Patrizia Guglielmo

Quality of life in elderly patients with acute myeloid leukemia: patients may be more accurate than physicians

Background The aim of this study was to evaluate changes in quality of life scores and their association with therapy and survival in unselected elderly patients with acute myeloid leukemia. Design and Methods From February 2003 to February 2007, 113 patients aged more than 60 years with de novo acute myeloid leukemia were enrolled in a prospective observational study. Two different quality of life instruments were employed: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – C30 (EORTC QLQ-C30) and a health-related quality of life questionnaire for patients with hematologic diseases (QOL-E). Results Forty-eight patients (42.4%) received intensive chemotherapy and 65 (57.6%) were given palliative treatments. Age greater than 70 years (P=0.007) and concomitant diseases (P=0.019) had a significant impact on treatment allocation. At diagnosis, general quality of life was affected [median QOL-E standardized score 54, interquartile range 46–70; median EORTC global score 50, interquartile range 41–66]. Most patients were given a good ECOG Performance Status (< 2), which did not correlate with the patients’ perception of quality of life. At multivariate analysis, palliative approaches (P=0.016), age more than 70 years (P=0.013) and concomitant diseases (P=0.035) each had an independent negative impact on survival. In a multivariate model corrected for age, concomitant diseases and treatment option, survival was independently predicted by QOL-E functional (P=0.002) and EORTC QLQ-C30 physical function (P=0.030) scores. Conclusions Quality of life could have an important role in elderly acute myeloid leukemia patients at diagnosis as a prognostic factor for survival and a potential factor for treatment decisions.

Beta-1-lntegrin Expression in Adult Acute Lymphoblastic Leukemia: Possible Relationship with the Stem Cell Antigen CD34

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

All-Trans-Retinoic-Acid- and Growth-Factor- Mediated Induction of Alkaline Phosphatase Activity in Freshly Isolated Chronic Myeloid Leukemia Cells

Reduced or absent neutrophil alkaline phosphatase (NAP) activity is a common feature of neutrophilic granulocytes from patients with chronic myeloid leukemia (CML). In this study we examined whether NAP activity could be restored in vitro by stimulating CML cells with different promoters such as all-trans-retinoic acid (ATRA), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). The results obtained indicated that ATRA and G-CSF, either alone or in combination, were effective in inducing NAP activity in CML cells, whereas GM-CSF was not. Further, NAP restoration in ATRA- and G-CSF-treated cultures was accompanied by increased morphologic differentiation of the CML clone. It might be concluded that the CML clone could be driven in vitro by ATRA and G-CSF both to achieve granulocytic maturation and to correct functional NAP-related defects.

Familial B-cell chronic lymphocytic leukemia in a population of patients from Southern Italy.

We investigated the prevalence of chronic lymphocytic leukemia (CLL) in 9650 relatives of 510 CLL patients from 5 different regions (Apulia, Basilicata, Campania, Calabria, and Sicily) of Southern Italy. Data collection included a family history questionnaire. In our series of 510 CLL patients, 53 families with 2 or more individuals who had chronic lymphoproliferative disease (CLD) or other hematological malignancies were identified. In these families, 27 cases of CLL, 10 of indolent non-Hodgkin’s lymphoma, and 7 of multiple myeloma were identified in relatives of CLL probands. Twenty-two relatives developed hematological malignancies other than CLD (19, acute leukemia; 3, chronic myeloid leukemia). In this study the prevalence of CLD in relatives of 510 CLL patients was 8.6% (44/510), and the prevalence of CLL in the same series was 5.2% (27/ 510). Considering the presence of clusters of individuals with hematological malignancies, overall our series contained 4 families showing a cluster with more than 2 cases. The most frequent pattern of affected family members was represented by 39 families (39/53 [73%]) with affected siblings or cousins only. Twenty siblings had CLL. The other families showed a multigenerational pattern with an affected parent-offspring relationship in only 11 (21%) of the cases and with a combination of the first 2 categories in 3 (6%) of the families. In 8 families belonging to both the last 2 mentioned groups, the affected offspring had an earlier disease onset than their parents, suggesting anticipation. We estimated the size and examined the pattern of familial aggregation of hematological malignancies, in particular CLL/CLD, in a specific geographical area. CLL was the most frequent disease in relatives, mainly siblings, of our CLL patients. Our results may be a contribution to the characterization of the epidemiological distribution pattern of CLL.

