Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study.

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P =.0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P =.14), relapse-free survival (34% versus 9% at 2 years, P =.031) and overall survival (22% versus 12%, P =.046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P =.0089) and daunorubicinol (P <.0001) were significantly higher in CsA-treated patients. Survival (P =.0003) and induction response (P =.028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML.

Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003).

Current information on Waldenström macroglobulinemia (WM) is based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were enrolled in a prospective observational multicenter clinical trial. Of these, 182 patients with symptomatic or progressive disease were treated with 4 to 8 cycles of therapy with a purine nucleoside analogue, fludarabine (FAMP; 30 mg/m(2) of body-surface area daily for 5 days every 28 days). A serum beta2-microglobulin (beta2M) level below 3 mg/L and a hemoglobin level of at least 120 g/L (12 g/dL) at presentation predicted a lower likelihood of requiring therapy. The overall rate of response to FAMP therapy was 36% (95% confidence interval, 29%-44%), with 2% complete remissions. Patients who were 70 years old or older had a substantially lower likelihood of response (odds ratio, 0.34; P =.004) than younger patients. On multivariate analysis, a serum beta2M level of 3 mg/L or higher, hemoglobin level below 120 g/L, and serum IgM level below 40 g/L [4 g/dL] were significant adverse prognostic factors for survival. We developed a simple staging system for WM by using these variables and identified 4 distinct subsets of patients with estimated 5-year overall survival rates of 87%, 64%, 53%, and 22%, and 5-year progression-free survival rates of 83%, 55%, 33%, and 12%. Prognosis in WM is highly variable and serum beta2M was the dominant predictor of a need for therapy and of survival. FAMP has activity against WM. Our staging system may provide guidance for a risk-based approach to the treatment of WM.

Significance of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients.

BACKGROUND: In patients with B-cell chronic lymphocytic leukemia (CLL), considerable disease heterogeneity within clinical stages necessitates the search for relevant prognostic indicators, particularly those that may help to determine the need for early therapeutic intervention. In the current study, the authors investigated the role of p53 mutations and chromosomal abnormalities in 30 patients with CLL. METHODS: Thirty patients were screened for p53 mutations. Half of the group had aggressive disease characterized by leucocytosis, lymph node enlargement, organomegaly, and shortened tumor doubling time. Because 95% of p53 mutations reside in "hot-spot" regions of exons 5-9 of the p53 gene, the authors sequenced these exons completely for mutation detection. RESULTS: Sequence analysis identified p53 mutations in 14 of 30 patients that were distributed equally among patients with aggressive disease and nonaggressive disease. There were six mutations in exon 7, five mutations in exon 5, and one mutation each in exons 6 and 8. Five of 15 patients with clinically aggressive disease had mutations in exon 7. Only one patient with nonaggressive disease had an exon 7 mutation. Abnormal cytogenetics were present in 22 of 30 patients (73%). Most patients with the p53 mutation (13 of 14 patients; 93%) displayed abnormal cytogenetics. Twelve of 15 patients with aggressive disease and 9 of 15 patients with average disease exhibited abnormal karyotypes. CONCLUSIONS: The presence of p53 mutations did not predict clinical behavior or disease outcome, although the frequency of mutations appears to be higher than reported previously. In this study, mutations of exon 7 (5 of 6 patients) occurred in patients with clinically aggressive disease. The significance of this observation warrants further examination.

Clinical and quality of life outcomes of laparoscopic and open splenectomy for haematological diseases.

OBJECTIVE: To study the outcome of open and laparoscopic splenectomy for haematological diseases in terms of quality of life and haematological measures. DESIGN: Prospective non-randomised study. SETTING: Tertiary care hospital, USA. PARTICIPANTS: 44 patients, 27 treated laparoscopically and 17 by open splenectomy. MAIN OUTCOME MEASURES: Quality of life judged by the SF-36 and adequacy of control of the haematological disease. RESULTS: Both quality of life and haematological disease were significantly improved by operation; laparoscopically treated patients had less pain. CONCLUSION: In properly selected patients laparoscopic splenectomy is preferable to open splenectomy.

Laparoscopic excision of accessory spleen.

BACKGROUND: Laparoscopic splenectomy has become an accepted procedure in the management of several hematologic diseases. Less clear is the effectiveness of laparoscopic excision of accessory spleens after initial splenectomy in the management of recurrent hematologic disease. We report here our early experience of this technique. METHODS: All patients who underwent laparoscopic excision of accessory spleens (LEAS) after initial splenectomy were reviewed for preoperative studies, technical success, and effects on either platelet count or hemoglobin level. RESULTS: In 5 patients LEAS was attempted. Two patients had initial open splenectomies, and 3 had initial laparoscopic splenectomies. Hematologic diagnoses were immune thrombocytopenic purpura (3), chronic lymphocytic leukemia-induced thrombocytopenia (1), and autoimmune hemolytic anemia (1). All patients underwent preoperative damaged red blood cell scintigraphy, which demonstrated functioning splenic tissue, and abdominal computed tomography scans, which demonstrated a nodule in 4 of 5 patients. LEAS was technically successful in 4 patients, with the 1 failure also being the patient in whom the computed tomography scan could not demonstrate the accessory spleen. However, only 2 of the 4 patients after LEAS had durable hematologic responses to surgery, despite follow-up damaged red blood cell scintigraphy showing no residual functioning splenic tissue. CONCLUSION: LEAS can be technically successful when the accessory spleen is demonstrated on both damaged red blood cell scintigraphy and computed tomography scan; therefore, adequate visualization in both studies is required. However, hematologic response to excision may be less effective than with the initial splenectomy. Further study is needed to determine the causes of these outcomes.

