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R Bassan

Publications and source records attributed to R Bassan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Acute lymphoblastic leukaemia occurring as second malignancy: report of the GIMEMA archive of adult acute leukaemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto.

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre-pre-B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL. The leukaemogenic activity of the cytotoxic drugs employed for the treatment of PM may have played a potential role in only a proportion of patients, opening the possibility that some sALL patients may have developed two or more malignancies due to individual predisposing factors.

Adolescent↗
PubMed1999

Cellular uptake and antiproliferative effects of therapeutic concentrations of idarubicin or daunorubicin and their alcohol metabolites, with or without cyclosporin A, in MDR1+ human leukemic cells.

Ways of restoring an altered drug sensitivity in P-170 glycoprotein (MDR1) positive leukemias are being actively sought for, mostly using MDRI negative regulators together with the MDR1-sensitive anthracycline-type drugs daunorubicin and mitoxantrone. Because idarubicin is less vulnerable to MDR1-mediated transport and could thereby represent a better companion to MDR1 inhibitors, we assessed the ability of the anti-MDR1 agent cyclosporin A to modulate this function in multidrug resistant T-lymphoblastic CEM cells challenged in vitro with either daunorubicin or idarubicin. In order to obtain information of potential interest for the design of a clinical trial, we adopted drug plus metabolite concentrations and exposure times close to the in vivo pharmacokinetics of equimyelotoxic doses of intravenous daunorubicin 45 mg/m2 or idarubicin 10-12 mg/m2, respectively, plus infusional cyclosporin A 16 mg/kg/d. Study methods were cytofluorimetry for the detection of intracellular drug uptake, retention and pro-apoptotic effects (binding of fluoresceinated annexin V), and the standard MTT assay as growth inhibition test. The results showed significantly greater drug uptake (at 30'), retention (at 12 hours), and apoptotic cell rates with idarubicin+/-idarubicinol than daunorubicin+/-daunorubicinol (p<0.05), and a further potentiation of these effects by cyclosporin A. Differing from daunorubicin, idarubicin intracellular accumulation and, by inference, related apoptotic changes were increased by cyclosporin A only in the early phase of drug-cell interaction; a potential advantage towards a reduced toxicity by CsA delivered as short rather than prolonged infusion in the in vivo setting. MTT assay results were also in favour of idarubicin but greatly influenced by cyclosporin A itself. Altogether, study results in MDR1+ cells incubated with CsA 1500 ng/ml plus idarubicin+idarubicinol 100+20 ng/ml, that are peak levels achievable in vivo with an idarubicin dose > or = 12 mg/m2 plus cyclosporin A 16 mg/kg/d, were in the range of those obtained with standard-dose daunorubicin in MDR1- cells (p=n.s.). In summary, an idarubicin plus short-course cyclosporin A combination could be considered for the management of MDR1+ leukemias, where it may represent a more effective and less toxic option than daunorubicin plus continuous infusion cyclosporin A.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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

Short course infusional idarubicin plus intermittent cytarabine and etoposide for refractory hematologic malignancies: clinical and preliminary pharmacological results.

