[Concern about the safety of erythropoietin in cancer patients]. / Voorzichtig met erytropoëtine bij patiëten met kanker.

Erythropoietin has been shown to shorten survival in cancer patients under certain circumstances. Possible mechanisms are an increase in thrombotic events, tumour progression, and induction of angiogenesis. The FDA advises its use in oncology only as a replacement for blood transfusions in patients receiving chemotherapy. In these patients, a rise in haemoglobin above 7.4 mmol/l should be avoided.

Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study.

Recent investigations have suggested a role for marrow ablative chemotherapy and radiotherapy given with autologous bone marrow transplantation (auto-BMT) in the treatment of acute myeloid leukemia (AML), but prospective studies have not been reported. We assessed the comparative values of auto-BMT and allogeneic marrow transplantation (allo-BMT) in 117 15- to 60-year-old consecutive patients (median, 43 years) with AML following remission-induction therapy. In 32 cases of the 90 (77%) complete responders, auto-BMT (nonpurged) was undertaken at a median of 3.8 months and in 23 eligible cases human leukocyte antigen (HLA)-matched allo-BMT occurred at 3.0 months after attainment of remission. Thus, nearly 60% of complete responders had access to transplantation, the others being withdrawn because of relapse, refusal, or other causes. Median time of regeneration to neutrophils 0.5 x 10(9)/L and platelets 20 x 10(9)/L were 39 and 63 days following auto-BMT versus 21 and 19 days after allo-BMT, respectively. AML relapse was the predominant cause of failure after auto-BMT (17 of 32) and procedure-related death was seen in three of 32 patients. The actuarial rates of relapse at 3 years are 60% (auto-BMT) and 34% (allo-BMT) (log-rank, P = .03). Patients treated with auto-BMT and allo-BMT have an overall survival of 37% and 66% at 3 years posttransplant, respectively (P = .05). Relapse-free 3-year survival rates are 35% and 51%, respectively (P = .12). Survival of the nongrafted complete responders is less than 10%. This study shows that allo-BMT in adult patients with AML in first complete remission (CR) results in more rapid hematopoietic reconstitution, is followed by fewer recurrences, and provides better survival than auto-BMT.

Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group.

PURPOSE: To investigate the value of intensive consolidation chemotherapy not followed by maintenance therapy in adult acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: A multicenter phase II trial was conducted in 130 adult patients with ALL between 16 and 60 years of age. After standard induction therapy, postinduction chemotherapy was given: three courses of high-dose cytarabine (2,000 mg/m2 every 12 hours for four doses) in combination with amsacrine (course one), mitoxantrone (course two), and etoposide (course three). CNS prophylaxis consisted of 10 injections of intrathecal methotrexate (IT MTX). Patients younger than 50 years with an HLA-identical sibling were eligible to receive allogeneic bone marrow transplantation (BMT). RESULTS: Ninety-five patients (73%) achieved complete remission (CR); 82% were younger than 50 years and 41% were older than 50 years. Seventeen patients (13%) were resistant to chemotherapy, and 18 (14%) died during induction treatment. Only age and performance status were significantly associated with response (P<.001 and .03, respectively). Death during consolidation occurred in four patients. The estimated 5-year overall survival (OS) was 22% for the entire group and 26% for patients younger than 35 years. Disease-free survival (DFS) at 5 years was 28% +/- 6 for patients younger than 35 years, 25% +/- 9 for patients between 35 and 50 years, and 0% for patients older than 50 years. Increasing age (P<.01) and expression of CD34 (P<.01) were adverse factors. Only three patients (3%) developed an isolated CNS relapse. CONCLUSION: Intensive consolidation including high-dose cytarabine not followed by maintenance therapy provides an outcome for adult patients with ALL that may be worse or even inferior compared with studies using long-term maintenance therapy. High-dose cytarabine in combination with IT MTX was effective for CNS prophylaxis.

