Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

High-vs low-dose cytarabine combined with interferon alfa in patients with first chronic phase chronic myeloid leukemia. A prospective randomized phase III study.

A prospective randomized phase III study was performed to evaluate whether intensified cytarabine would induce a higher response rate and longer event-free interval as compared to low-dose cytarabine in chronic myeloid leukemia (CML). One hundred and eighteen patients with CML in early chronic phase entered the study. Twenty-eight out of 32 patients assigned to group A received two cycles of a combination of intensified cytarabine and idarubicin followed by interferon alfa (IFN-alpha) maintenance, 28 patients in group B received standard treatment by a combination of low-dose cytarabine and IFN-alpha. Forty-nine patients with a human leukocyte antigen-identical sibling donor proceeded to allogeneic stem cell transplantation (allo-SCT) and nine patients were excluded from the analysis. Hematological response was observed in 97% of the patients in group A vs 86% of the patients in group B during the first year of treatment. In group A, 16 patients (50%) achieved a major cytogenetic response, which compared to seven patients (25%) with a major cytogenetic response in group B. With a median follow-up of 58 months (range 34-76), event-free survival was not significantly different between arms A and B. The estimated 5-year survival rate was 56% in the intensified arm and 77% in the low-dose arm (P = 0.05). Recipients of allo-SCT showed a 5-year estimated survival rate of 55%. Although intensified cytarabine induced a higher initial percentage of major and complete cytogenetic responses, responses were not sustained by IFN-alpha maintenance therapy.

Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia.

PURPOSE: The hematopoietic growth factors (HGFs) introduced into induction chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to treatment outcome by at least two mechanisms. HGFs given on days simultaneously with CT might sensitize the leukemic cells and enhance their susceptibility to CT. HGFs applied after CT might hasten hematopoietic recovery and reduce morbidity or mortality. MATERIALS AND METHODS: We set out to evaluate the use of granulocyte-macrophage colony-stimulating factor (GM-CSF; 5 microg/kg) in a prospective randomized study of factorial design (yes or no GM-CSF during CT, and yes or no GM-CSF after CT) in patients aged 15 to 60 years (mean, 42) with newly diagnosed AML. GM-CSF was applied as follows: during CT only (+/-, n = 64 assessable patients), GM-CSF during and following CT (+/+, n = 66), no GM-CSF (-/-, n = 63), or GM-CSF after CT only (-/+, n = 60). RESULTS: The complete response (CR) rate was 77%. At a median follow-up time of 42 months, probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years were 38% and 37% in all patients. CR rates, OS, and DFS did not differ between the treatment groups (intention-to-treat analysis). Neutrophil recovery (1.0 x 10(9)/L) and monocyte recovery were significantly faster in patients who received GM-CSF after CT (26 days v 30 days; neutrophils, P < .001; monocytes, P < .005). Platelet regeneration, transfusion requirements, use of antibiotics, frequency of infections, and duration of hospitalization did not vary as a function of any of the therapeutic GM-CSF modalities. More frequent side effects (eg, fever and fluid retention) were noted in GM-CSF-treated patients predominantly related to the use of GM-CSF during CT. CONCLUSION: Priming of AML cells to the cytotoxic effects of CT by the use of GM-CSF during CT or accelerating myeloid recovery by the use of GM-CSF after CT does not significantly improve treatment outcome of young and middle-aged adults with newly diagnosed AML.

Successful treatment of veno-occlusive disease of the liver with urokinase in a patient with non-Hodgkin's lymphoma.