BACKGROUND AND OBJECTIVE: Idarubicin (IDA) is relatively immune to the multidrug resistance P-gp mechanism that is frequently expressed in recurrent and refractory hematologic malignancies. Owing to rapid metabolism in vivo, a continuous infusion (CI) of IDA might prolong exposure time to the parent drug rather than its more P-gp susceptible alcohol metabolite. For this reason we developed a brief retreatment schedule incorporating CI IDA in order to obtain clinical as well as preliminary pharmacological data in patients with refractory leukemias and lymphomas. DESIGN AND METHODS: Eligible patients had either advanced-stage acute myeloid or lymphoid leukemias (AML, ALL) or high-grade non-Hodgkin's lymphomas (NHL) which failed curative-intent frontline or salvage regimens in use at our institution during the study period (July-October 1992). CI IDA 5 mg/m2/d was employed together with intermittent (every 8 hours) intermediate-dose cytarabine (500 mg/m2) and etoposide (200 mg/m2); all drugs were given for 2-4 days. A preliminary pharmacokinetic evaluation of CI IDA was carried out in three patients, including a comparison with bolus delivery in one. The in vitro effects of CI-type vs bolus-type IDA delivery in terms of intracellular IDA accumulation and related pro-apoptotic activity were assessed in P-gp- and P-gp+ human leukemic CEM cells by means of cytofluorimetry (IDA fluorescence intensity = FI, annexin V expression), with and without the addition of P-gp inhibitor cyclosporin A (CsA). RESULTS: Complete (2) or partial (4) responses were achieved in a total of 12 patients (17% and 33%, respectively), despite prior treatments with anthracyclines (100% of cases) and cytarabine-etoposide (33% of cases). Hematological toxicity caused the duration of treatment to be reduced from 4 days to 2 days after the first 4 patients. The procedural death rate was 42% (5/12), which was probably related in part to the sum of adverse prognostic characteristics: median patient age 55 years, two-thirds of cases having previously failed second/third-line regimens. The pharmacokinetic study showed an increased plasma AUC value with CI IDA in one patient (2.9-fold increase vs bolus delivery) due to the prolonged presence of low IDA plasma levels (10-20 ng/mL vs 50 ng/mL), as seen in two other cases as well. On the other hand, the in vitro study did not prove to be in favor of CI IDA because the FI threshold (> 1500 units) associated with increased apoptosis of P-gp+ cells (> 10%) was achieved only with bolus-type IDA exposure (50 ng/mL for 30') plus CsA. INTERPRETATION AND CONCLUSIONS: This short regimen demonstrated activity against end-stage leukemias and lymphomas and might prove to be more effective and less toxic in younger patients and in those with less advanced disease. In view of the results from plasma pharmacokinetics and in vitro intracellular IDA accumulation and apoptosis assays in lymphoblastic CEM cells, CI IDA 5 mg/m2/day may not represent a better therapeutic option than a rapid bolus injection, particularly in P-gp+ neoplasms. If obtaining an adequate intracellular drug concentration is the primary treatment goal, a higher CI IDA dosage, the addition of a P-gp down-regulator such as CsA and others, and in vivo study focusing on tumor samples from patients could all be helpful.

Aged↗
PubMed1998

A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HIDAC) and new anthracycline-type drugs (mitoxantrone, idarubicin) are the mainstay of several active regimens against relapsed and refractory acute myeloid leukemia (AML). The present study was undertaken to assess the feasibility, toxicity, and antileukemic activity of carboplatin (CBDCA) added to a combination of the two former agents. DESIGN AND METHODS: Two regimens (R) of CBDCA plus HIDAC and either mitoxantrone or idarubicin (crossover) were sequentially evaluated. R-1 consisted of CBDCA 300 mg/m2/d (24-hour infusion) on days 1-4, HIDAC 1 g/m2/bd on days 1-5, and mitoxantrone/idarubicin 12/6 mg/m2/d on days 1-3, followed by granulocyte colony-stimulating factor (G-CSF). R-2, an attenuated-toxicity regimen, consisted of CBDCA and G-CSF as above, HIDAC on alternate days (1, 3, 5), and mitoxantrone/idarubicin 8/5 mg/m2/dose. Intended post-remission therapy included a similar, lower intensity course and a myeloablative phase supported by an allogeneic or autologous blood cell transplant. RESULTS: Twenty-nine patients (median age 53 years, one child) formed the study group: 10 (34%) had a primary refractory disease (8 to idarubicin-cytarabine-etoposide, ICE), 6 (21%) were at second or subsequent relapse, and 5 (17%) had a first remission lasting < 12 months. In addition, 4 patients (14%) had received prior HIDAC and 10 (34%) were relapsing after a bone marrow/blood cell transplant. Twelve patients were treated with R-1 and 17 with R-2. The complete response rate was 25% with R-1 and 53% with R-2, due to a significantly lower death rate by pancytopenic complications (p = 0.023). The probability of response by risk class was: primary refractory 30% (43% with R-2), > 2nd relapse 33% (50% with R-2), 1st relapse < 12 months 40% (50% with R-2), 1st relapse > 12 months 50% (75% with R-2), prior HIDAC 75%, and prior transplant 30% (33% with R-2). Seven patients could undergo an autologous (n = 5) or allogeneic (n = 2) bone marrow/peripheral blood cell transplant after one consolidation cycle. Overall survival was 4.2 months, significantly longer in responders (complete and partial: median 11 months) than non-responders (p < 0.001). Median duration of complete remission was 10 months and 2-year probability 0.31, but no patient remained disease-free at 3 years. INTERPRETATION AND CONCLUSIONS: R-2 was well tolerated, exerted a significant activity in high-risk AML, and is amenable to further improvements. However, the lack of long-term disease-free survivors indicates the need for innovative post-remission strategies.

