Per Boye Hansen

Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma

The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)-maxi-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.gov as #NCT00514475.

Consumption, overdose and death from analgesics during a period of over‐the‐counter availability of paracetamol in Denmark

Abstract. During the period 1978–1986, annual sales of paracetamol in Denmark increased from 1 million defined daily doses (DDD) (3 g) to 47 million DDD, while the number of admissions and deaths from overdose increased from 26 to 202 and from 1 to 3–4, respectively. The corresponding figures for salicylates are a decrease in sales from 113 to 94 million DDD, an increase in admissions from 282 to 595, and an increase in deaths from 5 to 22. From 1 January 1984 paracetamol became available on an over‐the‐counter basis. The figures for 1983 and 1984 were an increase in sales from 14 to 28 million DDD, an increase in admissions from 114 to 198, and an increase in deaths from 0 to 4. The number of deaths from opioid overdose remained constant at a value of about fifty during this period, the mortality per dose being about 20‐fold higher than for paracetamol and salicylates. Dextropropoxyphene‐related deaths increased twofold to 121 in 1986, with unchanged sales figures. A campaign launched by the National Board of Health resulted in a reduction in the number of deaths from dextropropoxyphene to 66 in 1987. The main effect of over‐the‐counter release of paracetamol was a dramatic increase in sales, without the epidemic of deaths observed a decade ago in the UK. It is suggested that the higher mortality of paracetamol poisonings in the UK compared to Denmark is related to the dextropropoxyphene content of the combination product, which is not available in Denmark. From an epidemiological toxicological viewpoint such combinations are not justified.

Human immunodeficiency virus-associated malignant lymphoma in eastern Denmark diagnosed from 1990 to 1996 : Clinical features, histopathology, and association with Epstein-Barr virus and human herpesvirus-8

Abstract: The clinicopathological features of human immunodeficiency virus (HIV)‐associated lymphoma were investigated in a retrospective study of 85 adult patients in eastern Denmark diagnosed during the period 1990–1996. The possible pathogenetic role of Epstein‐Barr virus (EBV) and human herpesvirus 8 (HHV‐8) in these tumours was also studied. Seventy patients (82%) presented with extranodal disease and 26 (31%) had CNS involvement at diagnosis. Diffuse large cell B‐cell lymphoma was the most frequent histological subtype, comprising 65 of 79 cases available for microscopic re‐evaluation (82%) and including 20 of 23 evaluable patients with CNS lymphoma (87%). EBV RNA was demonstrated by in situ hybridization in 51 of 65 evaluable tumours (79%) and in 14 of 16 cases (88%) with CNS‐lymphoma. Three cases showed a T‐cell phenotype. The presence of HHV‐8 DNA was analysed by PCR in 32 cases. A strong band consistent with tumour cell infection was detected in only one case, weaker bands being seen in 4 cases. None of these patients had primary effusion lymphomas. In conclusion, Danish AIDS‐related lymphomas are of predominantly high‐grade B‐cell type with extranodal localization and atypical presentation. Our results provide further evidence that EBV plays a major role in the pathogenesis of large cell AIDS‐related lymphoma, whereas HHV‐8 does not appear to contribute significantly to the development of solid lymphomas in this group of patients.

Different membrane expression of CD11b and CD 14 on blood neutrophils following in vivo administration of myeloid growth factors

Summary. During the administration of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) or granulocyte‐macrophage CSF (rhGM‐CSF) we studied the early and late changes of membrane antigen density on neutrophils. RhG‐CSF and rhGM‐CSF both caused an early transient reduction in blood neutrophilic granulocyte‐concentration within the first 30 min after treatment followed by a marked later increase during the subsequent 24 h. During the early neutropenia quantitative flow cytometry showed an associated marked increase in the density of membrane CD11b from 169 × 103 before to 568 × 103 A.U. per cell induced by rhGM‐CSF but a non‐significant change by rhG‐CSF, suggesting that different mechanisms may be responsible for the transient neutropenia. The subsequent neutrophil granulocytosis was followed by a significantly (P<0.05) increased density of the CD14 antigen from 6.1 × 103 before to 15.9 × 103 A.U. per cell during treatment with rhG‐CSF. but not by rhGM‐CSF administration.

CD34+ megakaryoblastic leukaemic cells are CD38-, but CD61+ and glycophorin A+: improved criteria for diagnosis of AML-M7?

The aim of this flow cytometry study in acute megakaryoblastic leukaemia (AML-M7) was to describe the membrane phenotype of CD34+ progenitor subsets and compare these with the phenotypes expressed by other AML FAB types. Following conventional histopathological diagnosis mononuclear cells from bone marrow and blood were examined in seven patients with AML-M7 and compared with results from 26 sequential patients with AML-M0 to AML-M6. The CD34+ subsets in AML-M7 patients differed from that of patients with AML-M0 to AML-M6 as the CD34+ CD61+ and the CD34+ Glycophorin A+ subsets were median 31% and 20%, respectively, compared to 4% and 2% in the AML-M0 to AML-M6 (P = 0.0005). Only 1% of the CD34+ progenitors were CD34+ CD38+ in AML-M7 compared to 72% in other AML subtypes (P < 0.000). these findings suggest that the cd34+ cell compartment in AML-M7 consists of early lineage-specific progenitors. In conclusion, flow cytometry analysis of CD34+ subsets may improve the diagnostic safety in AML-M7 and consequently the prognostic significance of immunophenotyping in acute leukaemia.