A 38-year-old man with a non-Hodgkin's lymphoma of intermediate grade malignancy attained partial remission after three courses of CHOP (cyclophosphamide+hydroxydaunorubicin+vincristine+prednisolone). He was assigned to undergo autologous bone marrow transplantation (ABMT). The conditioning regimen consisted of cyclophosphamide and whole body irradiation. Two weeks later he developed veno-occlusive disease (VOD) of the liver. Doppler sonography confirmed the diagnosis showing a reversal of the blood flow in the portal vein. In addition a large thrombus was present in the inferior caval vein. Protein C level was strongly reduced (28%). Because of clinical deterioration intravenous urokinase was started. The transaminases normalised rapidly and the patient showed a dramatic clinical improvement. There were no major bleeding complications. Repeat Doppler sonography showed a normal antegrade flow in the portal vein. This case suggests that a coagulopathy in the hepatic vascular bed might contribute to the development of VOD and that patients with VOD are at risk for other thrombotic complications. Furthermore it shows that urokinase with platelet support can be given safely and effectively to a patient with VOD and severe thrombocytopenia.

Efficacy of etoposide and mitoxantrone in patients with acute myelogenous leukemia refractory to standard induction therapy and intermediate-dose cytarabine with amsidine. Dutch Hematology-Oncology Working Group for Adults (HOVON).

Thirty-seven newly diagnosed patients with acute myeloid leukemia (AML) who were not in complete remission (CR) after induction chemotherapy with cytarabine and daunorubicin followed by intermediate-dose cytarabine and amsacrine, were treated with mitoxantrone and etoposide in a prospective, open multicenter study. The aim was to examine the efficacy and the toxicity of mitoxantrone and etoposide in a patient population with bad prognosis because of refractoriness to two standardized induction courses. Twelve patients attained CR (32.4%). Responders were found only among the patients with documented susceptibility (i.e. partial remission) to the previous therapy. In responding patients the median remission duration and disease-free survival was 15+ months (range 3-52+). Toxicity was mainly hematologic and characterized by prolonged hypoplasia; one patient died in aplasia. Granulocytes and platelets recovered unexpectedly early in six of 22 non-responders. This study suggests that AML patients refractory to two standardized chemotherapy courses can still attain a durable CR after an additional course, here with mitoxantrone and etoposide, provided they show some responsiveness to the previously given cytostatic drugs.

A randomized study of granulocyte colony-stimulating factor applied during and after chemotherapy in patients with poor risk myelodysplastic syndromes: a report from the HOVON Cooperative Group. Dutch-Belgian Hemato-Oncology Cooperative Group.

The purpose of this study was to determine the safety and efficacy of filgrastim as an adjunct to induction and consolidation chemotherapy in poor risk patients with myelodysplastic syndrome (MDS). Filgrastim was given both during and after chemotherapy with the objective to accelerate hematopoietic repopulation and enhance the efficacy of chemotherapy. In a prospective randomized multicentre phase II trial, a total of 64 patients with poor risk primary MDS were randomized to receive either granulocyte colony-stimulating factor (G-CSF, filgrastim, AMGEN, Breda, The Netherlands) 5 microg/kg/day subcutaneously or no G-CSF in addition to daunomycin (30 mg/m2/days 1, 2 and 3 intravenous bolus) and cytarabine (200 mg/m2 days 1-7, continuous infusion). The overall complete response rate was 63%: 73% for patients receiving filgrastim as compared to 52% in the standard arm (P = 0.08). Overall survival at 2 years was estimated at 29% for patients assigned to the filgrastim arm and 16% for control patients (P = 0.22). The median time for recovery of granulocytes towards 1.0 x 10(9)/l post-chemotherapy was 23 days in the filgrastim-treated patients vs 35 days in the standard arm (P = 0.015). There were no differences in time of platelet recovery, length of hospital stay, duration of antibiotic use or infectious complications between the two treatment groups. However the earlier recovery of neutrophils in the filgrastim group was associated with a reduced interval of 9 days between the induction and consolidation cycle. In patients with poor risk MDS the use of filgrastim during and after induction therapy results in a significantly reduced neutrophil recovery time. Further study may be warranted to see if the apparent trend of the improved response to chemotherapy in combination with filgrastim can be confirmed in greater number of patients and to assess the effect of the addition of filgrastim on survival.

Fever and neutropenia in cancer patients: the diagnostic role of cytokines in risk assessment strategies.