Acute Disease↗
PubMed1998

Outcome assessment of age group-specific (+/- 50 years) post-remission consolidation with high-dose cytarabine or bone marrow autograft for adult acute myelogenous leukemia.

BACKGROUND AND OBJECTIVE: To assess outcome of an age-adapted post-remission strategy for adult patients with acute myelogenous leukemia (AML, FAB-M3 excluded), including autologous bone marrow transplantation (ABMT) or high-dose cytarabine (HIDAC) consolidation. DESIGN AND METHODS: AML patients in first complete remission (CR) after doxorubicin-cytarabine-thioguanine (DoxAT) chemotherapy were scheduled to receive two identical early consolidation courses followed by HIDAC (1 g/m2/bd for 6 days), if aged > 50 years, or HiDAC plus total body irradiation (TBI) plus ABMT if aged < 50 years, the bone marrow being harvested prior to the HiDAC/TBI regimen and unpurged. Results were examined by treatment intention and in actual treatment groups, by selected pretreatment and therapy-related variables, and compared with age and disease matched historical patients treated with DoxAT consolidation without additional HIDAC or ABMT. RESULTS: One-hundred and eight (70%) of 153 patients achieved a response and were evaluable after a follow-up of 3.3-8.8 years. According to treatment intention, long-term relapse-free survival (RFS) was significantly improved in both age groups compared with controls (< 50 years: 41% vs 15%, p < 0.05; > 50 years: 33% vs 22%, p < 0.005). Actually, 41 patients proceeded to ABMT and 24 to the HIDAC cycle (including 5 aged < 50 years), 23 had early consolidation only (1: refusal; 1: inadequate marrow harvest; 21: complications), 10 relapsed and 2 died very early into remission, 7 were submitted to an allogeneic BMT, and one denied any post-remission therapy. The long-term RFS rates for ABMT and HIDAC groups were 53% and 54% (47% for 19 patients aged > 50), respectively, significantly better than for historical patients or those unable to go beyond early consolidation (p < 0.005, adjusted for early adverse events). Overall 5-year survival rate was 40% (p < 0.0001), 54% for CR patients, 60% after ABMT, and 65% after HIDAC. Relative to the ABMT and HIDAC intensive treatment groups, only the presence of hepatosplenomegaly at diagnosis was associated with a significantly worse outcome like that of the control study. INTERPRETATION AND CONCLUSIONS: This age-adapted double post-remission consolidation strategy with ABMT (allo-BMT) or HIDAC was applicable to only about two thirds of responders and was effective in about half these cases, regardless of patient age or specific treatment modality. While the loss of CR patients from treatment realization was unrelated to the study design and depended mainly on recurrence of AML and toxic complication, the exact place of ABMT vs HIDAC consolidation remains unsettled, calling for a new study in comparable patient and risk groups.

Bone Marrow Transplantation↗
PubMed1997

Long-term haematological reconstitution following BEAM and autologous transplantation of circulating progenitor cells in non-Hodgkin's lymphoma.