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.

Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group.

PURPOSE AND METHODS: Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS: A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION: In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

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.

Cancer, fatigue and the return of patients to work-a prospective cohort study.

Fatigue is a highly prevalent and debilitating symptom in cancer survivors. The aim of this study was to assess the impact of fatigue and other cancer-related symptoms on the return to work of cancer survivors. A prospective inception cohort study with 12 months of follow-up was initiated. At 6 months following the first day of sick leave, levels of fatigue, depression, sleep problems, physical complaints, cognitive dysfunction and psychological distress were assessed, in addition to clinical, sociodemographic and work-related factors. Data were obtained from one academic hospital and two general hospitals in the Netherlands. 235 patients who had a primary diagnosis of cancer and underwent treatment with curative intent were included. The rate of return to work was measured at 6, 12 and 18 months. Hazard ratios (HRs) for the duration of sick leave up to 18 months following the first day of sick leave were calculated. The rate of return to work increased from 24% at 6 months to 64% at 18 months following the first day of sick leave. Fatigue, diagnosis, treatment type, age, gender, depression, physical complaints and workload were all related to the time taken to return to work. Fatigue scores were also strongly related to diagnosis, physical complaints, and depression scores. Fatigue at 6 months predicted a longer sick leave with a hazard ratio of 0.71 (95% Confidence Interval (C.I.) 0.59-0.85), adjusted for diagnosis, treatment type, age and gender. In a multivariate Cox regression analysis, diagnosis, treatment, age, physical complaints and workload remained the only significant predictors of duration of the sick leave. 64% of cancer survivors returned to work within 18 months. Fatigue levels predicted the return to work. This was independent of the diagnosis and treatment, but not of other cancer-related symptoms. Better management of cancer-related symptoms is therefore needed to facilitate the return to work of cancer patients.

Extensive early apoptosis in frozen-thawed CD34-positive stem cells decreases threshold doses for haematological recovery after autologous peripheral blood progenitor cell transplantation.

Stem cell doses necessary for engraftment after myelo-ablative therapy as defined for fresh transplants vary largely. Loss of CD34+ cell quality after cryopreservation might contribute to this variation. With a new early apoptosis assay including the vital stain Syto16, together with the permeability marker 7-AAD, CD34+ cell viability in leucapheresis samples of 49 lymphoma patients receiving a BEAM regimen was analysed. After freeze-thawing large numbers of non-viable, early apoptotic cells appeared, leading to only 42% viability compared to 72% using 7-AAD only. Based on this Syto16 staining in the frozen-thawed grafts, threshold numbers for adequate haematological recovery of 2.8-3.0 x 10(6) CD34+ cells/kg body weight determined for fresh grafts, now decreased to 1.2-1.3 x 10(6) CD34+ cells/kg. In whole blood transplantation of lymphoma patients (n = 45) receiving a BEAM-like regimen, low doses of CD34+ cells were sufficient for recovery (0.3-0.4 x 10(6)CD34+ cells/kg). In contrast to freeze-thawing of leucapheresis material, a high viability of CD34+ cells was preserved during storage for 3 days at 4 degrees C, leaving threshold doses for recovery unchanged. In conclusion, the Syto16 assay reveals the presence of many more non-functional stem cells in frozen-thawed transplants than presumed thus far. This led to a factor 2.3-fold adjustment downward of viable CD34+ threshold doses for haematological recovery.

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.

Platelet volume analysis for differential diagnosis of thrombocytosis.

