Ugo Consoli

Multidrug resistance mechanisms in chronic lymphocytic leukaemia

Summary. We evaluated the presence of P‐glycoprotein (P‐gp)‐170, multidrug resistance protein (MRP), lung resistance protein (LRP)‐56 and Bcl‐2 in CD19‐positive cells from 100 cases of chronic lymphocytic leukaemia (CLL). P‐gp‐170 was found in 73% of the CLL cases with no significant difference regarding stage or previous treatment. LRP‐56 protein was homogeneously distributed with no differences for stage or treatment. MRP protein was detected at a low level of expression in 49·4% of CLL patients with no differences for stage or treatment. Bcl‐2 protein was expressed at a high level in all CLL patients and higher levels were found in the advanced stage. This leads us to conclude that P‐gp, MRP, LRP‐56 and Bcl‐2 are frequently expressed in CLL. P‐gp, MRP and LRP are not correlated to stage or previous treatment. Bcl‐2 is higher in advanced‐stage patients. The clinical and biological significance of these zMDR mechanisms in CLL remains to be fully explained.

G-CSF alone vs cyclophosphamide plus G-CSF in PBPC mobilization of patients with lymphoma: results depend on degree of previous pretreatment

Summary:We performed a randomized study to compare ‘G-CSF alone’ (administered at dose of 10u2009mcg/kg/day) and ‘cyclophosphamide plus G-CSF’ (cyclophosphamide at dose of 4u2009g/m2 and G-CSF at dose of 10u2009μg/kg/day), as PBPC mobilization schedules in 52 patients with NHL or HD. Randomization was stratified according to the amount of previous chemotherapy (⩽2 and >2 lines of previous chemotherapy). Mean CD34+ cell peak in P.B., mean ‘Total CD34+ cells’ harvested and percentage of patients successfully mobilized, in the group mobilized with ‘G-CSF alone’ vs the group mobilized with ‘cyclophosphamide plus G-CSF’, were: 35.3 × 106 vs 45.8 × 106/l (P=0.3), 5.4 × 106 vs 6.8 × 106/kg (P>0.9) and 50 vs 61% (P=0.4). No differences were observed in the stratum of less pretreated patients. However, in the stratum of patients who had previously received more than two lines of chemotherapy, CD34+cell peak (P=0.05) and percentage of successful mobilization (P=0.01) were higher when ‘cyclophosphamide plus G-CSF’ was used. Using logistic regression, both age and mobilization with ‘G-CSF alone’ were significantly associated with a low CD34+ cell peak in P.B. However, in the stratum of less pretreated patients, only age was significantly associated with this risk.

Acute promyelocytic leukemia during pregnancy: report of 3 cases.

Acute promyelocytic leukemia (APL) is characterized by onset at a young age and a life-threatening hemorrhagic diathesis, which is attributed to a disseminated intravascular coagulation (DIC)-like coagulopathy. The discovery of all-trans-retinoic acid has changed the course of APL treatment by reducing the onset of DIC and inducing a complete and durable remission in more than 90% of patients. The occurrence of APL during pregnancy is not a frequent event, but the management of these patients raises many therapeutic and ethical dilemmas and requires a careful clinical case evaluation of fetal and maternal risk, coagulation status, the parents’ wishes, and therapeutic options. Here we describe 3 patients with APL diagnosed during pregnancy. Clinical data and the therapeutic approaches are presented. In the discussion, we analyze clinical decisions and therapeutic options and compare our cases with those found in the literature. Int J Hematol. 2004;79:31-36.

Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma

BACKGROUNDnA combination of bortezomib (1.3 mg/m(2)), melphalan (5 mg/m(2)), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated.nnnPATIENTS AND METHODSnFifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, base schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, weekly schedule).nnnRESULTSnSide-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in weekly schedule (36% versus 66% in base schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7-50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months).nnnCONCLUSIONnTaken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.

A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients

A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients

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.

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.