Biomedical subjects

E Pogliani

Publications and source records attributed to E Pogliani.

At least 19 recordsLinked to original sources

PubMed2002

Diffuse bronchiolo-alveolar carcinoma in a dog.

An eight-year-old female German wirehaired pointer was presented with signs of respiratory distress. Clinical examination, laboratory results, thoracic radiography and echocardiography indicated the presence of a diffuse interstitial lung disease with secondary appropriate erythrocytosis, pulmonary hypertension and cor pulmonale. Transthoracic fine needle aspiration biopsy of the lung suggested malignant epithelial neoplasia. A primary lung cancer with an unusually diffuse distribution of miliary/micronodular lesions was found at postmortem examination. Histological diagnosis was bronchiolo-alveolar carcinoma. Bronchiolo-alveolar carcinoma can occasionally occur in a diffuse fashion involving most or all of the lung parenchyma. In man, diffuse bronchiolo-alveolar carcinoma is considered a great imitator of other, more common diffuse interstitial forms of lung disease. This case report indicates that it is also a differential diagnosis to consider in dogs.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2001

The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case.

The PAX5 gene, encoding the B-cell-specific activator protein, is a critical determinant of commitment to the B-lymphocyte pathway. This gene, mapped at 9p13, is juxtaposed to the immunoglobulin heavy chain (IgH) gene as a result of the t(9;14)(p13;q32), a rare but recurring translocation found in a subset of B-cell non-Hodgkin's lymphoma cases. In all of these, this translocation results in deregulated expression of the gene product because of the proximity of IgH. We present here the molecular characterization of a previously reported acute lymphoblastic leukemia case carrying a t(9;12)(q11;p13) translocation. Using 5' rapid amplification of cDNA ends PCR, a novel chimeric transcript was identified that contained the NH(2)-terminal region of PAX5 and most of the ETV6/TEL gene on 12p13. According to the fusion transcript, the resulting chimeric protein would retain the PAX5 paired-box domain and both the helix-loop-helix and DNA binding domains of TEL. Thus, it is reasonable to hypothesize that this protein could act as an aberrant transcription factor. This is the first report of PAX5 rearrangement in a human malignancy resulting in a chimeric transcript.

Base Sequence↗

PubMed2001

Risk-oriented postremission strategies in adult acute lymphoblastic leukemia: prospective confirmation of anthracycline activity in standard-risk class and role of hematopoietic stem cell transplants in high-risk groups.

INTRODUCTION: Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon. MATERIALS AND METHODS: From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate. RESULTS: Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass. CONCLUSION: The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

Adolescent↗

PubMed2001

Sensitivity to the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of disease.

STI571 (CGP57148B) is an inhibitor of BCR/ABL, the cause of chronic myeloid leukaemia (CML). A difference exists between CML patients in chronic phase, in which responses to STI571are durable, and patients in blast crisis, who generally experience only transient responses. Leukaemic cells from six CML patients from whom samples could be obtained during chronic phase and at the time of blast crisis (BC) were compared for sensitivity to STI571, using an in vitro assay. BC samples showed a sensitivity similar to that obtained during chronic phase, suggesting that no substantial intrinsic resistance to STI571 was present in BC.

Adult↗

PubMed2001

Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma.

The aim of the present study was to retrospectively evaluate whether a high-dose sequential chemotherapy programme (HDS: cyclophosphamide, methotrexate, etoposide) administered prior to autologous transplantation could optimize the salvage of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. Between 1985 and 1999, 103 patients (median age 43 years, range 16-65) from eight Italian centres and one Swiss centre, with refractory (n = 38) or relapsed (n = 65) diffuse large B-cell and T-cell lymphoma, were treated using HDS followed by high-dose regimens with autologous haematopoietic stem cell transplantation. Eighty-three patients responded to the HDS regimen (81%, 95% C.I., 73- 88%) and 79 eventually achieved a complete response (CR) after autotransplantation (90%, 95% C.I., 81- 96%). None of 20 cases resistant to HDS attained CR. Treatment-related mortality was 4%. After a median follow-up of 24 months (range 6-174 months), 3-year estimates of overall survival, event-free survival and disease-free survival were 47% (95% C.I., 36-59%), 44% (95% C.I., 34-54%) and 64% (95% C.I., 50-74%) respectively. Multivariate analysis showed that chemosensitivity to HDS represented the strongest predictor of both CR and survival. This retrospective study shows that salvage treatment using HDS had relatively low toxicity and was associated with remarkable response rates, allowing further effective therapy with high-dose autograft programmes.