We report on long-term haematological recovery and clinical outcome after high-dose chemotherapy supported by circulating progenitor cells (CPC) transplantation in non-Hodgkin's lymphoma (NHL) patients, and analyse the role of variables which might influence engraftment. 63 consecutive NHL patients were enrolled in this study. Two groups of patients were considered for analysis: the first 34 patients had untreated diffuse large cell lymphoma with unfavourable prognostic factors. A second group of 29 patients underwent transplantation for resistant or relapsing NHL with low, intermediate and high grade histology. All patients received the BEAM conditioning regimen. As already reported in many studies, all patients showed a rapid haematological reconstitution. 43 patients (68%) achieved long-term complete trilineage engraftment within a median of 107 d from CPC transplantation. The neutrophil count was the first parameter reaching complete normalization, and haemoglobin was the last. Failure to meet the trilineage levels was due to lack of platelet recovery and was more frequent in patients transplanted in the setting of salvage protocols. By Kaplan-Meier analysis, the probability of a full reconstitution was 80% in patients to whom transplant was offered as part of a front-line therapy and 50% when transplant was given in the salvage programmes. Multivariate analysis showed that sustained long-term haematological reconstitution was significantly related to younger age, the time taken to achieve short-term reconstitution, and bone marrow involvement.

Adolescent↗
PubMed1997

The role of idarubicin in adult acute lymphoblastic leukaemia: from drug resistance studies to clinical application.

Idarubicin (4-demethoxydaunorubicin) is more potent and less cardiotoxic than daunorubicin or doxorubicin. These properties suggested a role in acute myelogenous leukaemia, that was confirmed by prospective randomized trials. In acute lymphoblastic leukaemia of adults, on the contrary, there is very little information regarding idarubicin. We have used idarubicin since 1991 and found, in a retrospective comparison with a doxorubicin regimen, a decreased incidence of primarily refractory disease. The role of idarubicin in the postremission phase could not be assessed in detail but an early intensive use of anthracyclines, either idarubicin or doxorubicin, was associated with an improved outcome in early-B CD10+ and t(9;22)/BCR-leukaemias. Concurrent in vitro studies demonstrated that idarubicin, at pharmacologically relevant concentrations, was less sensitive to P-glycoprotein-mediated drug efflux than daunorubicin and was a more effective agent to use with cyclosporin-A to circumvent this drug resistance mechanism. Idarubicin is a very effective drug for the early management of adult acute lymphoblastic leukaemia and may be presently considered (along with cyclosporin-A or other modulator) as the reference anthracycline for cases overexpressing the P-glycoprotein drug resistance mechanism.

Adolescent↗
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↗
PubMed1996

Factors for rapid and sustained hematopoietic reconstitution by circulating progenitor-cell transplantation in non-Hodgkin's lymphoma.

Circulating progenitor cells (CPCs) mobilized from bone marrow will replace the use of bone marrow transplantation because hematopoietic reconstitution is more rapid using the former technique. We report on early and late recovery of hematopoiesis after CPC transplantation in patients with non-Hodgkin's lymphoma (NHL) and analyze the role of variables possibly influencing engraftment. From December 1992 through September 1995, 57 consecutive NHL patients were enrolled in this study. Patients could be divided into 2 groups: the first comprised 32 patients with untreated diffuse large-cell lymphoma and unfavorable prognostic factors; the second comprised 25 patients with resistant or relapsing NHL of low-and high-grade histology. All patients received high-dose chemotherapy (carmustine, cytarabine, etoposide, and melphalan; BEAM) followed by CPC transplantation. In all, 25 patients were treated with granulocyte colony-stimulating factor (G-CSF) after CPC administration. The time to short-and long-term hematologic engraftment and variables correlating with multilineage long-term reconstitution were examined. The time to bilineage (neutrophils and platelets) hematopoietic reconstitution did not differ in G-CSF-treated and-untreated patients. In contrast, the time taken to reach a neutrophil count of 0.5 x 10(9)/1 and a WBC of 1 x 10(9)/1 was significantly shorter in G-CSF-treated patients. Overall, 33 patients achieved long-term, complete trilineage engraftment after a median of 117 days from CPC transplantation. The leukocyte count was the first parameter to reach full engraftment and hemoglobin was the last. According to Kaplan-Meier analysis, 80% of the patients are projected to reconstitute fully at 12 months after transplantation. Univariate and multivariate analyses showed that sustained, long-term hematopoiesis was significantly related to a younger age, an early bilineage reconstitution, and the quantity of CD34+ cells infused.

