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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 127 records · Page 7Linked to original sources
PubMed1997

Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Transplantation of marrow from unrelated donors was investigated in patients with Philadelphia chromosome-positive (Ph1+) acute lymphoblastic leukemia (ALL) who lacked a suitable family donor. Eighteen patients underwent transplantation at our center between 1988 and 1995. The median patient age was 25 years (range, 1.7 to 51 years). Seven patients were in first complete remission, 1 in second remission, 3 in first relapse, and the remaining 7 had more advanced or chemotherapy refractory leukemia at transplant. All patients were conditioned with cyclophosphamide and total body irradiation followed by marrow transplants from closely HLA-matched, unrelated volunteers. Posttransplant graft-versus-host disease (GVHD) prophylaxis included methotrexate with either cyclosporine or FK506. Graft failure was not observed. Severe (grades III-IV) GVHD appeared in 6 of 17 evaluable patients and chronic extensive GVHD in 7 of 13 patients at risk. Five patients had recurrent ALL after transplantation and another 4 died from causes other than leukemia. Six patients transplanted in first remission, 2 in first relapse, and 1 in second remission remain alive and leukemia-free at a median follow-up of 17 months (range, 9 to 73 months). The probability of leukemia-free survival at 2 years is 49% +/- 12%. These data indicate that unrelated donor marrow transplantation is an effective treatment option for patients with early stage Ph1+ ALL without a family match and suggest that in such patients an unrelated donor search should be initiated as soon as possible after diagnosis.

Adolescent↗
PubMed1997

Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose.

Transplantation of hematopoietic stem cells from an HLA-compatible unrelated volunteer is an option for patients with acute leukemia lacking a family match. However, criteria for patient and donor selection and the most effective transplant procedures, including the number of hematopoietic cells, remain to be defined. We tested factors influencing outcome of 174 patients with primary acute leukemia receiving non-T-cell depleted marrow from unrelated donors. Median patient age was 20 years (range, 0.5 to 54 years). A multivariable analysis found that leukemia in remission at the time of transplantation was associated with improved leukemia-free survival (relative risk [RR] of treatment failure: 0.5, confidence interval [CI]: 0.3 to 0.7), and presence of blasts in the peripheral blood, as opposed to marrow involvement only or isolated extramedullary relapse, was associated with impaired outcome (RR of treatment failure: 2.5, CI: 1.7 to 5.0). The use of donors with a limited HLA-mismatch was associated with decreased leukemic relapse (RR: 0.5, CI: 0.3 to 0.9) but no improvement in leukemia-free survival compared with HLA-matched unrelated donors. Transplantation of a marrow cell dose above the median value of 3.65 x 10(8)/kg was associated with faster neutrophil (RR: 1.5, CI: 1.1 to 2.0) and platelet (RR: 4.5, CI: 2.7 to 7.5) engraftment, and decreased incidence of severe acute graft-versus-host disease (RR: 0.6, CI: 0.4 to 0.9). In patients transplanted in remission, the use of a marrow cell dose above the median translated into less nonleukemic death (RR: 0.2, CI: 0.1 to 0.4) and better leukemia-free survival (RR of treatment failure: 0.3, CI: 0.2 to 0.6). Transplant in remission with a high dose of marrow cells was associated with the best outcome in both children and adults.

Acute Disease↗
PubMed1997

Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial.

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day -1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving > or =28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

Adolescent↗
PubMed1997

Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation.

