Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.

Transforming growth factor-beta and multidrug resistance in chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) frequently respond to initial treatment, but then become resistant to chemotherapy. Studies have shown one important cause of chemotherapeutic resistance to be multidrug resistance (MDR). To investigate the potential role of MDR and transforming growth factor-beta (TFG-beta), a potent growth inhibitor of B lymphocytes, in the development of chemotherapeutic resistance in CLL, we evaluated 22 CLL patients for loss or mutation of TGF-beta receptors (TbetaR), plasma TGF-beta1 levels, and expression of MDR1 mRNA. Receptor crosslinking and immunoprecipitation experiments did not demonstrate loss of TbetaRs in any patients studied. No relationship between plasma TGF-beta1 levels and expression of MDR1 mRNA was seen. Correlation of plasma TGF-beta1 levels to disease stage revealed a consistent decline in plasma TGF-beta1 levels with advancing disease stage (P = 0.031).

Multi-drug resistance in chronic lymphocytic leukemia.

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were repeated as patients became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC-833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but not with either the MTT assay or any of the monoclonal antibodies. None of the tests correlated with prior chlorambucil treatment. Correlation of dox retention with the monoclonal antibodies was mild to moderate and became stronger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 increases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especially MRK-16). Patients who become resistant to VAD more frequently express p-gp 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-A (CsA) ex vivo, and correlates better with stage of disease.

Superwarfarin poisoning.

BACKGROUND: Superwarfarin sodium exposure or poisoning is a growing public health problem. There were 5133 reported cases of superwarfarin exposure and poisoning in 1988 and 13 423 cases in 1995. Cases may be associated with accidental exposure, suicide attempts, or Munchausen syndrome, and may be difficult to diagnose. PATIENTS AND METHODS: Patients from northern Wisconsin with superwarfarin exposure or poisoning were examined at a tertiary referral center in rural Wisconsin to determine what led to their exposure and to review the clinical manifestations, diagnosis, treatment, and prevention of superwarfarin poisoning. RESULTS: Eleven cases satisfied the criteria for superwarfarin exposure or poisoning. All 7 children included in the study had accidentally ingested superwarfarin, 2 adults had Munchausen syndrome, and 1 teenager and 1 adult had attempted suicide using superwarfarin. Nine of the 11 cases had taken brodifacoum. The patients who had accidentally ingested superwarfarin or attempted suicide using it were easily diagnosed, while diagnosis was markedly delayed for the 2 patients with Munchausen syndrome. Full reversal of anticoagulation was quickly achieved in the cases of accidental ingestion and attempted suicide. We examined and treated the patients with Munchausen syndrome for months before establishing a diagnosis and fully reversing the anticoagulation. None of the patients in our study died of superwarfarin poisoning. CONCLUSIONS: Superwarfarin exposure or poisoning is a growing public health problem that should be part of the differential diagnosis of patients who present with a coagulopathy consistent with vitamin K deficiency in the absence of coumadin therapy, liver disease, or the use of an inhibitor, and whose conditions do not resolve with large doses of parenteral vitamin K1 therapy.

The treatment of older adult patients with acute myeloid leukemia by triple infusion chemotherapy.

Adult patients (> or = 56 years old) with acute myeloid leukemia (AML) received induction therapy consisting of daunorubicin (60 mg/m2), etoposide (80 mg/m2), and cytarabine (200 mg/m2) daily for 5 days by continuous i.v. infusion (120 hours). The initial protocol was modified so that patients who were not hypoplastic after the first cycle of chemotherapy received a second cycle of treatment, utilizing 30 mg/m2 of daunorubicin/24 hours for 5 days plus etoposide and cytarabine as used in the first cycle. Two courses of consolidation with etoposide and cytarabine at the same dose and schedule were given. Patients were then maintained on cytarabine monthly. Twelve of 29 previously untreated patients (41%) achieved complete remission (CR). Excluding patients with secondary AML, 48% of all patients (11/23) achieved CR, including 56% > or = 70 years old. The median duration of CR was 41 weeks and median survival of CR patients was 54 weeks. Six of 13 patients (46%) with relapsed AML achieved CR. Toxicity in these older adult patients has been mild. Two patients (8%) had severe mucositis and one had severe (bloody) diarrhea. Most patients developed a mild transient asymptomatic rash. Triple infusion chemotherapy (TIC) may be as effective as other chemotherapy regimens for AML in older adults and has acceptable toxicity.