Adolescent↗

PubMed2001

Response to fludarabine in B-cell chronic lymphocytic leukemia patients previously treated with chlorambucil as up-front therapy and a CHOP-like regimen as second line therapy.

BACKGROUND AND OBJECTIVES: Fludarabine (FAMP) is the most active single agent in relapsed and refractory patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear whether it should be used immediatly after failure of chlorambucil (CLB). We addressed such an issue retrospectively analyzing a series of patients in whom FAMP was used as third-line therapy after a sequential use of CLB and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimen, respectively. DESIGN AND METHODS: On a retrospective basis, 57 B-CLL patients fulfilling the above mentioned criteria and followed-up in seven different hematologic institutions, were evaluated. RESULTS: Of 57 patients who were evaluated for response, 3 (5.2%) achieved a complete response (CR), 30 (52.6%) had a partial response (PR) and the remaining 24 (42.1%) failed to respond to FAMP. Overall median survival from the start of FAMP therapy was 30 months. Survival by tumor response did not show any difference between responders and non-responders (p = 0.536). The survival was significantly shorter in the group of patients with progressive disease than in all other patients included in our study (p = 0.05). Using each patient as his own control (McNemar test) we attempted to evaluate the value of FAMP in inducing a therapeutic response after failure of previous therapies. Among the 37 patients resistant to CLB the response rate was 40.3% with FAMP (p = 0.037) and only 17.5% with CHOP (p = 1.0). Among 35 patients resistant to a CHOP-like regimen, the response rate was 29.8% (p = 0.066) after FAMP therapy. INTERPRETATION AND CONCLUSIONS: From our results, it seems that FAMP works better than a CHOP-like regimen in patients resistant to CLB although results do not translate into a survival advantage for responders.

Adult↗

PubMed2000

Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571.

BACKGROUND: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. RESULTS: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment. CONCLUSION: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.

Animals↗

PubMed2000

Role of early anthracycline dose-intensity according to expression of Philadelphia chromosome/BCR-ABL rearrangements in B-precursor adult acute lymphoblastic leukemia.

INTRODUCTION: The use of anthracycline antibiotics in adult acute lymphoblastic leukemia (ALL) has resulted in an improved outcome to remission induction therapy. However,the exact role of these drugs in consolidation therapy is less clear, especially in specific ALL subsets. MATERIALS AND METHODS: A retrospective analysis was conducted on the outcome of 308 patients (median age 35 years, range 13-75) with the most frequent subtype, early-B ALL, treated between 1974 and 1998 on eight consecutive protocols. Anthracycline-related effects were assessed by evaluating the impact of planned anthracycline dose-intensity (A-DI) on long-term outcome. A-DI (in mg/m(2)/week) during the first twelve weeks of consolidation therapy was classified as either "high" (doxorubicin>20, idarubicin>7) or "low". RESULTS: Complete remission was achieved in 78% of cases. With a median follow-up of 6.5 years, on multivariate analysis, disease-free survival (DFS) correlated only with expression of the Philadelphia (Ph) chromosome and/or associated BCR-ABL rearrangements (Ph/BCR(+)) (P=0.0001) and planned A-DI (P<0.0001). On this basis, four major prognostic groups with significantly different DFS could be identified: (1) Ph/BCR(-), "high" A-DI (n=102), median 3.5 years and 41% at five years, respectively; (2) Ph/BCR(-), "low" A-DI (n=64), 1.3 years and 16%; (3) Ph/BCR(+), "high" A-DI (n=35), 1.7 years and 20%; (4) Ph/BCR(+), "low" A-DI (n=39), 0.75 years and 0%. When analyzed separately for Ph/BCR(-) (n=166) and Ph/BCR(+) (n=74) patients, the A-DI effect on DFS was preserved in the former (P=0.018) whereas, in Ph/BCR(+) patients, only age <50 years (P=0.004) and blast count <25 x 10(9)/l (P=0.02) correlated with better DFS. However, Ph/BCR(+) patients with the best prognostic profile (age <50 years and blast count <25 x 10(9)/l; n=21) who were treated on "high" A-DI regimens experienced a median DFS of 2.2 years with DFS 21% at five years, compared to 0.67-1 years and 0-10% in other cases (n=53, P<0.01). CONCLUSION: A "high" A-DI may act as a positive treatment-related prognostic factor in early B-lineage ALL. Although mainly restricted to patients with Ph/BCR(-) ALL, A-DI could also influence the outcome in Ph/BCR(+) patients with other favorable prognostic factors.