Cancer patients treated with chemotherapy are susceptible to bacterial infections. Therefore, all neutropenic cancer patients with fever receive standard therapy consisting of broad-spectrum antibiotics and hospitalization. However, febrile neutropenia in cancer patients is often due to other causes than bacterial infections. Therefore, standard therapy should be re-evaluated and new treatment strategies for patients with variable risk for bacterial infection should be considered. This paper reviews the changing spectrum of microorganisms and resistance of microorganisms to antibiotics in infection during neutropenia and discusses new strategies for the selection of patients with low-risk for bacterial infection using clinical and biochemical parameters such as acute phase proteins and cytokines. These low-risk patients may be treated with alternative therapies such as oral antibiotics, early discharge from the hospital or outpatient treatment.

Selective oral antimicrobial prophylaxis for the prevention of infection in acute leukaemia-ciprofloxacin versus co-trimoxazole plus colistin. The EORTC-Gnotobiotic Project Group.

230 leukaemic patients were entered into a randomised, prospective, multicentre trial of either ciprofloxacin (1 g/day) or co-trimoxazole (1920 mg/day) plus colistin (800 mg/day) for the prevention of infection during granulocytopenia. Bacteraemia due to resistant gram-negative rods occurred only in the co-trimoxazole-colistin group though both regimens were effective for selective gastrointestinal tract decontamination. However, there were fewer patients without any infective complications (31% vs. 18%: P = 0.02), fewer febrile days [mean (S.D.) 5.9 (1.1) vs. 8.2 (1.4): P = 0.0242], a lower proportion of infective events (0.9 (0.16) vs. 1.2 (0.18): P = 0.005) and fever occurred later (median 19 vs. 14 days: 0.025 less than P less than 0.05) in the co-trimoxazole-colistin group. The choice of prophylactic regimen therefore appears to depend upon whether or not protection against gram-negative infection is required or better systemic prophylaxis overall.

Aggressive chemotherapy for acute leukaemia frequently causes intestinal protein leakage.

Cytostatic drugs are known to produce disturbances in intestinal absorption of carbohydrates. To further explore the gastrointestinal (GI) toxicity of cytostatic therapy, 37 patients with acute leukemia were investigated during and/or after remission induction courses by the use of the differential sugar absorption test (DSAT) and the intestinal clearance of alpha-1-antitrypsin (ClAAT). The ratio of the lactulose to the mannitol excretion in the urine was found abnormal in 44% of the tests. The ClAAT was increased in 74% of tests. The tests results differed considerably from patient to patient and depended on the chemotherapy course; correlation between the tests was low, probably indicating the unrelated pathophysiological processes were measured. After haematological regeneration, abnormal test results normalised. It is concluded that aggressive chemotherapy not only causes a reduction in the absorption of sugars, but commonly also protein leakage. These GI side-effects are reversible, and the application of both tests in combination provides a practical and reproducible method for investigation of GI toxicity in patients treated with cytostatic drugs.

Routine radiography does not have a role in the diagnostic evaluation of ambulatory adult febrile neutropenic cancer patients.

Cancer patients treated with chemotherapy are susceptible to bacterial infections. When an adult patient presents with febrile neutropenia, standard diagnostic care includes physical examination, laboratory diagnostics, chest X-ray (CXR) and sinus radiography. However, the yield of routine radiography in the diagnostic evaluation of ambulatory adult febrile neutropenic patients with normal findings at their physical examination is questionable. Two CXRs and one sinus X-ray were obtained in 109 and 106 febrile neutropenic episodes after chemotherapy in ambulatory adult patients who had no clinical signs suggesting pulmonary infection or sinusitis. We found that in only two of 109 (1.8%; 95% Confidence Interval (CI): 0.3-5.8%) febrile neutropenic episodes without clinical signs of new pulmonary disease, the CXR showed a consolidation suggesting pneumonia. In addition, in five of 88 (5.7%; 95% CI: 2.2-12.0%) febrile episodes in asymptomatic patients, sinus X-ray suggested sinusitis. In none of these seven episodes was a change of antibiotic therapy necessary. In the absence of clinical signs indicating pneumonia or sinusitis, the yield of CXR and sinus radiography in ambulatory adult cancer patients presenting with febrile neutropenia is minimal; CXR and sinus radiography should no longer be performed on a routine basis.