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617.

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

Trisomy 15, sex chromosome loss, and hematological malignancy.

We report 6 patients with myelodysplasia who, on routine cytogenetic studies, demonstrated trisomy 15. Four of these also had sex chromosome loss. A review of the literature revealed 6 other cases of trisomy 15 with sex chromosome loss and 22 cases of trisomy 15 as the sole chromosomal abnormality. All cases had hematologic malignancy or myelodysplasia. Trisomy 15 is uncommon but tends to be associated with myelodysplasia in older subjects, and with sex chromosome loss in about one third of cases.

Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

Bryostatin 1 is a natural product isolated from the marine bryozoan Bugula neritina in 1982 and is currently undergoing evaluation in a number of malignancies. Twenty-five patients with relapsed, low-grade non-Hodgkin's lymphoma or chronic lyphocytic leukemia (CLL) received bryostatin 1 by 72-h continuous infusion every 2 weeks at a dose of 120 microg/m2 per course. Patients who progressed while receiving bryostatin 1 alone could participate in a feasibility study by receiving vincristine administered by bolus i.v. injection immediately after the completion of the bryostatin 1 infusion. The dose of vincristine was escalated in groups of three patients as follows: level 1, 0.5 mg/m2; level 2, 1.0 mg/m2; and level 3, 1.4 mg/m2 with vincristine doses capped at 2.0 mg for all patients. Bryostatin 1 alone resulted in one complete remission and two partial remissions. Nine patients received sequential treatment with bryostatin 1 and vincristine. The addition of vincristine at a dose of 2 mg was feasible and caused the expected dose-related sensory neuropathy. Phenotypic analysis by flow cytometric analysis on pre- and post-bryostatin 1-treated peripheral blood lymphocytes revealed up-regulation in the coexpression of CD11c/ CD22 on CD20+ B cells in two of four CLL patients studied, which is consistent with in vitro findings of differentiation of CLL cells to a hairy cell phenotype.

Heparin-induced thrombocytopenia and thrombosis.

Heparin remains the most commonly used parenteral medication in hospitalized patients. Heparin induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis syndrome or the white clot syndrome are important complications of heparin use. This article provides an in-depth review of the etiopathogenesis, clinical manifestations, diagnosis, and management options in patients with HIT. Clinical problems associated with HIT such as antiphospholipid antibody syndrome and venous gangrene are described. The management options of HIT patients during cardiac interventional procedures and coronary surgery as well as recent advances in therapeutic options are summarized.

Clinical significance of Y chromosome loss in hematologic disease.

We have studied 215 male patients (aged 45-97 years) whose sole cytogenetic abnormality was clonal loss of the Y chromosome in metaphase cells from unstimulated cultures. The patients comprised a control group with no evidence of hematologic disease and four disease case groups: 1) myelodysplastic syndrome (MDS), refractory anemia, refractory anemia with excess blasts (RAEB), RAEB in transformation, and chronic myelomonocytic leukemia; 2) acute myelogenous leukemia; 3) myeloproliferative disorder (MPD), chronic granulocytic leukemia, and polycythemia vera; and 4) B-cell lymphoma/leukemia. The frequency of cells with Y loss increased with age and was significantly greater in cases than in controls, but it was not correlated with survival or with prior therapy. The frequency of cases with a -Y clone was 6.3% of male karyotypes and represented 16.4% of all abnormal male cytogenetic reports. Much of the difference between cases and controls appears to be accounted for by a greater frequency of cases with > 75% Y loss. A value of 81% chromosome Y loss maximized the combined sensitivity (28%) and specificity (100%) for predicting disease status, but a 75% cutoff provided the best estimate of disease risk. Even in older males, if > 75% of metaphase cells are 45,X,-Y, they probably represent a disease-associated clonal population, and it is possible that the critical genetic change is not visible through the microscope. This observation is true for MDS, MPD, B-cell disease, and especially acute myelogenous leukemia. The prognostic association of Y chromosome loss for survival appears to be neutral or favorable. Genes Chromosomes Cancer 27:11-16, 2000.

Waldenström's macroglobulinemia in young African-American adults.

We have identified five African-American patients with Waldenström's macroglobulinemia (WM) diagnosed at a young age (ages 35, 38, 38, 40, 51; 4 males, 1 female). All had a history of intravenous heroin abuse and four also used cocaine. Their manner of presentation and clinical course were typical. Three of three patients tested for the hepatitis C virus (HCV) were positive and three of three patients tested were HIV negative. The potential relationship between intravenous drug abuse and/or HCV to development of WM in this group of young patients is provocative, especially since a polyclonal increase in serum IgM is commonly seen in chronic intravenous heroin addicts. More recently, the contribution of HCV is being evaluated in lymphoproliferative disorders. Although WM is typically a disease of older people, it should also be considered in the differential in a young patient with a suggestive clinical picture.