Successful treatment of advanced idiopathic myelofibrosis with imatinib mesylate

To the Editor: Idiopathic myelofibrosis (IM) is a clonal myeloproliferative disorder characterized by bone marrow fibrosis, extramedullary hemopoiesis, splenomegaly and leuko-erythroblastic blood picture (1). Till date, conventional treatments for IM have been directed toward the alleviation of symptoms and have shown limited efficacy without improving overall survival (2). As such, investigations on new therapeutic strategies are warranted. Here we describe two cases of IM in the advanced stage of the disease who were successfully managed with imatinib mesylate (Glivec, Novartis, Basel, Switzerland). The patients were two males, aged 63 and 59 years, respectively, whose diagnosis was confirmed by standard criteria (2) and scored as high risk according to Lille scoring system (3). One of the patients (case 2) presented HBV-related hepatic cirrhosis also. Cytogenetic analysis of bone marrow samples revealed in both cases a normal karyotype and molecular analysis showed no finding of Bcr-Abl fusion gene. Both patients underwent conventional treatment with hydroxyurea; however, after a median time of 21.5 months, they become drugrefractory. Peripheral blood analysis showed uncontrollable hyperleukocytosis in the two patients (median WBC count: 59.8 · 10/L) with morphologic features of accelerated phase; case 1 showed a decrease in Hb concentration (Hb: 8.9 g/dL), while case 2 needed weekly red blood and platelet cell transfusions because of anemia (Hb: 7.2 g/dL) and severe platelet reduction (PLT: 9.0 · 10/L). All of them exhibited elevated lactate dehydrogenase (LDH) levels (median 900.5 U/L). The pictures of bone marrow specimens confirmed diagnosis of accelerated phase of the disease. Cytogenetic re-evaluation showed no clonal abnormalities in case 1, while case 2 presented monosomy 7 in 10% of the metaphases. Again, there was no finding of BcrAbl fusion gene. Therapy with imatinib mesylate, at a daily dosage ranging from 200 to 400 mg (according to toxicity) was then started. No other cytotoxic or supportive agents were combined to imatinib mesylate. Patients exhibited a prompt hematologic response within 2 wk of therapy. In particular, case 2 did not need any further cell transfusions. Table 1 shows clinical data at 3 months of therapy. Imatinib mesylate normalized or reduced the WBC count (case 1, WBC: 10.8 · 10/L; case 2, WBC: 16.2 · 10/L), leaded to an increase in both Hb concentration and platelet count, reduced LDH levels and the degree of hepato-splenomegaly. Bone marrow examination revealed a reduction in the count of myeloblasts and promyelocytes with pictures of hypercellular marrow. No other cytogenetic abnormalities were detected. Imatinib mesylate administration is still going on with minimal side effects (fluid retention and musculoskeletal pain). The therapeutic role of imatinib mesylate therapy in chronic myeloproliferative disorders other than CML remains to be explored. Few trials have been reported to date and, although clinical results were not pronounced, partial responses (spleen size reduction, improvement in Hb concentration and platelet count) were documented (4–6). Even if two

T Cell Receptor δ-Chain Gene Rearrangement in a Novel Case of Adult NK Cell Leukemia

Malignancies arising from natural killer (NK) cells are being increasingly recognized as distinct clinicopathological entities. We here report the characteristics of a peculiar case of NK-cell acute leukemia with unusual agranular morphology and rearrangement of the T-cell receptor (TCR) δ-chain gene.

In vitro apoptotic response of freshly isolated chronic myeloid leukemia cells to all-trans retinoic acid and cytosine arabinoside.

