Does subclinical hypothyroidism explain the increased susceptibility of women to torsades de pointes?

Among 20 consecutive patients (65% women) with drug-associated torsades de pointes, chemical evidence for hypothyroidism was found in only 10% of both women and men. Subclinical hypothyroidism is therefore unlikely to account for the consistently observed sex difference in the propensity to torsades de pointes.

Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma.

PURPOSE: To determine the incidence, natural history, and risk factors associated with myelodysplastic syndrome (MDS) occurring as a late complication following autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma. METHODS: We retrospectively reviewed the charts of all 262 patients who underwent autologous bone marrow transplantation for non-Hodgkin's lymphoma at the Dana-Farber Cancer Institute from 1982 through 1991. Although patients received a variety of treatments before they were eligible for transplant, identical myeloablative therapy (cyclophosphamide 60 mg/kg/d for 2 days plus total-body irradiation twice daily for 3 days) was administered in each case. By collecting data on pretransplant and early posttransplant variables, we attempted to identify risk factors for the development of MDS. RESULTS: The crude overall incidence of posttransplant MDS or acute myeloid leukemia (AML) was 7.6%. The actuarial risk at 6 years was 18% +/- 9%. The median time of onset was 31 months (range, 10 to 101) after transplant or 69 months (range, 27 to 141) after initial treatment for lymphoma. Pretreatment variables predictive for the development of MDS (univariate analysis) included prolonged interval between initial treatment and the transplant procedure (P = .003), increased duration of exposure to chemotherapy (P = .019) or to alkylating agents (P = .045), and use of radiation therapy (P = .032) or pelvic radiation (P = .003) before transplant. CONCLUSION: MDS is a potential complication of autologous bone marrow transplantation for non-Hodgkin's lymphoma; bone marrow stem-cell damage sustained before the transplant may be the most important risk factor.

A phase II study of continuous infusion recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.

Glutamic acid decarboxylase antibodies, autonomic nerve antibodies and autonomic neuropathy in diabetic patients.

To clarify whether GAD-ab are associated with diabetic autonomic neuropathy and/or complement fixing antibodies against sympathetic ganglia, adrenal medulla, and vagus nerve, we examined 133 diabetic patients (95 with IDDM). GAD-ab were determined by a radioligand binding assay using in vitro expression of recombinant GAD-65 whereas sympathetic ganglia antibodies, adrenal medulla antibodies, vagus nerve, and ICA were evaluated by indirect immunofluorescence assays. Autonomic nerve function was evaluated by objective tests (heart rate reactions to deep breathing and to tilt). In the total material of 133 patients, GAD-ab were detected in 36 patients, all of whom had IDDM. The frequency of GAD-ab was similar (38%) in IDDM patients with and without signs of autonomic neuropathy (21 of 55 vs 15 of 40). In addition, there were no significant associations between GAD-ab and autonomic nerve antibodies; GAD-ab were detected in 9 of 21 (43%) of patients with and in 27 of 112 (24%) of patients without sympathetic ganglia antibodies, in 5 of 15 (33%) of patients with and 31 of 118 (26%) without adrenal medulla antibodies, and in 5 of 15 (33%) with and 31 of 118 (26%) of patients without vagus nerve antibodies. The frequency of ICA, however, was significantly increased in patients with sympathetic ganglia antibodies compared with those without sympathetic ganglia antibodies (10 of 21 [48%] vs 21 of 112 [19%]; p < 0.01). In conclusion, GAD-ab were neither associated with disturbed autonomic nerve function nor with antibodies against autonomic nerve structures.

Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma.

Forty patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and either anti-B-cell monoclonal antibody (MoAb)-treated autologous, anti-T-cell MoAb-treated HLA-matched sibling allogeneic or syngeneic bone marrow transplantation (BMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and 17 had received prior radiotherapy. At the time of BMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells; 34 patients had residual monoclonal marrow plasma cells and 38 patients had paraprotein. Following high-dose chemoradiotherapy, there were 18 complete responses (CR), 18 partial responses, one non-responder, and three toxic deaths. Granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 23 (range, 12 to 46) and 25 (range, 10 to 175) days posttransplant (PT), respectively, in 24 of the 26 patients who underwent autografting. In the 14 patients who received allogeneic or syngeneic grafts, granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 19 (range, 12 to 24) and 16 (range, 5 to 32) days PT, respectively. With 24 months median follow-up for survival after autologous BMT, 16 of 26 patients are alive free from progression at 2+ to 55+ months PT; of these, 5 patients remain in CR at 6+ to 55+ months PT. With 24 months median follow-up for survival after allogeneic and syngeneic BMT, 8 of 14 patients are alive free from progression at 8+ to 34+ months PT; of these, 5 patients remain in CR at 8+ to 34+ months PT. This therapy has achieved high response rates and prolonged progression-free survival in some patients and proven to have acceptable toxicity. However, relapses post-BMT, coupled with slow engraftment post-BMT in heavily pretreated patients, suggest that such treatment strategies should be used earlier in the disease course. To define the role of BMT in the treatment of myeloma, its efficacy should be compared with that of conventional chemotherapy in a randomized trial.

Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of relapse.

The prognosis for adults with B lineage ALL who have relapsed after an initial remission is poor. High-dose chemoradiotherapy followed by autologous BMT can induce prolonged clinical remissions in some children with recurrent ALL. In this study, we evaluated the efficacy of autologous BMT in adults. Autologous marrow was treated in vitro with J5 and J2 monoclonal antibodies (CD10/CD9) plus rabbit complement to purge residual ALL cells. Twenty-two adults with B lineage ALL were treated with high-dose chemoradiotherapy followed by infusion of J2/J5 purged autologous BM. The median age was 28 years (range 18-54 years). Twenty-one of 22 patients had experienced at least one relapse prior to BMT. All patients achieved complete hematologic engraftment. Disease-free survival (DFS) in this cohort of patients was 20%, with all survivors alive and free of disease between 2.5 and 7.5 years post-BMT. Age at the time of BMT was an important prognostic factor, with patients < 28 years old faring much better than older individuals (DFS, 45% vs 0%, p = 0.01). Our experience suggests that high-dose chemoradiotherapy followed by infusion of J2/J5 purged autologous marrow is as efficacious in young adults as it is in children and is a reasonable alternative for patients who lack HLA-matched donors. Results in older adults are poor, however, and demonstrate the need for more effective transplant strategies in these individuals.

Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia.

Twenty patients with poor prognosis B-cell chronic lymphocytic leukemia (B-CLL) underwent uniform high-dose chemoradiotherapy followed by rescue with multiple monoclonal antibody-purged autologous bone marrow (BM) (12 patients) or T-cell-depleted allogeneic BM from HLA-identical siblings (8 patients) in a pilot study to assess the feasibility of BM transplantation (BMT) in this disease. All had poor prognosis disease by either staging, BM pattern, tumor doubling time criteria, or cytogenetics. All patients achieved remission criteria (defined as < or = 2 adenopathy, absence of splenomegaly, < or = 20% of the intertrabecular space involved on BM biopsy) before BMT. Despite the use of fludarabine, a median of three treatment regimens were required to achieve BMT eligibility. After BMT, all patients achieved complete hematologic engraftment. Toxicities were not significantly different between autologous versus allogeneic BMT. Two toxic deaths were observed. Of 19 evaluable patients, 17 clinical complete clinical remissions (89%) were observed, with 2 patients (1 allogeneic and 1 autologous) exhibiting persistent BM disease. Complete clinical remissions were documented at the phenotypic and molecular level for the majority of patients in whom dual fluorescence for CD5 and CD20 (15 of 15; 100%) and Ig gene rearrangements (11 of 14; 79%) were performed. Although long-term follow-up is needed to assess any potential impact on the disease-free and overall survival of these patients, this study shows the feasibility of using high-dose chemoradiotherapy and BMT in patients with poor prognosis B-CLL.

Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: a pilot study.