Postgrafting cyclosporine (CSP) given for 35 days resulted in establishment of stable marrow grafts from DLA-identical canine littermates after otherwise suboptimal, but nevertheless, lethal conditioning with 450 cGy of total body irradiation (TBI). We now asked whether sustained allografts could be achieved after sublethal TBI or without TBI. Five groups of recipients were studied. Dogs in group 1 were given 200 cGy TBI and postgrafting CSP, 15 mg/kg twice daily by mouth on days -1 to 35 posttransplant. Dogs in group 2 were given 200 cGy TBI and methotrexate (MTX), 0.4 mg/kg intravenously (I.V.) on days 1, 3, 6, and 11 along with CSP. Dogs in group 3 were given 200 cGy TBI and CSP along with mycophenolate mofetil (MMF), 10 mg/kg twice daily subcutaneously (S.C.) on days 0 to 27 after transplant, a novel immunosuppressive combination. Dogs in group 4 were given 100 cGy TBI and MMF/CSP. Dogs in group 5 were not given TBI and they received MMF/CSP posttransplant. Allografts were assessed by (Ca)n dinucleotide repeat polymorphism studies in cells from peripheral blood, lymph nodes, and marrow. Dogs in group 1 had transient mixed donor-host hematopoietic chimerism for no more than 4 weeks. Three of six dogs in group 2 had transient mixed chimerism for 3 to 11 weeks, and three have remained stable mixed chimeras for up to 60 weeks now. Four of five dogs in group 3 have remained stable mixed chimeras for 54 to 57 weeks now, while one lost the allograft after 12 weeks. All dogs in groups 4 and 5 rejected their allografts after 2 to 12 weeks. In summary, the establishment of stable mixed hematopoietic chimerism following nonmyelosuppressive and nontoxic conditioning programs has remained a difficult goal. Here we present evidence in a large random-bred animal species that this goal may be achievable with pharmacological immunosuppression postgrafting, capable of inhibiting both host-versus-graft (HVG) and graft-versus-host (GVH) reactions in the setting of DLA-identical grafts.

Animals↗
PubMed1997

Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Adult↗
PubMed1997

Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy.

The purpose of this report is to describe the results of stem cell transplantation as initial treatment for secondary acute myeloid leukemia (AML). Forty-six patients (median age 42 years) with secondary AML (17 therapy-related, 29 myelodysplasia-related) who had not received remission induction chemotherapy underwent allogeneic (n = 43) or syngeneic (n = 3) transplantation. The 5-year actuarial disease-free survival was 24.4%, and the cumulative incidences of relapse and nonrelapse mortality were 31.3% and 44.3%, respectively. Lower peripheral blood blast count was associated with a lower risk of relapse (P = .05) and shorter time from AML diagnosis to transplant was associated with a lower risk of nonrelapse mortality (P = .02) and improved disease-free survival (P = .026). Patients with therapy-related secondary AML tended to have lower disease-free survival (P = .16) and a higher relapse rate (P = .16) than patients whose leukemia was not therapy-related. The results of these 46 previously untreated patients were compared to 20 patients (median age 36 years, 12 therapy-related, 8 myelodysplasia-related) transplanted with chemotherapy-sensitive disease after induction chemotherapy (first complete remission [n = 6], second complete remission [n = 3], first untreated relapse [n = 11]). We found no statistically significant difference in outcome between these 2 groups of patients. These results suggest that prompt transplantation should be considered after diagnosis of secondary AML or, if possible, high-risk myelodysplasia, particularly in patients with low peripheral blast counts. Innovative transplant strategies are needed to reduce the high risks of relapse and nonrelapse mortality seen in this patient population.

Adolescent↗
PubMed1997

Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team.