Heparin small pool high yield purified factor VIII: in vivo recovery and half-life of routinely produced freeze-dried concentrate.

New approaches and techniques for improving source material collection and Factor VIII production at Blood Bank level have been reported recently. Heparin has been shown to be of importance in increasing yields and stability of FVIII in the purification and concentration process. Work has been done to develop on a routine scale the heparin double cold precipitation technique for the production of a freeze-dried high yield purified FVIII concentrate. The product has been tested clinically in 4 severe hemophilia A patients for recovery, half-life and acute side-effects, using two dosages over 8 infusions. There was no significant difference between the two dosages. Mean recovery 99.1% and mean half-life 8 hr, ranging from 6.5 to 10.3 hr. No side-effects justify further exploration of the potential of heparin for high yield purified FVIII production.

Fournier's gangrene as first presentation of promyelocytic leukemia.

A 50-year-old male is described who presented with Fournier's gangrene as what is probably the first manifestation of a newly diagnosed acute myelogenous leukemia (AML), promyelocytic type or variant type M3 according to the FAB classification. Despite aggressive fluid resuscitation, tuned infusion of vasoactive drugs, appropriate antibiotics and extensive surgical debridement, the patient died within 24 h as a result of irreversible septic shock.

Changes of buoyant density during the S-phase of the cell cycle. Direct evidence demonstrated in acute myeloid leukemia by flowcytometry.

Studies with synchronized or exponentially growing bacteria and mammalian cell lines are not able to demonstrate small changes in buoyant density during the cell cycle. Flowcytometric analysis of density separated acute myeloid leukemia cells, a system not dependent on time-related variables, shows that the cellular buoyant density increases slightly with up to 0.008 g/ml during the S-phase, at least in cryo-preserved cells used in this study. This contrasts with the generally accepted belief that S-phase cells have a lower or constant buoyant density. A practical implication is that separation of cell (sub)populations based on differences in buoyant density could be flawed to the extent that these populations contain S-phase cells.

Recovery of murine myelopoiesis after cytostatic reduction by Ara-C. Effect of bacitracin-induced changes in the intestinal microflora and influence of timing.

The influence of intestinal flora modulation by oral bacitracin on the recovery of myelopoiesis after Ara-C was studied in C3H/Law mice. Bacitracin resulted in a 3-5 log increase of Gram-negative bacteria and a 10-fold increase of the intestinal endotoxin concentration. Initiation of bacitracin before Ara-C stimulated the initial rebound increase of colony-forming units for granulocytes and macrophages (CFU-GM) from 23.2 +/- 1.3 to 28.4 +/- 1.4 x 10(3) per femur. Starting the bacitracin after Ara-C advanced the second phase of the rebound CFU-GM increase with 6 days. An important role in the recovery of myelopoiesis after cytostatic drugs in C3H/Law mice is suggested for the intestinal Gram-negative microflora, probably mediated by bacterial endotoxin.

Modulation of the intestinal microflora by the non-absorbable antibiotic vancomycin leads to a reduction of the tumor load in liver and spleen in a leukemic rat model.

Based on previous studies where it was shown that non-absorbable antibiotics can influence the normal hematopoiesis via changes in factors related to the intestinal microflora, the influence of vancomycin on the progression of acute myeloid leukemia was investigated in the BNML rat model. Oral vancomycin, which selectively reduces Gram-positive bacteria in the gut, leads to diminution of the leukemic load in liver and spleen by 30-60%. This 'antileukemic effect' is not dependent on Gram-negative bacteria as source for endotoxin. The presumed mechanism is a decrease of the leukemic growth fraction caused by alterations in the absorption of substances from intestinal Gram-positive bacteria.

Influence of high versus low intestinal concentration of gram-negative bacteria and endotoxin on the susceptibility of murine myelopoiesis in bone marrow and spleen to cytostatic treatment with Ara-C.