PURPOSE: Using high-dose therapy and autologous bone marrow transplantation (ABMT) to overcome cellular resistance and eradicate minimal disease, we initiated a pilot study during first remission in patients with non-Hodgkin's lymphoma (NHL) to examine whether the long-term disease-free survival (DFS) rate can be improved for patients with poor-prognosis intermediate/high-grade NHL. PATIENTS AND METHODS: Twenty-six patients with advanced-stage diffuse intermediate/high-grade B-cell NHL (including 16 patients with diffuse small cleaved-cell [DSC]) were selected at presentation by histologic and clinical characteristics to have less than a 25% probability of long-term DFS with conventional treatment. After induction chemotherapy, 16 patients were in complete remission (CR) and 10 were in a minimal disease state. Patients were then treated with high-dose cyclophosphamide, total-body irradiation (TBI), and anti-B-cell monoclonal antibody-purged ABMT. RESULTS: Following ABMT, no acute in-hospital treatment deaths occurred, and engraftment of granulocytes and platelets was significantly faster than for patients undergoing ABMT who were in second or subsequent remission. Of 26 patients, 21 remain in CR maintained without continued therapy, three relapsed in sites of prior nodal disease (4.8, 5.4, and 28 months post-ABMT), and two died in remission. The DFS rate is estimated to be 85% at 28 months and thereafter. The median follow-up period for the 21 patients who are alive and disease-free is 32 months. CONCLUSION: This pilot study suggests that consolidation of first remission with ABMT may improve the long-term DFS rate for diffuse intermediate/high-grade NHL patients at high risk for relapse.

Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma.

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti-B4 (CD19) monoclonal antibody with the protein toxin "blocked ricin." In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4-bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.

Long-term follow-up of a phase III study of recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancies.

One hundred and twenty-eight patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and acute lymphoblastic leukemia (ALL) previously reported from a phase III trial of rhGM-CSF or placebo following autologous bone marrow transplantation (ABMT) were investigated for the development of late toxicities. Median follow-up is 36 months. No apparent long-term deleterious effects on BM function were observed. Moreover, disease-free survival and overall survival were similar for patients on both treatment arms, arguing for the long-term safety of recombinant human granulocyte macrophage-colony-stimulating factor (rhGM-CSF). The only factors predictive for both a high risk of relapse over time and mortality were having the diagnosis of ALL and/or undergoing ABMT in resistant relapse. We attempted to identify clinical variables before BM harvest, at the time of marrow infusion, or events within the first 100 days posttransplant, which might predict speed of neutrophil recovery in the setting of placebo or rhGM-CSF administration after ABMT. Only previous exposure to agents that deplete stem cells led to a significant delay in neutrophil recovery, suggesting their avoidance in patients who may undergo ABMT. Nevertheless, even those patients benefited from rhGM-CSF. For all patients, rhGM-CSF and agents that deplete stem cells were the strongest independent predictors for neutrophil engraftment. With the increasing use of newer hematopoietic growth factors both alone and in combination, long-term follow-up is essential to confirm the same safety that we report with rhGM-CSF.

POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature.

A 27-year-old white man with no significant risk factors for coronary artery disease presented with a 9-month history of progressive impotence, gynecomastia, lower extremity paresthesias, and extensive myocardial infarction and subsequently developed ulcerative proctitis. A diagnosis of POEMS syndrome was made based on the clinical presentation; additional physical findings of papilledema, clubbing, and hyperpigmentation; and laboratory findings of an immunoglobulin G M component of the lambda subtype, elevated cerebrospinal fluid protein, and typical sclerotic bone lesions. Abnormal in vitro binding of the patient's serum immunoglobulin to testicular tissue was also seen. Cardiac catheterization showed evidence of diffuse coronary artery narrowing and left ventricular wall motion abnormalities. Diffuse coronary involvement and ulcerative proctitis have not been previously described in POEMS syndrome. It is hypothesized that an abnormal immunoglobin (or fragment) is responsible for both findings. Furthermore, the detection of antitesticular autoantibodies suggests the possibility of an interaction between the antibody and Leydig cells, leading to an alteration in the synthesis and release of sex steroids and thereby explaining the gonadal failure seen in this syndrome. Long-term glucocorticoid therapy for the past 5 years has resulted in marked subjective and objective improvement.

Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.

PURPOSE: Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. PATIENTS AND METHODS: From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. RESULTS: Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. CONCLUSIONS: We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.

Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia.

The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte-macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA-compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.

Immune-mediated cytopenia following bone marrow transplantation. Case reports and review of the literature.