The results of the Coulter counter S plus II platelet volume analysis were studied in 100 patients with reactive thrombocytosis (platelet count greater than 500 X 10(9)/l), in 30 patients with myeloproliferative thrombocytosis, and in 32 patients with chronic myeloproliferative disease and a platelet count less than 500 X 10(9)/l. Patients with reactive thrombocytosis had considerably lower mean platelet volumes than those with myeloproliferative thrombocytosis, or normal subjects. The opposite was true for the platelet distribution width. This index for platelet heterogeneity was normal in reactive, but increased in myeloproliferative thrombocytosis. There were no differences in mean platelet volume or platelet distribution width between patients with myeloproliferative disease and a high or normal platelet count. The increased platelet heterogeneity in myeloproliferative disease was caused by an increase of both small and large platelets. The platelet distribution width seemed to be the best variable for the differential diagnosis of thrombocytosis. A platelet distribution width greater than 17 was found in 26 of the 30 patients with myeloproliferative thrombocytosis but in only five of the 100 patients with reactive thrombocytosis. A normal platelet distribution width in a patient with a high platelet count strongly suggests reactive thrombocytosis.

Increased mean platelet volume in septicaemia.

An increased mean platelet volume (MPV), measured by the Coulter counter model S plus, was found in 13 of 25 patients with proven septicaemia but in none of 25 patients with localised bacterial infection and negative blood cultures. The increase in MPV was found both in patients with normal and low platelet counts and was not related to a particular micro-organism. Patients who responded favourably to antibiotic treatment all had normal MPVs after one week of treatment. However, 9 of 11 patients with a prolonged course of their infection due to endocarditis or abdominal abscesses had raised MPVs after seven days of treatment, and four patients who died of infection in the first week all had increased MPVs on the day of their death. An increased MPV in a patient with bacterial infection possibly indicates that the infection has become invasive--that is, that septicaemia has occurred. A persistent rise or further increase indicates that treatment is inadequate.

Thrombocytopenic purpura as first manifestation of human immunodeficiency virus type I (HIV-1) infection.

We report three cases of thrombocytopenic purpura associated with HIV-1 infection. The clinical picture is indistinguishable from classic autoimmune thrombocytopenic purpura (AITP). All three patients initially responded to treatment with high dose methylprednisolone. One patient had an incomplete remission on low dose prednisone, while another responded to zidovudine treatment. The third patient underwent splenectomy because he showed no response to treatment with low dose prednisone or zidovudine. The pathogenesis of HIV-associated thrombocytopenic purpura (HIV-TP) is still controversial. Two hypotheses are frequently mentioned: non-specific deposition of circulating immune complexes and complement versus specific auto-antibodies against platelets are suggested to be the cause of the increased clearance of platelets. In cases of severe thrombocytopenia, the therapy of first choice is initial high dose methylprednisolone, followed by either low dose prednisone in the presence of a relatively unaffected cellular immunity, or zidovudine, when the cellular immunity is already severely impaired.

Effectiveness of low dose cyclosporine in acquired aplastic anaemia with severe neutropenia.

Six patients with acquired aplastic anaemia were treated with cyclosporine (5 mg/kg/day) either alone or in combination with corticosteroids. A favourable response was observed in 4, including 2 patients presenting with an absolute granulocyte count of less than 0.2 x 10(9)/l. The 6th patient showed no effect after 6 wk of therapy and was thereafter successfully treated with anti-thymocyte globulin (ATG). Side effects of cyclosporine therapy were minimal (maximum follow-up 20 months). Temporary discontinuation of the drug in 1 patient resulted in a relapse which responded to reinstitution of therapy. Our results indicate that cyclosporine may be an effective, well-tolerated agent in acquired aplastic anaemia even in previously untreated patients with severe neutropenia.

[Diarrhea due to Clostridium difficile toxin in hemato-oncological patients]. / Diarree door een toxine van Clostridium difficile bij hemato-oncologische patiënten.

