Gunnar Grimfors

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life

Summary. We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S‐Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony‐stimulating factor (G‐CSF) + Epo. S‐Epo ≤ 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S‐Epo > 500 U/l and ≥ 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G‐CSF + Epo. The overall response rate was 42% with 28·3% achieving a complete and 13·2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0·001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0·01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48–74%) to treatment with G‐CSF + Epo. The majority of these patients have shown complete and durable responses.

A Combination of Granulocvte Colonv- Stimulating Factor and Erythiopoietin may Synergistically Improve the Anaemia in Patients with Myelodysplastic Syndromes

In an attempt to obtain a synergistic effect on the hemoglobin levels in anaemic patients with myelodysplastic syndromes (MDS), granulocyte colony-stimulating factor (G-CSF) and erythropoietin (epo) were combined in a clinical phase II trial. Twenty-two patients with MDS were included in the study. G-CSF was given alone for six weeks and then in combination with epo for the following twelve weeks. Eight (38%) of 21 evaluable patients showed a significant increase in hemoglobin. One patient with a previous response and subsequent failure to epo alone improved after the addition of G-CSF. Responses were more frequent in patients with less advanced pancytopenia, lower endogenous levels of serum-epo and in those with ring sideroblasts in the bone marrow. The response frequency of 38% is higher than in any study of epo as monotherapy. Moreover, patients with ring sideroblasts, who respond poorly to epo alone, showed a response rate of 60%. Our findings suggest a synergistic in vivo effect of granulocyte-CSF and erythropoietin in patients with myelodysplastic syndromes.

Treatment of myelodysplastic syndromes with retinoic acid and 1α-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study

Abstract: 63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low‐dose ara‐C (arm A) and low dose ara‐C in combination with 13‐cis‐retinoic acid (13‐CRA) and 1α‐hydroxy‐vitamin D3 (1α D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13‐CRA and 1α D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side‐effects than arm A (p = 0.005). Therapeutic effects of 13‐CRA and 1α D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Therapeutic effects of low‐dose cytosine arabinoside, alpha‐interferon, 1α‐hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara‐C, α‐interferon (IFN), 1α‐hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low‐dose ara‐C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara‐C and IDR treatment was generally well‐tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara‐C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.

Biological markers may add to prediction of outcome achieved by the international prognostic score in Hodgkin's disease

BACKGROUND The International Prognostic Score (IPS) identifies seven independent factors predicting progression-free and overall survival in advanced stage Hodgkins disease (HD). The IPS is also applicable in limited disease. However, the IPS does not identify patients with a very poor prognosis. The aim of this study was to define biological markers which may add to the IPS in predicting outcome. PATIENTS AND METHODS One hundred forty-five patients (> 15 years) with HD of all stages and histopathology subgroups were included. In addition to factors included in the IPS, serum levels of CRP, sCD4, sCD8, sCD25, sCD30, sCD54, interleukin (IL)-10, beta2-microglobulin and thymidine kinase were analysed. RESULTS The strongest predictors of a poor cause-specific survival (CSS) in univariate analyses were: increased serum levels of IL-10, sCD30 and CRP, anaemia, low levels of albumin (P < 0.001); stage IV (P = 0.003), age > or = 45 years (P = 0.006), increased serum levels of sCD25 (P = 0.010), low lymphocyte counts (P = 0.020). Serum IL-10 added prognostic information to that achieved by the IPS: patients with a high score and increased serum IL-10 had a very poor outcome with a five-year CSS of 38%. Patients with increased serum levels of sCD30 and a high score also had a poor outcome with a five-year CSS of 54%. CONCLUSION Serum levels of IL-10 and sCD30 may add to IPS in prediction of outcome in HD, and should be validated in large, prospective studies.

Epstein-Barr virus expression in Hodgkin's disease in relation to patient characteristics, serum factors and blood lymphocyte function.

SummaryEpstein–Barr virus (EBV) expression was investigated by immunohistochemistry (latent membrane protein 1 [LMP-1]) and in situ hybridization (EBV encoded RNA [EBER]) in biopsies from 95 patients with untreated Hodgkin’s disease (HD). Tumour EBV status was related to EBV antibody titres, spontaneous and concanavallin A induced blood lymphocyte DNA synthesis, serum levels of soluble (s) CD4, sCD8, sCD25, sCD30, sCD54, β2-microglobulin, thymidine-kinase, routine chemistry, patient characteristics, complete remission and survival. The median follow-up time was 145 months (range 60–257). Tumour EBV-positive (n = 30; 33%) and negative (n = 62; 67%) patients did not differ with regard to sex, age, stage, presence of bulky disease or B-symptoms, remission rate or survival. The proportion of EBV+ cases was significantly higher among patients with mixed cellularity histopathology (58%) as compared to the nodular sclerosis subtype (18%; P < 0.001). The total white blood cell (WBC) counts were significantly lower in EBV+ patients (P < 0.01), who also had significantly higher levels of sCD54 (P < 0.02) and a tendency towards lower levels of sCD30 (P = 0.056). Patients in the tumour EBV+ group had significantly higher IgG antibody titres to restricted early antigen (EA-R) (P < 0.02). Hence, clinical features and outcome were not related to tumour EBV status. However, HD patients with EBV+ tumours had elevated sCD54 levels, higher antibody titres to EA-R and decreased total WBC counts. A potential causal relationship between EBV tumour status and these findings needs to be further explored.