Modified vincristine, doxorubicin, and dexamethasone regimen in the treatment of resistant or relapsed chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group study.

BACKGROUND: Thirty-six patients with relapsing or refractory chronic lymphocytic leukemia were entered into a Phase II study of the Eastern Cooperative Oncology Group. METHODS: A modified VAD regimen was given: a 96-hour infusion of 1.6 mg vincristine and 36 mg/m2 doxorubicin with dexamethasone 40 mg by mouth daily for 4 days every 3 weeks. The treatment was continued until two cycles beyond maximal response, which was evaluated after two and six cycles. RESULTS: Of the 33 evaluable patients, 7 (21%) achieved a partial response (PR), with no complete remissions. One-third of the patients (11 of 33) had progressive disease and 15 of 33 (45%) had stable disease, as defined by the National Cancer Institute Working Group criteria. The median duration of PR was 6.5 months, with a median survival time of 14.8 months. A PR was achieved by 3 of 19 patients (16%) who had received prior vincristine +/- doxorubicin and 4 of 14 patients (28%) who had not received vincristine or doxorubicin. Of the nine patients whose disease was refractory to prior therapy, five (55%) achieved a PR. The neurotoxicity of VAD was reduced by decreasing the frequency of the dexamethasone, but 22 of 36 (61%) patients still became infected. Only on infection (2.8%) was life threatening, and there were no infectious deaths. CONCLUSIONS: Because fludarabine has shown superior responses, VAD should be reserved for patients who do not respond to alkylating agents and fludarabine and in whom alternative treatments are not appropriate.

Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders.

Thrombotic and hemorrhagic disorders are common complications of the myeloproliferative disorders. Endothelial cells release both procoagulant and profibrinolytic factors, which may contribute to these hemorrhagic or thrombotic complications. The pre- and postvenous stasis levels of the procoagulant and profibrinolytic factors produced by endothelial cells were correlated with the occurrence of complications in polycythemia rubra vera (PRV) patients (n = 29) and essential thrombocythemia (ET) patients (n = 17) compared with normal patients (n = 17). Tissue plasminogen activator (tPA) activity, plasminogen activator inhibitor (PAI) activity, von Willebrand's factor (vWF) activity and antigen (vWF:Ag), and factor VIII activity were measured. The resting tPA activity was significantly higher in the two disease groups compared with normal controls, but no difference between the levels of tPA and either complication within the disease groups was observed. Significantly elevated tPA following venous stasis was observed in the patients of both disease groups who had bleeding complications. Significant decreases, compared with the normal group, in both resting and postvenous stasis levels of PAI were observed in the disease groups regardless of complication history. The subjects from both disease groups with thrombotic complications had significantly elevated resting vWF and both resting and postvenous stasis vWF:Ag levels compared with normal controls. The endothelial cell is likely to be responding to abnormal hemostasis rather than being primarily involved in the genesis of a hyper- or hypocoaguable state.

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial.

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Treatment of advanced non-Hodgkin's lymphoma in adults.