BACKGROUND: Both immunosuppressive therapy and bone marrow transplantation are accepted treatments for patients with aplastic anemia. Choosing one of these therapies for a given patient depends not only on donor availability but also on such factors as patient age. OBJECTIVE: To compare survival rates and long-term complications after bone marrow transplantation or immunosuppressive therapy in patients with acquired aplastic anemia and to identify prognostic factors associated with improved survival. DESIGN: Center-based, retrospective analysis. SETTING: Referral center for patients with aplastic anemia. PATIENTS: 395 patients with acquired aplastic anemia. INTERVENTION: Bone marrow transplant from an HLA-identical, related donor or immunosuppressive therapy. MEASUREMENTS: Kaplan-Meier survival curves, results of log rank tests, and cumulative incidence curves. RESULTS: Of 168 bone marrow transplant recipients, 89% had sustained engraftment. Forty-six patients developed grade II to IV acute graft-versus-host disease, and 68 developed chronic graft-versus-host disease that required therapy. Of 227 patients who received immunosuppressive therapy, 44% achieved a complete, partial, or minimal response. Fifty-four percent died or had no response to therapy. Actuarial survival at 15 years was 69% for bone marrow transplant recipients and 38% for patients receiving immunosuppressive therapy (P < 0.001). Improved survival was associated with having bone marrow transplantation as primary therapy, being younger, having no transfusion before transplantation, and having a higher absolute neutrophil count. Disease duration, year of therapy, sex, refractoriness to platelet transfusions, and previous treatment with androgens or corticosteroids did not significantly affect survival. CONCLUSIONS: Data from this center suggest that bone marrow transplantation may be preferred for younger patients with acquired aplastic anemia who have matched, related donors. Long-term survival is excellent for patients who respond to either form of therapy.

Actuarial Analysis↗
PubMed1997

Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts.

Survivors of allogeneic marrow transplants are immunodeficient for at least 1 year after grafting. Multiple defects of immunity have been found; however, it is not known which defect primarily accounts for the high infectious morbidity of these patients. Twenty-nine allograft recipients who were in complete remission of the original disease were examined for the following parameters of immunity at 1 year after transplant: infection score (gauging the number and severity of infections within the 6 months prior to the annual exam), serum total IgM, IgG, and IgA, anti-Haemophilus influenzae IgG, anti-Streptococcus pneumoniae IgG, skin test reactivity, and the blood counts of B cells, CD4+ T cells, CD8+ T cells, and their subsets. THe only parameter inversely correlated with the infection score was CD4+ T cell count (P = 0.005 in univariable analysis, P = 0.06 in multivariable analysis). We conclude that infectious morbidity of long-term transplant survivors is related to the reconstitution of CD4+ T cells.

Adolescent↗
PubMed1997

In vivo radioprotective effect of AcSDKP on canine myelopoiesis.

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) interferes with G1/S-phase progression, and the resulting cell cycle arrest is thought to protect hematopoietic stem cells against injury by cycle-active cytotoxic agents. We investigated the radioprotective effect of AcSDKP in a canine radiation model. Dogs were given total-body irradiation (TBI) at an exposure rate of 10 cGy/min, either without further therapy (control) or with administration of AcSDKP at 0.05-500 micrograms/ kg/24 h beginning before and continuing until after completion of TBI. At 400 cGy of TBI, one of 28 control dogs and one of eight AcSDKP-treated dogs recovered hematopoiesis (p = 0.40). At 300 cGy, seven of 21 control dogs recovered hematopoiesis compared with five of five AcSDKP-treated dogs (p = 0.01). In dogs given 300 cGy and AcSDKP, the granulocyte nadirs were less profound (p = 0.04) and occurred later (p = 0.04) than among controls; platelet kinetics did not differ. These data suggest, therefore, that AcSDKP provides a radioprotective effect in dogs exposed to 300 cGy TBI. Such an effect might be beneficial in recipients of intensive radiation therapy. Conceivably, the effect on hematopoietic recovery could be amplified by growth factor administration after irradiation.

Animals↗
PubMed1997

Glucocorticoids fail to enhance the effect of FK506 and methotrexate in prevention of graft-versus-host disease after DLA-nonidentical, unrelated marrow transplantation.