We describe 3 cases of immune-mediated cytopenia occurring after bone marrow transplantation (BMT). In 1 case, only the platelet line was affected, whereas in the other 2 cases more than 1 cell lineage was involved simultaneously. Two of the cases presented with falling peripheral blood counts following apparently normal early engraftment, while in 1 of the cases the affected lineage failed to appear in the peripheral blood despite normal engraftment of the other lineages. In all 3 cases the cytopenia improved following the initiation of treatment with systemic corticosteroids. Immune-mediated cytopenia following bone marrow transplantation may occur via alloimmune or autoimmune mechanisms. Alloimmune cytopenias have arisen in the context of major or minor mismatches in the ABO system, but cases related to mismatches in the Rh system and other erythroid and non-erythroid alloantigen systems may also occur. Alloimmune cytopenias have been reported primarily in the setting of allogeneic BMT, whereas autoimmune cytopenias have been reported following both allogeneic and autologous BMT. Immune-mediated cytopenia may present as early as the day of transplant, or as late as many months afterward. The possibility of immune-mediated cytopenia should always be considered when unexpected peripheral blood cytopenia is present, or when unexpected hemolysis develops, following bone marrow transplantation. The diagnosis is supported by a normal appearance of the affected lineage or lineages in the bone marrow, the absence of other apparent causes for the cytopenia, and the presence of the relevant auto- or allo-antibodies in the serum. However, any of these features may be absent in individual cases. The importance of these syndromes lies in the fact that they may be life-threatening, yet they often respond well to steroids or other standard immunosuppressive measures. It is important to be aware that effective prophylactic measures are available for patients receiving ABO- or Rh-incompatible marrow.

Aggregation of subclinical autonomic nervous system dysfunction and autoantibodies in families with type I diabetes.

The purpose of our study was to evaluate the occurrence of autonomic nervous system autoantibodies (ANS) in the nondiabetic family members of insulin-dependent (type I) diabetic subjects. We studied 24 families, including 45 nondiabetic parents and 53 nondiabetic siblings of a type I diabetic proband. One hundred one nondiabetic population control subjects were also studied. Stored sera from nondiabetic family members and control subjects were evaluated for the presence of complement-fixing (CF) adrenal medullary antibodies (CF-ADM), sympathetic ganglia antibodies (CF-SG), and vagus nerve antibodies (CF-V) by indirect immunofluorescence. HLA-DR3 and -DR4 typing was performed on 42 nondiabetic family members and 104 diabetic subjects. One or more CF-ANS were in 45 of 93 (40%) nondiabetic family members compared to 2 of 70 (2.8%) control subjects. CF-SG were in 28 of 92 (30%) family members compared to 0 of 101 control subjects (P = 0.0001). CF-V were in 25 of 95 (26%) family members compared to 0 of 76 control subjects (P = 0.0001). CF-ADM were in 10 of 83 (12%) family members compared to 2 of 70 (2.8%) control subjects (P = 0.056). There was no HLA-DR3 or HLA-DR4 association with ANS. Subclinical autonomic dysfunction was demonstrated in 3 of 4 family members with autoantibodies compared to 0 of 4 family members without autoantibodies.

Hepatic dysfunction following T-cell-depleted allogeneic bone marrow transplantation.

We reviewed the medical records of 97 patients undergoing T cell-depleted allogeneic bone marrow transplantation at our institution from 1984 to 1990 to determine the incidence of hepatic dysfunction, including venoocclusive disease of the liver following BMT. All patients received allogeneic marrow that had been purged with monoclonal antibody to the CD6 surface antigen (T12) and rabbit complement as the sole method of graft-versus-host disease prophylaxis. No additional immunosuppressive agents were routinely administered to these patients. Overall, 55% of patients in our series developed two-fold elevations in serum bilirubin, SGOT, or alkaline phosphatase within the first 30 days following BMT. A five-fold elevation in any liver function test was noted in only 19% of patients. Logistic regression analysis revealed that the presence of GVHD, female sex, and administration of amphotericin B all were independently associated with laboratory evidence of hepatic dysfunction. While LFT abnormalities were common in our series, they were generally mild, and the development of VOD was rare. Only three patients (3.1%) fulfilled clinical criteria sufficient to establish a diagnosis of VOD. Among the 86 patients whose ablative regimen consisted of cyclophosphamide (60 mg/kg x2) and total-body irradiation (1200-1400 cGy in 200 cGy fractions), only 1 patient (1.2%) developed VOD. Our experience suggests that patients undergoing allogeneic BMT are at low risk for VOD and other serious hepatic complications when they receive high-dose cyclophosphamide, fractionated TBI, and T cell-depleted marrow without hepatotoxic medications for GVHD prophylaxis.

Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma.