The haematopoietic recovery after i.v. cytarabine was studied in C3H/Law mice as a measure for stem cell susceptibility in relation to the intestinal Gram-negative bacteria (GNB) and endotoxin. Reduction or elevation of GNB and endotoxin was induced by either polymyxin or bacitracin, both non-absorbable antibiotics. Bacitracin caused less suppression of the splenic cellularity after cytarabine, and an advancement of the recovery of femoral nucleated cells. The femoral recovery of CFU-GM exhibited a biphasic pattern. The speed and height of the rebound increase of CFU-GMs were significantly affected by the antibiotics. Thus, (modulation of) the murine intestinal microflora influences the haematopoietic recovery after cytostatic drugs. The mechanisms involved are complex; intestinal endotoxin seems to play a role.

Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia?

The clinical use of autologous marrow transplantation in acute myeloid leukemia (AML) has been hampered by the inability to collect adequate numbers of cells after remission induction chemotherapy and the notably delayed hematopoietic regeneration following autograft reinfusion. Here we present a study in which the feasibility of mobilizing stem cells was investigated in newly diagnosed AML. Among 96 AML patients, 76 patients (79%) entered complete remission. Mobilization was undertaken with low dose and high dose schedules of G-CSF in 63 patients, and 54 patients (87%) were leukapheresed. A median of 2.0 x 10(6) CD34+ cells/kg (range 0.1-72.0) was obtained in a median of three leukaphereses following a low dose G-CSF schedule (150 microg/m2) during an average of 20 days. Higher dose regimens of G-CSF (450 microg/m2 and 600 microg/m2) given during an average of 11 days resulted in 28 patients in a yield of 3.6 x 10(6) CD34+ cells/kg (range 0-60.3) also obtained following three leukaphereses. The low dose and high dose schedules of G-CSF permitted the collection of 2 x 10(6) CD34-positive cells in 46% and 79% of cases respectively (P = 0.01). Twenty-eight patients were transplanted with a peripheral blood stem cell (PBSC) graft and hemopoietic repopulation was compared with the results of a previous study with autologous bone marrow. Recovery of granulocytes (>0.5 x 10(9)/l, 17 vs 37 days) and platelets (>20 x 10(9)/l; 26 vs 96 days) was significantly faster after peripheral stem cell transplantation compared to autologous bone marrow transplantation. These results demonstrate the feasibility of PBSCT in the majority of cases with AML and the potential advantage of this approach with respect to hemopoietic recovery.

Deletion (8)(q22) as the only chromosomal abnormality in a patient with RAEB-t with progression to acute myelocytic leukemia.

Cytogenetic investigation of the bone marrow cells of an 88-year-old woman with refractory anemia with an excess of blasts in transformation with progression to acute myelocytic leukemia (AML), FAB classification M4, revealed a deleted chromosome #8 with the breakpoint at band q22 as the sole abnormality. This breakpoint is the same as that in t(8;21)(q22;q22), mostly found in patients with AML. This finding is discussed in relation to the possible oncogenesis of AML, which in this case may mean that the deletion of chromosome #8 at band 8q22 and the resultant loss of genetic material with possible antioncogenic activity is the critical event leading to malignant transformation in AML and not the translocation of the end of 21q next to 8q.

Intraspinal extramedullary haematopoiesis in a patient with myelofibrosis.

A 54-year-old patient with myelofibrosis developed paresis of the legs, and bladder dysfunction due to extramedullary haematopoiesis in the spinal channel. He was given palliative radiotherapy but died shortly afterwards. Although rare, the possibility of extramedullary haematopoiesis in the central nervous system should be considered when neurological symptoms appear in a patient with myelofibrosis, because good palliation is possible with timely radiotherapy.

[Diagnostic image (92). A man with fever during chemotherapy. Invasive pulmonary mycosis]. / Diagnose in beeld (92). Een man met koorts tijdens chemotherapie. Invasieve pulmonale mycose.

A 64-year-old male was treated for acute myeloid leukemia with idarubicin and cytarabin. He developed pulmonary mycosis (radiologically consistent with aspergillosis), which responded to intravenous amphotericin B.