Adolescent↗

PubMed2000

Differential recognition of a BCR/ABL peptide by lymphocytes from normal donors and chronic myeloid leukemia patients.

The BCR/ABL oncogenic fusion protein transforms normal bone marrow stem cells into neoplastic cells. It has been shown that peptides derived from the junctional region of this oncogenic fusion protein can be recognized by human T-lymphocytes obtained from normal donors. In this study, we investigated the immunogenicity in patients with chronic myeloid leukemia (CML) of a 17 mer b3/a2 Bcr/abl peptide (B/A1), which was shown to induce proliferative responses in lymphocytes from normal donors. A total of 56 CML patients in chronic phase were studied. Twenty-two patients were studied at diagnosis without any treatment (group I). Fourteen patients were receiving IFN (group II), 14 patients were being treated with hydroxyurea (group III), and 6 patients were on different regimens (group IV). Patients were initially assessed for general immunological competence using both in vivo and in vitro assays. Patients were also selected for the expression of HLA-DR0401, the HLA specificity known to present peptide B/A1 to CD4 lymphocytes. With the exception of the six patients in group IV, the results of all these assays (in vitro phytohemagglutinin/tetanus toxoid responses, in vivo skin reaction to ubiquitous antigens) in CML patients did not significantly differ from those obtained in normal donors, thus excluding the presence of generalized immunosuppression. Eight patients with HLA-DR0401 and a b3/a2 type of fusion were identified and further studied. In these eight patients dendritic cells were obtained from adherent peripheral blood mononuclear cells and used to stimulate CD4 lymphocytes. No patient developed a specific response to the bcr/abl peptide, although patients' lymphocytes proliferated in response to a promiscuous tetanus toxoid peptide in all but one case. In contrast, response to the bcr/abl peptide was observed in seven of eight HLA-DR0401 healthy donors tested. These data suggest that immunocompetent, HLA-DR0401+ CML patients are unable to respond to peptide B/A1, at difference from healthy donors. The implication of these results for the immunotherapy of CML is discussed.

Cell Division↗

PubMed1999

Electrolyte monitoring in patients undergoing peripheral blood stem cell collection.

In recent years peripheral blood stem cell (PBSC) collection for allogeneic or autologous transplantation has experienced an increased use in the onco-hematological setting. The latest generation cell separators allow a satisfactory and safe PBSC collection. Nevertheless, as in all therapeutic apheresis procedures, patients may experience procedure-related side-effects, mainly vasovagal reactions or symptoms related to hypocalcemia and/or hypomagnesemia. We investigated electrolyte changes in 18 patients, with a median age of 46 years (range 7-62), undergoing PBSC collection from January to April 1998. A significant decrease in total calcium in the final sample (9.65 +/- 0.7 mg/dL) with respect to the basal one (9.2 +/- 0.6 mg/dL, P < 0.05) was observed; also ionized calcium decreased markedly from the first sample drawn at +30 minutes: 1.22 +/- 0.14 vs. 1.03 +/- 0.15 mmol/L (P < 0.05), and a highly significant difference emerged when basal value were compared to the final value: 1.22 +/- 0.14 vs. 0.94 +/- 0.13 mmol/L (P < 0.0001). Similar findings affected potassium concentration: 4.1 +/- 0.4 vs. 3.3 +/- 0.3 mEq/L (P < 0.0001). Three out of eighteen patients (16.7%) reached a final potassium level <3.0 mEq/L, and eight out of eighteen (44.5%) showed a potassium concentration decrease >20% with respect to the basal value. A mild metabolic alkalosis occurred during the procedure: pH increased from 7.35 +/- 0.02 to 7.43 +/- 0.028 (P < 0.001), and plasma bicarbonate concentration increased from 27.48 +/- 2.21 to 32.44 +/- 2.52 mmol/L (P < 0.01). Sodium and chloride did not differ in the final sample with respect to the basal sample. None of our patients experienced clinically relevant side effects related to severe electrolyte changes (i.e., >20% with respect to the basal value). Because our current therapeutic schedules include patients older than 50 years in the PBSC collection and transplantation program and since it is well known that subclinical myocardial disease may occur in up to 4% of middle-aged males, we suggest that patients aged 50 or older undergoing PBSC collection procedures be carefully monitored in order to identify significant electrolyte variation, especially if they present with low serum potassium levels. However, further investigation of larger patient series are needed to determine the clinical relevance of serum potassium changes during apheresis.