Tissue Eosinophilia in Relation to Immunopathological and Clinical Characteristics in Hodgkin's Disease

Eosinophils frequently infiltrate tissues involved by Hodgkins disease (HD), and blood eosinophilia is frequently observed. However, the clinical significance and the mechanisms underlying eosinophilia need further elucidation. In this study the grade of eosinophilic infiltration (Eol) was evaluated in biopsies from 259 HD-patients. In a selected group (n = 32), the numbers of Hodgkin-Reed-Stemberg (HRS)-cells were counted, and the phenotype of small lymphocytes, the expression of cytotoxic lymphocyte-associated proteins, CD3-chain, HLA-DR, proliferation markers, latent membrane protein 1 (LMP-1) and blood lymphocyte function were evaluated. Samples from 88 HD patients (34%) showed high Eol. Significantly higher Eol was seen in nodular sclerosis 2 (NS2; p < 0.001), bulky disease (p < 0.05) and in patients < 50 years (p < 0.05). Patients with high EoI did not differ from the remainder with regard to distribution of sex, stage, B-symptoms, blood lymphocyte function and outcome. HRS-cells were significantly more frequent in NS HD as compared to mixed cellularity (MC) (p < 0.001) irrespective of EoI. LMP-1-expression, proliferative fraction and phenotypes of small lymphocytes did not differ between the cases with low and high EoI, respectively. MC HD samples had significantly higher numbers of small cells positive for CD8 (p < 0.01), T-cell intracellular antigen-1 (p < 0.01) and Granzyme B (p < 0.05) than NS. LMP-1-positive cases had significantly higher frequency of CD8-positive cells than LMP-1-negative. In conclusion, high EoI remains a feature of certain clinical subgroups of HD. However, there was no association between the degree of EoI and numbers of HRS-cells, phenotypes of small lymphocytes, EBV status and clinical outcome. Determination of EoI is of limited diagnostic and prognostic clinical value in HD. However, the differences in small cell distribution of CD8, TLA-1, GrB and CDS7 between the histopathological groups and between LMP-1-expressing/non-expressing cases may contribute to our understanding of the biology of the disease.

Intensive Treatment and Stem Cell Transplantation in Chronic Myelogenous Leukemia: Long-Term Follow-Up

In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1–3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1–3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. ≈60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed.

Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase – a report from the Swedish CML Group

Summary. In attempting to restore the chronic phase (CP) of chronic myelogenous leukaemia (CML), the Swedish CML group utilized an intensive chemotherapy protocol for 83 patients (aged 16–79 years) in accelerated (AP, n = 22) or blastic phase (BC, n = 61). Most patients received a combination of mitoxantrone (12 mg/m2/d) and etoposide (100 mg/m2/d) together with cytosine arabinoside (1 g/m2 b.i.d) for 4 d. Overall, 39 patients (47%) achieved a second CP (CP2)/partial remission (PR). Responding patients < 65 years were eligible for ablative chemotherapy followed by an allogeneic (SCT) or a double autologous stem cell transplant (ASCT). Seventeen of 34 responders < 65 years failed to proceed to transplantation as a result of early disease progression (n = 15) or disease‐related complications (n = 2). The remaining 17 patients underwent SCT (n = 9; including four unrelated donor SCT) or ASCT (n = 8). Only one of the eight ASCT patients had a second ASCT; the remaining seven failed because of progression (n = 5) or hypoplasia (n = 2). The median duration of CP2/PR was 6 months (range 1–72 months). Five patients achieved a longer CP2/PR than CP1. The 1 year survival was 70% for SCT/ASCT patients (median survival 21 months), 50% for responding patients overall, but only 7% for non‐responders (P < 0·001). Three SCT/ASCT patients are long‐term survivors (65+, 66+ and 73+ months). In conclusion, approximately half of the patients achieved a CP2/PR after intensive chemotherapy, with a clear survival advantage for responders vs non‐responders. Subsequent SCT/ASCT was feasible for half of the responders (< 65 years), and one individual underwent double ASCT. Novel therapeutic options for CML patients in AP/BP are needed.

Treatment of multiple myeloma with interferon alpha: the Scandinavian experience

IFNα is a biologic therapeutic agent with documented antitumoural effect in multiple myeloma. 15% of previously untreated myeloma patients achieve a clinical response to IFNα alone with a possible dose‐response relationship. A particularly good effect is noted in IgA myelomas treated with natural IFNα.