In two patients with multiple myeloma, men aged 72 and 54 years, diarrhoea developed upon chemotherapy with vincristin, doxorubicin and dexamethasone (VAD). In the second patient, diarrhoea developed after subsequent peripheral stem cell mobilisation. Pseudomembranous colitis was seen in the first patient during endoscopy but an enzyme immunoassay of the faeces was false negative for Clostridium difficile enterotoxin. The bacterium was later cultured from stool samples and toxins were detected in a repeated immunoassay. Stool samples of the second patient were positive for C. difficile enterotoxin. For both patients an antibiotic treatment resulted in a rapid recovery. In haemato-oncological patients, diarrhoea is often caused by oncolytic therapy. However, consideration should also be given to C. difficile infection as an alternative cause which is easily treatable.

[Thrombotic microangiopathy: thrombocytopenia and hemolytic anemia]. / Trombotische microangiopathie: trombocytopenie en hemolytische anemie.

Thrombotic microangiopathy is an acute and severe syndrome characterised by a combination of thrombocytopenia, haemolytic anaemia with a negative direct antiglobulin test, and fragmentocytes in the blood smear. The condition can be idiopathic but can also be caused by various underlying diseases. The main causes are thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. By measuring the von Willebrand factor cleaving protease activity, it now appears possible to distinguish between the different causes of thrombotic microangiopathy, although the sensitivity and specificity of this measurement still need to be clarified. In patients with haemolytic uraemic syndrome without preceding diarrhoea, one should search for infectious foci outside the gastrointestinal tract, using a polymerase-chain reaction to detect the two different verotoxin genes where necessary. Plasmapheresis treatment has reduced the fatality rate amongst patients with thrombotic thrombocytopenic purpura from 90% to 10-25%. Since patients benefit most from rapid institution of treatment, yet the diagnostics currently take several days, the recommendation in case of doubt regarding the original diagnosis is to apply initial plasma exchange therapy to all patients with thrombotic microangiopathy.

[Diagnostics for classification of anemia]. / De diagnostiek van anemie.

Examining peripheral blood smears provides valuable information in the diagnosis of anaemia despite large inter- and intraobserver variation. The classification of anaemia is usually based on the average erythrocyte size, referred to as the mean corpuscular volume (MCV). Microcytosis indicates a reduced haemoglobin synthesis caused by either an iron deficiency or haemoglobinopathy, a congenital disorder. Macrocytosis is the result of a disruption to the division and maturing of proerythroblasts in the bone marrow, due, for example, to vitamin B12 (folic acid) deficiency or excessive alcohol use. Furthermore, a high number of reticulocytes in the blood indicates an increased production of erythrocytes whereas a low total indicates an inadequate production level. In addition to the case history and the physical examination, the MCV and number of reticulocytes can provide guidance with respect to further diagnostic investigation.

[Autologous stem cell transplantation in haematological disorders,1980-2002]. / Autologe stamceltransplantatie bij hematologische aandoeningen, 1980-2002.

OBJECTIVE: To describe activities in the field of autologous stem cell transplantation in haematological disorders in the Netherlands in the periods before and after 1993 (at that time blood was introduced as source of stem cells). DESIGN: Descriptive, retrospective cohort study. METHOD: Data were collected from the Netherlands Stem Cell Transplantation Registry TYPHON. Details of all transplant patients were reported to TYPHON by the individual transplantation centres. In this overview we describe the changes in transplantation-related mortality, relapse rates and survival in the periods 1 January 1980-31 December 1992 and 1 January 1980-31 December 2002. RESULTS: The number of autologous stem cell transplantations increased almost five-fold in the period 1993-2002. Since 1993 the main indications for transplantation were multiple myeloma (MM) and non-Hodgkin lymphoma (NHL), as well as acute myeloid leukaemia (AML), which was the main indication in the period before 1993. In the period before 1993 most relapses were observed in patients with acute lymphoblastic leukaemia (ALL) and MM, which resulted in low survival rates. After 1993 no great differences in relapse or survival rates were observed between the different disorders. The survival rates for patients with ALL improved during the last research period, especially among younger patients (< 45 years). CONCLUSION: The number of autologous stem cell transplantations has increased considerably since 1993, especially in patients with MM and NHL.