Adolescent↗

PubMed1999

Clinical sensitivity to anthracyclines in PH/BCR+ acute lymphoblastic leukemia.

Translocation t(9;22) or Philadelphia chromosome (Ph)/BCR-ABL rearrangement positive acute lymphoblastic leukemia (Ph/BCR+ ALL) is associated with a very short survival of about one year in most patients. We analyzed long-term outcome of 76 adults with Ph/BCR+ ALL, in order to detect which factors were associated with longer survival. Modifiable prognostic factors included type of treatment, allogeneic marrow transplant (allo-BMT), and early anthracycline dose intensity (high = H/A, low = L/A); unmodifiable factors were age, gender, FAB morphology, phenotype, blast count, P190/210 transcript, hepatospleno-lymphadenopathy, LDH level. Median patient age was 43 years (range 15-71). Four favorable prognostic factors (FPF) were found associated with greater likelihood of complete remission (blast count < 50 x 10(9)/l, p = 0.08), longer remission duration (age < 50 years, p < 0.001; H/A, p < 0.05), and lower relapse rate (allo-BMT, p = 0.017). Age and anthracycline dose intensity exerted a synergistic prognostic effect. According to the cumulative incidence of FPF in each patient (FPF 0-1 = 29, 2-3 = 42, 4 = 5), the probability of survival increased from nil to 0.22 to 0.60 at 5 years (p < 0.005). Adult Ph/BCR+ ALL is relatively sensitive to anthracyclines, which therefore should be prescribed at full dosage to patients not eligible to allo-BMT or in the waiting list for unrelated donor transplantation.

Adolescent↗

PubMed1999

Induction-consolidation with an idarubicin-containing regimen, unpurged marrow autograft, and post-graft chemotherapy in adult acute lymphoblastic leukaemia.

Between 1991 and 1993 we conducted a collaborative trial in adult acute lymphoblastic leukaemia, introducing an idarubicin (IDA)-containing regimen for induction and early consolidation, and increasing consolidation intensity with an autologous bone marrow transplantation phase (ABMT, patients aged <51 years) followed by further chemotherapy for 12 weeks and low-dose maintenance for 6 months (ABMT patients) or 18 months. 96 patients were evaluable for antileukaemic response after induction with vincristine-prednisone-L-asparaginase plus cumulative IDA 36 or 20 mg/m2 (IVAP-1 and IVAP-2), and for disease-free survival (DFS) after a minimum follow-up >3.5 years with an off-therapy interval >1.5 years. The response rate was 44% (7/16) with IVAP-1 and 90% (72/80) with IVAP-2 (P=0.0001), due to regimen-related toxicities. Post-remission therapy was administered as planned to most cases but protocol violation was registered in some patients eligible to ABMT and post-graft chemotherapy. The 5-year disease-free survival (DFS) rate was 31%. Multivariate analysis indicated that DFS was improved in patients receiving a transplant (11 allogeneic, DFS 70%; 32 ABMT, 36%; 37 neither, 17%; P < 0.001) and was negatively affected by high-risk features such as blast cell count >25x10(9)/l, T-cell or mature B-cell immunophenotype, and t(9;22)/t(4;11) (all P values <0.05). The 5-year DFS rate was 54% for 26 patients with no high-risk factor, 26% for 35 patients with any one, and 6% for 18 patients with any two (P<0.005). IVAP-2 brought about a high complete response rate and post-remission treatment including ABMT was feasible and modestly toxic. In spite of the short post-graft chemotherapy phase, the long-term DFS rate was good in cases with no high-risk feature. However, because autografting may be redundant in the standard-risk category, its role requires further investigation for high-risk cases.

Adolescent↗

PubMed1999

The Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia.

The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.

Humans↗

PubMed1999

Fractionated cyclophosphamide added to the IVAP regimen (idarubicin-vincristine-L-asparaginase-prednisone) could lower the risk of primary refractory disease in T-lineage but not B-lineage acute lymphoblastic leukemia: first results from a phase II clinical study.