Adolescent↗
PubMed1996

Role of anthracyclines in the treatment of adult acute lymphoblastic leukemia.

In acute myelogenous leukemia, early treatment is usually attempted with the so-called 3+7 regimen, employing daunorubicin (DNR) or idarubicin (IDR) for 3 consecutive days. In acute lymphoblastic leukemia (ALL), the role of agreement regarding ANT dosage and schedule, preferable compound, and indications for remission induction and consolidation treatment phases. Here we review the role of these drugs in adult ALL. The results indicate that ANTs may offer the best survival chance when used at full dosage during induction and early consolidation treatment. IDR may be a better choice that DNR or doxorubicin, and CD10+ t(9;22)/bcr- ALL may have an excellent prognosis following an early dose-intensive ANT consolidation program.

Adult↗
PubMed1996

Age-adapted moderate-dose induction and flexible outpatient postremission therapy for elderly patients with acute lymphoblastic leukemia.

We report the results of a recent trial in elderly acute lymphoblastic leukemia (ALL) patients (> or = 60 years). Initial chemotherapy consisted of one 14-day course with single-dose idarubicin plus vincristine-prednisone-L-asparaginase. Idarubicin was preferred to other anthracyclines because of its shorter time to response. Sequential outpatient postremission therapy included single-dose idarubicin plus vincristine-cyclophosphamide-L-asparaginase pulses, cranial irradiation with intrathecal methotrexate-cytarabine, flexible weekly vincristine-cyclophosphamide alternating with cytarabine-teniposide, and two-year standard maintenance with mercaptopurine-methotrexate. Granulocyte colony-stimulating factor (G-CSF) was added to induction and early consolidation courses. Twenty-two patients mainly with high-risk features entered the study: median age was 64 years (60-73), 40% of cases were CD10- B-lineage and T-lineage ALL, 38% of CD10+ B-lineage ALL carried a BCR-ABL rearrangement, while 23% coexpressed myeloid antigen, 86% had L2 morphology, 50% had a blast count greater than 10 x 10(9)/1, 54% had hepato-splenomegaly and lymphadenopathy. The complete remission (CR) rate after induction therapy was 59%. A partial remission was obtained in two cases. There were four early deaths (18%) and three refractory ALL (14%). Median time to response was 21 days. With G-CSF, the median duration of absolute neutropenia was 10.5 days. Flexible postremission therapy was very well tolerated, causing no major toxicity. With a median follow-up of 2.6 years, 3 patients remain alive in first CR (23%), 2 of whom at 21.3 months and 39.6 months, respectively. Median survival of responders was 12 months compared to only 1.2 months for nonresponders (p < 0.001). This moderate-dose idarubicin-containing and G-CSF-supported regimen was associated with a high early remission rate in elderly ALL. Postremission therapy results were modest, though not appreciably different from the general experience in this patient population. Because further escalation of drug intensity appears unjustified, attempts to document and reverse drug resistance patterns and restore a dysregulated apoptosis must be considered.

Aged↗
PubMed1996

The natural history of monoclonal villous lymphocytosis: a chronic lymphoproliferative disorder of CD11c+ B cells.

The long-term outcome of three asymptomatic subjects with isolated persistent lymphocytosis of monoclonal villous B-cells (MVL) is reviewed. After 7.5 years, evolution to a splenic lymphoma variant (SLVL) was documented in only one patient, accompanied by a loss of interleukin-1beta autocrine production, confirming that MVL can be an early form of a malignant disorder. The clinical course was uneventful in the other two cases; a progressive lowering of lymphocyte count being noted in one. While the strict relationship of MVL to SLVL is confirmed, time to progression is unpredictable and the mechanisms by which it occurs still remain to be elucidated.

