Bosković D

Hypocellular myelodysplastic syndromes

The article is concerned with incidence, clinical features, response to therapy, and prognosis of patients with hypocellular myelodysplastic syndromes. Bone marrow (BM) cellularity <30% (or <20% in patients >70 yr) was found in 24 of 236 (10.2%) trephine biopsies. Median age was 61 yr, with significant male predominance (M/F=3.0) At diagnosis, median hemoglobin was 83 g/L, median platelet and neutrofil counts were 31 × 109/L and 1.2 × 109/L, respectively. According to FAB classification, 17 patients had RA, 6 had RAEB, and only 1 had RAEB-t. Beside marrow hypoplasia, the most prominent PH finding was megakaryocyte hypoplasia and dysplasia, found in two-thirds of cases, each. Comparison between hypocellular and normo/hypercellular MDS cases regarding clinicopathological features showed younger age, more severe cytopenia, less blood and BM blast infiltration, MK hypoproliferation, and more pronounced stromal reactions in former cases. Karyotypic abnormalities were present in 12.5% hypocellular cases, in contrast to 44.6% normo/hypercellular cases (p=0.0025). Eleven patients were treated with supportive therapy alone, six with danazol or androgens, six with immunosuppressive therapy, and one with LDARAC. However, complete or partial response was achieved in only four patients treated with danazol or androgens. None of the patients developed leukemia. Eleven patients died, so marrow insufficiency was the main cause of death. Median survival was 33 mo for hypocellular MDS, and 19 mo for normo/hypercellular MDS (p=0.09). The results confirm the existence of hypocellular variant of MDS, which seems to have better prognosis than those patients with normo/hypercellular disease.

In vitro drug sensitivity of leukemic progenitors and P-glycoprotein expression in adult acute myeloid leukemia: correlation with induction treatment outcome

Abstract: We have investigated the self‐renewal capacity (PE2) and in vitro sensitivity to cytosine‐arabinoside (ara‐C) and daunorubicine (DNR) of leukemic progenitors (CFU‐AML) to determine the significance of these tests for predicting induction treatment outcome in 75 adult acute myeloid leukemia (AML) patients. In addition, in a part of this group of patients (n = 46) we determined the expression of P‐glycoprotein (P‐gp) immunocytochemically and correlated those results with the therapeutic response. We have evaluated 66 patients who showed the following responses: 28/66 complete remissions (CR), 16/66 resistant leukemias (RL) and 22/66 early deaths (ED). The PE2 value was significantly higher in patients with RL than in patients with CR (p<0.00375). CFU‐AML sensitivity to ara‐C and DNR alone was not different between response groups, but the difference in CFU‐AML sensitivity to the combination of two drugs between patients with CR and RL was not significant, although a trend was noted (p<0.06). P‐gp expression was found in only 1/18 patients who achieved CR but in 9/11 patients with RL and 7/11 patients with ED, which is a highly significant difference (p<0.0006). We concluded that both PE2 and P‐gp expression in AML cells are valuable predictors of therapeutic response in adult AML and should be included in creating the best therapeutic approach to AML patients.

The proto-oncogene expression varies over the course of chronic myeloid leukemia

Abstract The chronic phase (CP) of chronic myeloid leukemia (CML) is characterized by the expression of chimeric BCR/ABL gene, extended survival, and profligate growth of maturing granulocyte stemline. The accelerated phase (AP) and blast crisis (BC) of CML are usually manifested by additionally acquired oncogene aberrations, resistance to therapy, advancing anaplasia, progressive organomegaly, and increased blast count. Abnormal expression of some proto-oncogenes may accompany or even precede AP or BC of CML. Our objective was to follow-up oncogene expression over time covering different clinical phases of CML. A total of 85 patients [44 females and 41 males; median age 51 years; range 16–75 years] were studied. At the start of the study, 29 patients were in CP, 25 in an AP, and 31 in BC. Temporal variation in expression (percentage positivity per 1000 analyzed cells) of c-kit, c-myc, H-Ras, cyclin A1, p53, bcl-2 and VEGF oncogenic proteins in CP, AP, and BC of CML was studied by immunohistochemical procedures. This was then correlated with parameters of clinical disease (organomegaly, duration of CP, AP, and BC) and laboratory (Hb, WBC and platelet counts, and the percentage of blasts) data. The level of c-kit expression differed significantly over the course of disease (x2, p = 0·025). Antiapoptotic bcl-2 protein increased significantly with the progression of CML (x2, p = 0·005). The expression of c-myc was most pronounced in the AP (Anova, p = 0·033) and then tended to decline. There was no significant difference in the level of expression of H-Ras, cyclin A1 and p53 over the course of disease. The expression of VEGF protein was most pronounced in the AP (Anova, p = 0·033) and it was inversely correlated with degree of splenomegaly (Pearson, r = −0·400, p = 0·011) and overall survival (log rank, p = 0,042). Conclusion: The changes in oncogene expression, assessed by immunohistochemical approach over the course of CML may have clinical relevance in deciding on and timing of therapy. Temporal distribution of changes in oncoprotein expression in CML requires further study at the molecular level.

Ribosome–Lamella Complexes in the Peripheral Blood of Patients with Chronic Lymphocytic Leukemia are Associated with Serological Immune Deficiency

The ribosome–lamella complex (RLC) is a cylindrical structure composed of different numbers of circular lamellae with associated particles, regarded as ribosomes, around a central core. Structures resembling RLC, but lacking the typical mature appearance of RLC, have been called pre-RLC. The authors have found RLCs and pre-RLCs in peripheral lymphocytes of 3 patients with chronic lymphocytic leukemia (CLL). The fact that CLL patients with RLCs were in early Rai clinical stages, had good clinical prognostic factors, and did not require immediate therapy indicates that RLCs occurred in the early course of some cases of CLL. Moreover, the presence of RLC was associated with hypogammaglobulinemia M.

40 – Modulation of Acute Myeloid Leukaemic Cell Growth by Human Macrophage Inflammatory Protein-1α

Publisher Summary This chapter presents a study in which the effect of the peptide LD78 (the human homologue of murine macrophage inflammatory protein-1α (MIP-1α) that shows 747 amino acid sequence homology with MIP-1α) on bone marrow acute myeloid leukemia (AML) progenitor cells as measured by in vitro CFU-AML growth is investigated. The results demonstrate the inhibitory effect of LD78 on AML cell growth of bone-marrow-derived progenitors, probably mediated by an effect on AML cell proliferation. This suggests that the normal inhibitory control mechanisms mediated by LD78 are still intact in AML progenitor cells. The observed inhibitory effect of LD78 in CFU-AML growth was not related to the type of AML as evaluated by the FAB criteria for classification of AML. The effect of MIP-1α on the proliferation of T-lymphocytes seems to be mediated in part by the inhibition of IL-2 production. The study demonstrates that LD78 is more active on AML progenitors than on AML cell proliferation. Inhibition of the AML cells, although less than that of the progenitors, indicates that more limited activity of LD78 on more mature leukemic cells is present in AML.