Although dramatic progress has been made in the treatment of advanced non-Hodgkin's lymphoma, a majority of patients eventually die from this disease. Improvements in histopathology, staging techniques, immunophenotyping, and knowledge of prognostic factors have improved our ability to choose appropriate treatment. Most low-grade lymphomas can be effectively palliated for many years, but eventually convert to large-cell lymphomas or become resistant to chemotherapy. Intermediate-grade lymphomas, especially diffuse large-cell lymphomas, may be cured in 30% to 60% of the cases with aggressive combination chemotherapy. The high-grade lymphomas require treatment similar to regimens designed to treat acute lymphocytic leukemia, including central nervous system (CNS) prophylaxis. Non-Hodgkin's lymphomas are becoming more common in patients with acquired immunodeficiency syndrome (AIDS), and may be effectively controlled before the immunodeficiency becomes too severe. All patients with high-grade lymphoma and others at high risk should be tested for human immunodeficiency virus (HIV). Patients who relapse may be salvaged with chemotherapy, and their diseases are potentially curable with autologous or allogeneic bone marrow transplantation. New treatments using monoclonal antibodies, biological response modifiers, and growth factors, should improve palliation and survival.

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma.

Fourteen patients with small cell carcinoma of the lung in relapse or with disease refractory to chemotherapy were treated with carmustine (BCNU) at doses of 600 to 1000 mg/m2 intravenously followed by autologous bone marrow transplantation. All patients previously were treated with cyclophosphamide, doxorubicin, vincristine, and etoposide. Seven of the 14 patients responded to the high-dose BCNU (50% response with 95% confidence limits ranging from 23% to 77%). Three patients had a complete response, and four had a partial response. Regrowth of tumor occurred within 60 days of treatment in the responding patients. Death occurred in six patients before the recovery of the platelet count to 50,000 cells/microliters. Although the response rate was high, the toxicity was excessive. In the dosage range of 600 to 1000 mg/m2 in heavily pretreated patients, BCNU is not recommended, but additional investigation may be warranted in patients with central nervous system metastases who previously were treated with radiation therapy.

High-dose dexamethasone for refractory or relapsing multiple myeloma.

In order to assess the efficacy and toxicity of dexamethasone as a single agent without the concomitant infusion of Adriamycin and vincristine (VAD), an ECOG pilot study was initiated using 40 mg by mouth daily for 4 days every week for 8 weeks. Patients who responded were then maintained on the same treatment, but at 2 week intervals. Of the 32 patients evaluable for response, three were completely refractory to all prior therapy. All patients had advanced disease and 26 had received multiple prior treatments. There were 13/32 (40%) objective responses by ECOG criteria. Of the 28 patients evaluable for subjective response, i.e., significant decrease in performance status and/or bone pain, eight (28.5%) responded. Of the 34 patients evaluable for toxicity, 19 patients (55%) had moderate to severe side effects, including nine who had central nervous system effects, three who had gastrointestinal bleeding, two who had pulmonary emboli, one with psychosis, and four who had serious infections with one death. Median survival for the entire group was 19 weeks, with 31 weeks in the responders and 9 weeks in the non-responders. Although high-dose dexamethasone is capable of producing a significant number of partial responses (40%), it is associated with excessive toxicity. Less frequent administration of the dexamethasone at 2 week intervals was well tolerated in the maintenance of partial response, but has not been studied for efficacy in induction of remission.

Treatment of venous thromboembolic disease. A pragmatic approach to anticoagulation and thrombolysis.

Heparin (Lipo-Hepin, Liquaemin Sodium) and warfarin sodium (Coumadin, Panwarfin) are the classic anticoagulants in use for venous thromboembolic disease. They work by modifying the coagulation mechanism, heparin having an immediate effect and warfarin having a more delayed effect. The most common adverse effects of anticoagulation therapy are hemorrhagic complications. Thrombolytic therapy should be considered in all patients with massive pulmonary embolism with hypotension and in patients with deep venous thrombosis in the popliteal area or higher. Such therapy has been shown to help preserve the pulmonary microcirculation after pulmonary embolism and to decrease the incidence of the postthrombotic syndrome following deep venous thrombosis. If certain clinical guidelines are followed rigidly, the incidence of significant bleeding complications is low. Although the use of tissue plasminogen activator in venoocclusive disease has been limited to isolated cases, results have been very promising.

