followed by autologous bone marrow transplantation. Thirty-eight percent of patients with ML, most of whom were transplanted in relapse and 13% of patients with ALL, mostly transplanted in remission, showed failed or delayed engraftment. Analysis of the total patient group showed that failure to recover platelet counts was significantly correlated with detection of disease in the marrow early after transplantation (p less than 0.001). Platelet recovery was also correlated with survival (p = 0.0001), disease-free survival (p = 0.0001), and the probability of relapse (p = 0.02). In those patients achieving engraftment, multivariate regression analysis failed to reveal any single in vitro test of marrow nucleated cell or progenitor cell numbers that significantly influenced time to achieve recovery of either granulocyte or platelet counts.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Antibody-radionuclide conjugates as part of a myeloablative preparative regimen for marrow transplantation.

The behaviors of an anti-Ia antibody (7.2) and an antibody directed at a lymphocyte adhesion molecule (S.5) radiolabeled with 131I were studied in normal dogs. Antibody 7.2 localized to spleen and, to a lesser extent, to marrow and lymph nodes. Antibody S.5 rapidly localized to marrow and spleen, achieving tissue/blood ratios greater than 6:1 within three hours of injection that were maintained for at least 48 hours. Prior treatment with cyclophosphamide (CY) markedly altered the distribution of S.5 but had much less effect on the distribution of 7.2 and almost no effect on the distribution of a control antibody. When animals were treated with increasing doses of 131I labeled to S.5, lethal myelosuppression occurred when a dose of 6 mCi/kg was reached. At this dose, the otherwise lethal effects of 131I could be reversed with autologous marrow transplant support.

Animals↗
PubMed1989

Stimulation of canine hematopoiesis by recombinant human granulocyte-macrophage colony-stimulating factor.

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on canine hematopoiesis was evaluated. rhGM-CSF stimulated granulocyte-macrophage colony formation of canine marrow depleted of accessory cells up to tenfold. Stimulation of colony formation was abrogated by anti-rhGM-CSF antiserum or heat inactivation. rhGM-CSF also stimulated in vivo canine hematopoiesis both when given as continuous i.v. infusion and as intermittent s.c. injections. Neutrophil, monocyte, and lymphocyte counts were increased three- to eightfold above controls, whereas values for eosinophils, reticulocytes, and hematocrits were not changed. Bone marrow histology after 2 weeks of treatment with rhGM-CSF showed hypercellularity with myeloid hyperplasia and left-shifted granulocytopoiesis. After discontinuation of rhGM-CSF, peripheral leukocyte counts returned to control level within 3-7 days. Platelet counts decreased rapidly after starting rhGM-CSF, to 5000-15,000 platelets/mm3, and increased within 24 h after stopping rhGM-CSF treatment, whereas marrow histology after 2 weeks of rhGM-CSF application showed the normal number and morphology of megakaryocytes.

Animals↗
PubMed1989

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

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

Adolescent↗
PubMed1989

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

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

Adult↗