Several steroid receptor-associated heat shock proteins can bind to FK506 as immunophilins. This has led to speculation that the steroid receptor and immunophilin signal transduction pathways are functionally interrelated. Indeed, in vitro work showed that FK506 treatment of intact L929 cells which were stably transfected with various reporter plasmids resulted in a potentiation of glucocorticoid hormone-induced glucocorticoid receptor-mediated gene transcription. These findings have raised the possibility of additive or synergistic immunosuppressive effects of FK506 and glucocorticoids. We tested this hypothesis in a canine model of GVHD prevention. Two groups of dogs were given 9.2 Gy total body irradiation followed by hematopoietic grafts from unrelated DLA-nonidentical donors. Among the first group of four recipients which were given FK506 and glucocorticoids, one rejected the graft, while three developed acute GVHD and died from associated complications between days 14 and 34. In the second group of nine recipients which were given FK506, glucocorticoids and methotrexate (MTX), only one dog became a long-term survivor while eight dogs died between days 21-114 with GVHD (n = 5) or FK506-associated toxicities (n = 3). Thus, addition of glucocorticoids to FK506 or FK506/MTX showed neither synergistic nor additive effects with respect to GVHD prevention in this model, and no survival advantages were seen compared to previously reported results with FK506 alone or FK506 and MTX in combination, respectively.

Animals↗
PubMed1997

Allogeneic marrow transplantation for primary myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocytosis.

Primary myelofibrosis is a clonal haemopoietic disorder, incurable with conventional therapy, and associated with a median survival of 4-5 years. Patients with polycythaemia vera and essential thrombocytosis who progress into a myelofibrotic picture also have a poor prognosis. Between 1980 and 1996, 13 patients with myelofibrosis due to one of these three myeloproliferative disorders (primary myelofibrosis [n=8], essential thrombocytosis [n=3], polycythaemia vera [n=2]) underwent allogeneic marrow transplantation in Seattle. The median age was 40 years (range 18-49). The median time from myeloproliferative diagnosis to transplantation was 39 months (range 5-192). Three patients received preparative regimens containing total body irradiation and 10 received busulphan-cyclophosphamide regimens. Nine patients received marrow from HLA-matched related donors, one from a one antigen mismatched related donor, and three from HLA-matched unrelated donors. The median time to both granulocyte and platelet engraftment was 21 d. Nine patients survive between 1.2 and 7.1 years post-transplant. Two patients relapsed at 1 year post-transplant, both of whom survive in a chronic myeloproliferative state. Four patients died of transplant-related complications between 43 d and 2.2 years post-transplant. At 1 year post-transplant the majority of the disease-free survivors have normal peripheral blood counts and none-to-minimal marrow fibrosis. These preliminary results are encouraging, and suggest that stem cell transplantation can be curative therapy for selected patients with myelofibrosis.

Adolescent↗
PubMed1997

Quasielastic light scattering study of the living human lens as a function of age.

PURPOSE: To determine contributions of molecular scattering elements to the increase with age in the light scattered from the human ocular lens in vivo. METHODS: We used quasielastic light scattering to measure autocorrelation functions of the intensity of light scattered in vivo from three locations (anterior, nuclear and posterior) along the optic axis in ocular lenses of 225 subjects, ranging from 17 to 63 years of age. We deduced probability distributions of key parameters (Is, If, Ii, IT), which describe contributions of slowly diffusing (Is), rapidly diffusing (If) and relatively immobile (Ii) scattering elements to the total light intensity (IT) scattered into the collection optics. We deduced characteristic time tau s and tau f that describe the Brownian motion of scattering elements. RESULTS: Probability distributions for each age decile show clearly defined shifts in key parameters with age. IT at the nucleus increases by a factor of three from age 20 to 60 years. This increase is produced principally by an approximate five-fold increase is Is. IT and Is and can be detected with an accuracy of approximately +/- 10%. We estimate threshold values for IT, which mark the boundary beyond which clinical cataract becomes manifest. This boundary represents 6 to 8 times the light scattering efficiency expected from the newborn lens. CONCLUSIONS: This methodology permits a sensitive, quantitative, clinically useful representation of the pre-cataractous molecular changes associated with aging in the living human lens.

Adolescent↗