Granulocyte dysfunction and myotonic dystrophy.

A 52-year-old Caucasian male with typical features of myotonic dystrophy (MD) developed a lung abscess and was found to have a mild atypical cyclic neutropenia. Granulocyte function testing revealed a defect in phagocytosis, bactericidal activity and chemotaxis. The defects were less severe at the nadir of the granulocyte counts. Skin windows demonstrated that the granulocyte defects were not just an in vitro artifact. The patient was treated with lithium carbonate and improved. Mobilization into a skin window and clinical MD were unchanged. Studies of his 10 children and 2 siblings, including granulocyte function tests and complete neurological evaluations were obtained. The 4 children with abnormal parameters of granulocyte function all had definite evidence of MD. Two children had equivocal findings of MD and the others were normal. There was minimal evidence of granulocyte dysfunction in these children. Twelve of 19 unrelated patients with MD had evidence of impaired granulocyte function with the most consistent defect being chemotaxis in response to bacterial factor. Mild granulocyte dysfunction is frequently associated with MD, but severe dysfunction with many defects is uncommon but can occur, as in this family. There was a tendency for the more severely afflicted members of this family to have more pronounced granulocyte dysfunction. Longitudinal testing in this family may determine any relationship between the granulocyte dysfunction and the onset of MD, as well as any correlation with the progression of the disorder. MD patients who develop infection should have granulocyte function tests as part of their evaluation.

Improved survival in the treatment of advanced Hodgkin's disease at a nonuniversity institution (1970-1979).

From 1970 through 1979, 89 patients with Hodgkin's disease were treated at the Marshfield Clinic/St. Joseph's Hospital. After the pathologic material was reviewed, the patients were analyzed to compare Group I (1970-1973) with Group II (1974-1979). Demographic characteristics in the two groups were similar. In the decade, 76% of patients achieved complete remission. In advanced-stage disease, 50% of patients achieved complete remission in Group I compared with 68% in Group II. At 5 years, 50% of patients were alive without COPP (cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy; with this treatment, 75% of patients survived (P = 0.02). There was improved survival comparing Group I (56% at 5 years) with Group II (76% at 5 years) patients with advanced disease (P = 0.004). More aggressive combination chemotherapy (COPP) was related to the improvement in survival (P less than 0.001). The advances in treatment made by cooperative groups and universities are being transferred to nonuniversity institutions, with appropriate improvement in survival of Hodgkin's disease.

High-dose cytosine arabinoside-associated pancreatitis.

Thirty patients with leukemia and lymphoma have been treated at our institution with high doses of cytosine arabinoside (Ara-C). Gastrointestinal symptoms were frequent after therapy, and 6 of the 30 patients had severe abdominal pain. Of the six, two had pancreatitis; two had normal amylase and lipase determinations; and in two, neither amylase nor lipase levels were determined. The two patients with pancreatitis are presented because this complication of high-dose Ara-C therapy has not been described. The authors conclude that pancreatitis can follow high-dose Ara-C chemotherapy and that patients with abdominal pain following this treatment be evaluated for pancreatitis.

Local intra-arterial streptokinase therapy for acute peripheral arterial occlusions. Should thrombolytic therapy replace embolectomy?

Locally administered low-dose streptokinase was used in 13 patients with acute arterial occlusions. Systemic fibrinolytic effects were noted in each of 11 patients in whom some effective thrombolysis was demonstrated. In the two patients with no angiographically demonstrable thrombolysis, a systemic lytic effect was absent. Bleeding complications were frequent (31%). Three patients required amputations and one patient died. The systemic lytic effects of streptokinase appear to be necessary for complete clot lysis. Locally administered streptokinase appears to have no significant benefit compared to high-dose systemic administration. Occlusions accessible to balloon embolectomy should probably be treated surgically, reserving fibrinolytic therapy for inaccessible lesions. More research is needed to clarify the specific indications, as well as to determine optimal methods of administration and dosage.