BACKGROUND AND OBJECTIVE: In a prior study, primary resistant acute lymphoblastic leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of resistant disease, fractionated cyclophosphamide (f-CY) was then added to the IVAP regimen. DESIGN AND METHODS: Study 08-96 was a prospective, collaborative phase II trial carried out at eight general hospital centers specialized in the care of hematologic malignancies. Historical IVAP-treated patients served as a retrospective control group. All consecutive, untreated patients (>15 years) with a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible. RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40 days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and 2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4 consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in mg/m(2)). RESULTS: Eighty-eight patients were evaluable (age range 15-74 years, blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first 39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and the last 27 patients were not given any f-CY. These changes were dictated by the results of interim analyses of the f-CY groups (RES-ALL rate not reduced, myelotoxicity increased). Altogether, compared with the historical IVAP and no f-CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY 1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count. However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5 of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21 (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small sample size, this difference was not statistically significant. INTERPRETATION AND CONCLUSIONS: This preliminary experience suggests that T-ALL may be more sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis could be tested in a larger clinical trial.

Adolescent↗

PubMed1998

Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia.

An unexpectedly high incidence of blast transformation after splenectomy has been reported in patients with myelofibrosis with myeloid metaplasia. However, whether this was associated with spleen removal after adjustment for risk factors was not determined. We conducted a multicenter historical cohort study of patients with myelofibrosis with myeloid metaplasia diagnosed from January 1970 through January 1994. A total of 549 patients (325 men and 224 women from 22 to 92 years of age; median age, 63 years) were included in the final data set. The Cox's proportional-hazards model was used to identify factors associated with blast transformation and death. To further adjust for factors related to spleen removal assignment, a propensity score for splenectomy was estimated using recursive-partitioning analysis. Blast transformation developed in 78 patients (14.2%). Patients who underwent splenectomy developed more blast transformations than those who were not splenectomized (23 of 87 [26.4%] v 55 of 462 [11.9%]; P < .001). The cumulative incidence of blast transformation 12 years after diagnosis was 27.0% in nonsplenectomized patients and 55.0% in splenectomized ones (P = . 01). The risk factors independently predictive of blast transformation included prior splenectomy (relative risk = 2.61), platelet count less than 100 x 10(9)/L at diagnosis (relative risk = 2.45), and the presence of blasts in peripheral blood at diagnosis (relative risk = 2.31). The relative risk of blast transformation in splenectomized patients increased from 2.2 at 48 months from diagnosis to 14.3 at 12 years. Patients with the same propensity score for splenectomy showed a higher risk for blast transformation on the basis of having undergone splenectomy (P = .02). In conclusion, the risk of blast transformation is significantly increased in subjects who underwent splenectomy and appears to be independent of factors related to spleen removal assignment.

Adult↗

PubMed1997

Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis.

The BCR/ABL fusion protein transforms myeloid stem cells. Both chronic myelogenous leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL) are associated with the expression of BCR/ABL proteins. This knowledge has not yet been translated into any specific tool to control ABL driven neoplastic cells growth. CGP57148B is an ATP-competitive inhibitor of the ABL protein kinase; it has been shown to inhibit the kinase activity of ABL both in vitro and in vivo and to inhibit the growth of v-abl and bcr/abl transfectants, as well as the in vitro formation of bone marrow (BM)-derived colonies in the presence of growth factors in some CML patients. These studies were performed to investigate the activity of CGP57148B on the spontaneous proliferation of both fresh and cultured, leukemic and normal, BCR/ABL positive and negative cells, and to study its mechanism of action. Six cell lines derived from BCR/ABL+ leukemias (K562, BV173, KCL22, KU812, MC3, LAMA84), thirteen BCR/ABL negative lines, both neoplastic (KG1, SU-DHL-1, U937, Daudi, NB4, NB4.306) and derived from normal cells (PHA blasts, LAK, fibroblasts, LCL, renal epithelial cells, endothelial cells, CD34(+) cells), and 14 fresh leukemic samples were tested using a tritiated thymidine uptake assay. The in vivo phosphorylation of the BCR/ABL protein was evaluated by western blot, while apoptosis was detected by the annexin V/propidium binding test. The induction of differentiation was assayed by immunofluorescence using multiple antibodies. All six BCR/ABL+ lines showed a dose dependent inhibition of their spontaneous proliferative rate, which was not accompanied by differentiation. The treatment caused, within minutes, dephosphorylation of the BCR/ABL protein, followed in 16-24 hours by a decrease in cycling cells and induction of apoptosis. No significant inhibition of DNA synthesis was observed in any BCR/ABL negative normal or neoplastic line at concentrations </=3 microM, with the exception of fibroblasts and CD34 cells. Proliferation inhibition was observed also when using fresh samples obtained from two Ph+ ALL and 12 consecutive CML patients. Induction of apoptosis was observed in these samples too. The activity of CGP57148B can be monitored in ex vivo isolated or cultured cells using a simple and reproducible assay, without the need for exogenously added growth factors. This molecule possibly exerts its effects through the inhibition of the kinase activity of BCR/ABL and the subsequent initiation of apoptosis, without inducing cell differentiation. Some normal cells are also affected. These data support the use of CGP57148B in initial clinical studies; possible toxic effects on BM and fibroblast-derived cells will have to be closely monitored. The in vivo monitoring of patients will have to be focused on the induction of apoptosis in leukemic cells.