Mutation analysis of the HFE gene associated with hereditary hemochromatosis in African Americans.

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African-American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population.

Factor VII G331D: a variant molecule involving replacement of a residue in the substrate-binding region of the catalytic domain.

An individual identified as having a dysfunctional factor VII was studied to seek underlying genetic defects. A heterozygous mutation in the factor VII gene exon 8 was identified as substitution of A for G at nucleotide position 10,909 [Gly331(GGC) to Asp (GAC)]. An abolished MspI restriction site was used to confirm heterozygosity for the defect. The mutation occurs within the substrate-binding pocket at a locus on the surface of the factor VII molecule containing a protein-protein interactive site for substrates, providing an explanation for the observed dysfunctional procoagulant activity.

Carboplatin infusion in relapsed and refractory acute myeloid leukemia--a Southwest Oncology Group trial.

Carboplatin (CBDCA) is an active agent in the treatment of acute leukemia and is associated with limited extramedullary toxicity. Simultaneous phase II trials were conducted by the Southwest Oncology Group in adult patients with relapsed or refractory acute myeloid leukemia (AML). CBDCA was given as a continuous infusion at a dose of 300 mg/m2 daily for 5 days. Three (8%) of the 37 eligible patients in the relapsed group achieved complete remissions (CRs) lasting 3, 4, and 26 months. Entry of patients was stopped early in the refractory group due to slow accrual and in the relapsed group due to low CR rate. For both groups combined, the CR rate was 3/45 or 7% (95% confidence interval 3-18%). There were 12 fatal toxicities. Four patients died of intracerebral hemorrhage, three of infection, and five of hepatic and/or renal failure. Nonhematologic grade 4 toxicity included diarrhea in three patients, hyperbilirubinemia in four, and mucositis and renal toxicity in one each. These results suggest that CBDCA should not be considered for treatment of relapsed or refractory AML patients with prior high-dose therapy.

IgG Antibodies Against Factor VIII in Normal Individuals.

Previously, we found noninhibitory antibody against factor VIII in a hemophilic subject. We screened sera from normal and hemophilic individuals for the presence of similar antibodies. Sera from 18 normal individuals and 17 hemophilia A subjects were tested for the presence of factor VIII antibodies. We also tested two commercial immunoglobulin preparations for the presence of similar antibodies. Serum from two normal individuals were found to have IgG1 and IgG2 antibodies against factor VIII. The two commercial immunoglobulin preparations also contained IgG1 and IgG2 antibodies against factor VIII. Conclusions: Sera of apparently normal individuals contain antibodies to factor VIII with no inhibitory qualities. Such antibodies against factor VIII appear to be a common occurrence.

A new approach to immunologic identification of factor VIII antibodies.

We tested for antibodies against factor VIII by using monoclonal antibody-purified factor VIII preparation as a source of antigen. The factor VIII was adsorbed on nitrocellulose membranes and stored in a refrigerator until later use. Plasma or serum was incubated with the factor VIII containing strip and the antibody was detected by another incubation with peroxidase-labelled antihuman immunoglobulin antibodies. The test was efficient in detecting antibodies in haemophilic and normal subjects with acquired inhibitors to factor VIII. It also detected antibodies to the factor VIII protein in a haemophilic subject with no evidence of inhibitor. The technique is simple, readily applicable, and serves as a useful screening tool for detecting factor VIII antibodies. The stability of the antigen-containing strips in a refrigerator is a practical advantage with potential commercial application.

Treatment of cyclophosphamide-induced intractable hemorrhagic cystitis.

We report the successful use of prostaglandin F2 alpha continous bladder irrigation in two patients for the treatment of intractable cyclophosphamide-induced hemorrhagic cystitis which was resistant to conventional therapy in two patients. A 0.7 mg% solution of prostaglandin F2 alpha was used for continuous bladder irrigation at a rate of 150 to 200 cc/hr for four days. The response was complete in both patients and no side effects were noted.

Discrepant In Vivo Recovery of Factor VIII:C Following Infusion of Two Different Monoclonal Factor VIII Preparations.

Background: We experienced decreased recovery of factor VIII:C after commercial monoclonal factor VIII infusions. We report the recovery data obtained from infusing two brands of monoclonal factor VIII. Methods: Factor VIII:C activity was measured before and after an infusion of one of two monoclonal factor VIII preparations. The increments were calculated and expressed as a function of units of factor VIII administered per kilogram. Results: Monoclate increments averaged 2.3% (range: 1.6-3.2%). Antihemophilic factor (human) method M (AHFM) yielded an average increment of 1.4% (range: 1-1.7%). Conclusions: The two monoclonal factor VIII preparations used are not equivalent in activity. In switching brands, one must recalculate the prescribed dose based on the institution's experience in recovery of VIII:C from the particular brand to be prescribed. Cost calculations and comparisons should be based on the recovered factor VIII:C increments rather the unit purchase price.