Chronic myeloid leukemia (CML) is a hematological malignancy resulting from clonal expansion and massive accumulation of leukemic myeloid cells that retain differentiation and maturation capacity. Since CML cell accumulation has been related to apoptosis inhibition by the product of the BCR-ABL gene, attempts to eradicate leukemic cells would require therapeutic drugs able to overcome this inherent resistance. Here, we investigated in vitro the apoptotic effect of all-trans retinoic acid (ATRA) and cytosine arabinoside (ARA-C), employed alone, in combination or in sequence, on freshly isolated cells from 10 patients with chronic-phase CML. Our cell cultures showed that both ATRA and ARA-C were able to induce apoptosis in CML cells, even if ARA-C resulted more effective than ATRA. The combined use of ATRA and ARA-C seemed to have only an additive effect while the sequential use did not show any advantage. These in vitro observations indicate that ATRA and ARA-C may be effective in reducing CML cells through apoptosis induction, suggesting that it could be worthwhile to examine ATRA and ARA-C combinations in the therapy of CML.

Alterations in Ornithine Decarboxylase and Transglutaminase Activities in Lymphocytes from Untreated Patients with Chronic Lymphocytic Leukemia

Ornithine decarboxylase (L-ornithine carboxylase, EC 4.1.1.17) and transglutaminase (R-glutaminylpeptide: amine gamma-glutamyltransferase, EC 2.3.2.13), enzymes implicated in the regulation of growth processes, were studied in lymphocytes from untreated patients with chronic lymphocytic leukemia. A marked increase of ornithine decarboxylase activity was found in lymphocytes from chronic lymphocytic leukemia patients when compared to normal human lymphocytes; in contrast, no transglutaminase activity was found in lymphocytes from untreated patients with chronic lymphocytic leukemia.

Thymostimulin in Aplastic Anaemia

Rosario Giustolisi, MD, Patrizia Guglielmo, MD, Emma Cacciola, MD, Rossella R. Cacciola, MD, Chair of Haematology, Università di Catania, Ospedale Ferrarotto, Via S. Citelli 6, I-95124 Catania (Italy) It has been demonstrated that T lymphocytes from peripheral blood and bone marrow of some patients with severe aplastic anaemia (SAA) were able to suppress hematopoiesis in vitro [1] and that among the T cells those bearing receptors for IgG (T/-cells) could be responsible for such a suppressive effect [2]. Furthermore, pure red cell aplasia (PRCA) might be correlated to an imbalance between T lymphocyte subpopulations with suppressor T cell predominance [3]. On the basis of these findings, immunotherapeu-tic approaches employing nonselective immuno-suppressive drugs and/or antilymphocyte globulin were attempted in the management of AA. These treatments are usually accompanied by severe side effects. We here report that in some cases of AA an immunoregulatory T-dependent abnormality can be Table I. Haematological and immunological parameters before and after Thymostimulin treatment

T lymphocyte subpopulations in the bone marrow and peripheral blood of untreated patients with myeloma.

SummaryThe quantitative distribution of the two main T lymphocyte subsets, recognizable by the ‘high’ and ‘low-affinity’ E rosette-forming cell technique of West, was studied in both the bone marrow and peripheral blood from ten untreated multiple myeloma (MM) patients. A reduced total T lymphocyte count, with a relative predominance of ‘low-affinity’ T lymphocytes (putative suppressor T cells), was found in the peripheral blood. Within a normal total T lymphoid cell count, a predominance of the T lymphocyte subset with ‘low-affinity’ characteristics was also observed in the bone marrow. An inverse correlation, that was statistically significant, was seen between the monoclonal malignant cellular B component and the ‘low-affinity’ T cell percentage in all cases. It is concluded, therefore, that such an imbalance between the ‘high’ and ‘low-affinity’ T subsets, with the latter predominating, could be of importance in the regulation of the growth rate of the monoclonal cellular B component.