Apoptosis↗

PubMed1997

Granulocyte colony-stimulating factor (G-CSF, filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs.

An early intensive anthracycline therapy can improve therapeutic outcome in adult acute lymphoblastic leukaemia (ALL) but is usually associated with marked myelosuppressive effects and significant morbidity by infections. To reduce this risk, we employed granulocyte colony-stimulating factor (G-CSF, filgrastim 5 microg/kg/d) as an adjunct to a myelotoxic, 14-day long induction regimen with idarubicin-vincristine-L-asparaginase-prednisone (IVAP). Owing to changes in study design, patients received 'late' (n = 28) or 'early' (n = 37) G-CSF from days 15 or 4 of IVAP, respectively, until resolution of severe neutropenia. Study endpoints included time to recovery from neutropenic nadir, duration of neutropenia <0.5 x 10(9)/l, incidence of infectious complications, assessment of variables affecting G-CSF response, clinical outcome and costs. Sixty-five consecutive cases were evaluable. Patients in early G-CSF group recovered significantly faster from the neutropenic nadir (p < 0.002), contracted less infectious complications (p = 0.007), and required less intravenous antibiotic (p = 0.008) and antifungal (p = 0.002) medications. Although these reductions did not compensate for the increased G-CSF treatment cost, the overall supportive care cost was not significantly increased by early G-CSF. Interestingly, T-ALL phenotype (p = 0.02) and higher neutrophil presentation count (p = 0.03) were associated with a shorter neutropenic course even with late G-CSF. Early G-CSF may be a valid approach to mitigate chemotherapy-induced neutropenia of IVAP and other similarly myelosuppressive adult ALL regimens.

Adolescent↗

PubMed1997

Interleukin-2 therapy in relapsed acute myelogenous leukemia.

PURPOSE: Several studies have been conducted in Italy to assess the activity of recombinant interleukin-2 (rIL-2) in patients with relapsed-refractory acute myelogenous leukemia (AML) and in AML patients in second complete remission (CR) who are not eligible for standard therapy. We report here the updated results of those studies. PATIENTS AND METHODS: Since 1988, a total of 24 patients with relapsed-refractory AML and < or = 30% bone marrow blasts (median blastosis, 15%), who were not suitable for further chemotherapy, were treated with a daily dose-escalating protocol of rIL-2 (8-18 x 10(6) IU/m2 x 5 days) by continuous intravenous infusion with a 72-hour rest period between each cycle. Patients achieving a response to induction therapy received subcutaneous maintenance rIL-2 therapy at lower doses for 5 days/month. Based on these encouraging results, a prospective randomized trial was initiated by the Italian cooperative groups GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto) and AIEOP (Associazione Italiana Ematologie e Oncologia Pedietrica) to assess the efficacy of this rIL-2 regimen in AML patients in second CR. Of 264 AML patients enrolled, 146 patients (55%) achieved a second CR in response to mitoxantrone, etoposide, and cytarabine; 32 patients who were not eligible for transplantation were randomized to rIL-2 (15 patients) or no treatment (17 control patients). Accural goals were never reached, however, due to low recruitment. RESULTS: In the pilot study, 13 patients (54%) obtained a CR, which persists in eight patients with a median follow-up of 64 months (range, 1-110 months) on maintenance rIL-2. In the randomized study, a trend in favor of improved disease-free survival was observed in the rIL-2 arm. CONCLUSIONS: Encouraging results have been obtained with rIL-2 therapy in AML patients with relapsed-refractory disease and limited blastosis and in patients in second CR. These results have prompted a large, multicenter, randomized study to evaluate the efficacy of high-dose rIL-2 therapy in AML patients with advanced disease but limited blastosis in relapse following cytoreductive chemotherapy or autologous transplantation.

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