BACKGROUND: The use of autologous bone marrow transplantation is increasing in the management of advanced cancers. Many investigators have attempted to "purge" autologous marrow of residual tumor cells because of concern that reinfused tumor cells might contribute to relapse. The efficacy of purging remains unproved. METHODS: We performed clonogenic assays in a tumor cell line in culture to determine the efficiency of immunologic purging. Amplification by the polymerase chain reaction (PCR) was used to detect residual lymphoma cells before and after purging of bone marrow from 114 patients with B-cell non-Hodgkin's lymphoma in whom a translocation (t(14;18] that could be amplified by PCR was detected at the time of their initial evaluation. RESULTS: Immunologic purging in vitro resulted in a 3-to-6-log destruction of cells in the tumor cell line. Residual lymphoma cells were detected by PCR in the bone marrow of all patients before purging. No lymphoma cells could be detected in the marrow of 57 patients after purging. Disease-free survival was increased in these 57 patients as compared with those whose marrow contained detectable residual lymphoma (P less than 0.00001). The ability to purge residual lymphoma cells was not associated with the degree of bone marrow involvement (P = 0.4494) or the previous response to therapy (P = 0.1298). CONCLUSIONS: The inability to purge residual lymphoma cells was the most important prognostic indicator in predicting relapse. These results provide evidence of the clinical usefulness of ex vivo purging of autologous bone marrow in the treatment of patients with lymphoma and suggest that the reinfusion of malignant cells in autologous marrow contributes to relapse

Autonomic nerve antibodies and autonomic nerve function in type 1 and type 2 diabetic patients.

Complement-fixing adrenal medulla (CF-ADM), sympathetic ganglion (CF-SG), and vagal (CF-V) nerve antibodies were determined in diabetic patients. Among 74 patients with Type 1 diabetes, CF-ADM was detected in 7 (10%) cases, CF-SG in 14 (19%) cases, and CF-V in 8 (11%) cases. Among 38 patients with Type 2 diabetes, CF-ADM was detected in 5 (13%) cases, CF-SG in 4 (11%) cases, and CF-V in 6 (16%) cases. There were associations between autonomic nerve antibodies and autonomic nerve function. CF-ADM and/or CF-SG were significantly (P less than 0.002) less prevalent in Type 1 diabetic patients with autonomic neuropathy than in those without [5/44 (11%) vs. 14/30 (47%)] and, in agreement with this, the brake index, a sign of parasympathetic and sympathetic autonomic nerve function, was significantly (P less than 0.005) higher (more normal) in these patients (-0.56 +/- 0.13 vs. -1.04 +/- 0.12). In Type 2 diabetic patients, the E/I ratio, an index of parasympathetic nerve function, was significantly (P less than 0.03) lower (more abnormal) in those with CF-V than in those without (-1.81 +/- 0.17 vs. -1.20 +/- 0.11). In conclusion, the frequency of sympathetic nerve antibodies was decreased in Type 1 diabetic patients with autonomic neuropathy, while in Type 2 diabetic patients parasympathetic nerve antibodies were related to severe parasympathetic neuropathy.

Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma.

Sixty-nine patients with a history of low-grade B-cell non-Hodgkin's lymphoma (NHL) in sensitive relapse or incomplete first remission underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). At ABMT, 51 patients had low-grade histology and 18 patients had a history of low-grade NHL that had undergone histologic transformation to a higher-grade NHL. Before ABMT, only 20 of the 51 low-grade patients and 10 of the 18 patients with transformed histologies were in complete remission. Moreover, at the time of marrow harvest, 24 of the low-grade and eight of the transformed histology patients had histologic evidence of lymphoma cells infiltrating the marrow. Following high-dose therapy, only one acute, in-hospital death was observed. There was no significant difference in the disease-free survival (DFS) between patients with low-grade and patients with transformed histologies. Among patients with low-grade NHL, the patients in complete remission before ABMT experienced significantly longer DFS than those in partial remission (P less than .05). This preliminary study suggests that some patients with relapsed low-grade NHL may experience prolonged DFS following high-dose ablative therapy.

Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer.

BACKGROUND: The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. RESULTS: No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500 x 10(6) per liter 7 days earlier than the patients who received placebo (19 vs. 26 days, P less than 0.001), had fewer infections, required 3 fewer days of antibiotic administration (24 vs. 27 days, P = 0.009), and required 6 fewer days of initial hospitalization (median, 27 vs. 33 days; P = 0.01). There was no difference in the survival rate at day 100. CONCLUSIONS: In patients undergoing autologous bone marrow transplantation for lymphoid neoplasia, rhGM-CSF significantly lessens morbidity. Further studies will be required to establish its optimal dosage and schedule of administration.