Fatal Virus-Associated Hemophagocytic Syndrome Associated With Coexistent Chronic Active Hepatitis B and Acute Hepatitis C Virus Infection

A 28‐year‐old man was admitted to our department with intermittent fever, hepatosplenomegaly and pancytopenia. Liver parameters and serum ferritin were markedly elevated. Bone marrow biopsy showed hypocellularity, histiocytic hyperplasia, and hemophagocytosis consistent with a virus‐associated hemophagocytic syndrome (VAHS). There was serological evidence of chronic active hepatitis B and acute hepatitis C virus infection. The patient died despite aggressive immunosuppressive and supportive treatment. Autopsy revealed signs of acute viral hepatitis with cholestasis. Histiocytes engaged in hemophagocytosis were observed in bone marrow and spleen. The condition was interpreted as VAHS associated with chronic active hepatitis B and acute hepatitis C virus infection. To our knowledge this is the first report of a hemophagocytic syndrome in that setting. Am. J. Hematol. 61:135–138, 1999.

Priming and treatment with molgramostim (rhGM-CSF) in adult high-risk acute myeloid leukemia during induction chemotherapy: a prospective, randomized pilot study

Abstract: In a randomized study of 18 adult patients with high‐risk or advanced acute myeloid leukemia (AML) we investigated the effect of supplementing conventional induction chemotherapy with recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF). For comparison, a historical control group of 90 patients treated for de novo AML with conventional chemotherapy during the previous period, 1984–1990, was also analyzed. Before induction chemotherapy, 10 patients were randomized to receiving rhGM‐CSF, starting on day 1 to 3 before chemotherapy and continued for a maximum of 21 days after the start of induction treatment. Fatal complications and treatment outcome did not differ between the study groups and historical controls. Nor were there any differences between the groups in terms of hematological toxicity, e.g. time to three‐lineage regeneration and need for supportive therapy. However, sequential weekly bone marrow examinations revealed a prolonged reduction of the relative number of myeloid (CD33‐positive) marrow cells in the rhGM‐CSF treated group. Although the small number of patients studied may not permit a definite conclusion, this randomized study did not demonstrate major beneficial effects of combining rhGM‐CSF with standard induction chemotherapy in high‐risk patients with AML.

Hematopoietic Growth Factors for the Treatment of Myelodysplastic Syndromes

Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or rh interleukin-3 (rhIL-3) effectively stimulate and expand marrow myelopoiesis resulting in a dose-dependent increment of peripheral blood neutrophils in most patients with myelodysplasias (MDS). Clinical outcome with fewer infections have been reported in a few studies using rhG-CSF or rhGM-CSF, including a large randomized, controlled trial with rhGM-CSF. Clinical effective stimulation of megakaryopoiesis and erythropoiesis are however infrequent. Recently, rh erythropoietin (rhEpo) has been used to overcome the ineffective erythropoiesis in MDS to reduce transfusions needed. However, the efficiency has been low in most studies with marked differences in response rates. The most impressive clinical results were obtained in patients with milder forms of MDS combined with low prestudy endogenous S-Epo levels. The possible synergistic effect of combining rhEpo with rhG-CSF or rhGM-CSF has been studied with erythropoietic response rates of about 40%. The safety of the cytokine administration seems acceptable with no significant stimulation of leukemic myelopoiesis and subsequent progression into overt acute myeloid leukemia. In conclusion, combinations of hematopoietic growth factors may be of clinical benefit in some patients with MDS. However, due to the cost and unpredictable clinical outcome there is a need for extended laboratory research to understand the functional defects of MDS stem cells and progenitors.

Short-term myeloid growth factor mediated expansion of bone marrow haemopoiesis| studied by localized magnetic resonance proton spectroscopy

Summary. Previously we have shown that short‐term myeloid growth factor priming of haemopoiesis prior to bone marrow harvest increased the yield of myeloid progenitors in the graft. The present study is intended to investigate the expansion of haemopoiesis by volume selective proton magnetic resonance spectroscopy (MRS).

Blood neutrophil increment after a single injection of rhG-CSF or rhGM-CSF correlates with marrow cellularity and may predict the grade of neutropenia after chemotherapy

Summary. The grade of neutropenia after chemotherapy seems to be correlated to the bone marrow cellularity as judged by biopsies. Prolonged blood neutropenia after sequential chemotherapy reduces dose intensity and increases the risk of severe infections. A predictive non‐invasive test for marrow cellularity is needed in the attempt to predict chemotherapy‐induced blood neutropenia.