Aged↗
PubMed1996

Molecular diagnosis and clinical relevance of t(9;22), t(4;11) and t(1 ;19) chromosome abnormalities in a consecutive group of 141 adult patients with acute lymphoblastic leukemia.

Over a time period of five years leukemic blast samples from 141 consecutive patients with adult ALL were referred to our laboratory, for molecular evaluation of chromosome abnormalities. The t(9;22), t(4;11) and t(1;19) which are most commonly found in adult ALL with a B-precursor phenotype were molecularly analyzed by similar RT-PCR based protocols. BCR-ABL transcripts generated by the t(9;22) translocation were demonstrated in 36 patients (25%) and were restricted to the 109 patients with B precursor ALL (33% of this group). Of 83 patients showing a, common phenotype (CD10+), 34 were BCR-ABL positive (41%) whereas only 2 out of 26 with Null ALL (HLADr+, CD19+, CD10) were positive. Interestingly, the percent of BCR-ABL positive CD1O+ ALL increases significantly with age being 20% in patients less than 30 years old and more than 50% in older patients. None of the T-ALL (24 patients) and B-ALL (8 patients) were positive. The majority of cases (67%) showed the p190 gene subtype. The cytogenetic diagnosis of Philadelphia chromosome was always confirmed by the molecular analysis and this approach allowed for the detection of the presence of the BCR-ABL rearrangement in 26 patients when a negative result or no metaphases were obtained. The complete remission rate was similar among BCR-ABL positive and negative patients but a shorter remission duration was observed in those showing molecular evidence of t(9;22) and this finding was significantly evident in CD1O+ ALL patients. By means of comparison, in most of the same adult ALL patients, we analyzed the yet unrecognized prevalence of the t(4;11) and t(1;19) translocations by the molecular analysis of their chromosomal breakpoints. Rearrangements of the ALL-1 gene on 11q23 band and ALL- l1AF.4 fusion transcripts specific for the t(4;11) were demonstrated in 7 out of the 21 Null ALL investigated, with no additional positive cases found among the other ALL subgroups. Overall the clinical behavior of t(4; 11) positive patients was dismal with a very short CR duration. Chimeric E2A-PBX1 transcripts generated by the t(1;19) were found in only two of the 87 B-precursor ALL analyzed. The presented results provide further evidence for the utility of RT-PCR based methods for the molecular diagnosis of chromosome translocations in ALL. The identification of such abnormalities can significantly contribute to the identification of more appropriate therapeutic options for standard and high risk ALL patients

Adolescent↗
PubMed1996

The role of anthracyclines in adult acute lymphoblastic leukaemia.

The role of anthracyclines (ANT) in the treatment of adult acute lymphoblastic leukaemia (ALL) is poorly defined as regards drug dosage, schedule, preferable compound, and indications for use in specific treatment phases or disease subset. We therefore reviewed ANT treatment results in adult ALL. Altogether, an early and intensive use of ANT would improve both initial response rate and long-term disease-free survival; idarubicin (IDR) exhibits a considerable antileukaemic activity deserving further evaluation as possible reference drug; and the prognosis of CD10+ t(9;22)/BCR-ABL- ALL can be particularly good following an early dose-intensive ANT consolidation program.

Adolescent↗
PubMed1996

G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation of resistant or relapsing acute leukemias.

Peripheral blood progenitor cells (PBPC) were mobilized by G-CSF in normal HLA identical siblings and used for allogeneic transplantation in eight patients with refractory or relapsed acute leukemias. G-CSF administration was well tolerated and no significant side-effects were registered. The number of circulating WBC peaked at day 5 after G-CSF (range: 22.6-74.6 x 10(9)/l) with a median of 65 CD34+ cells/microl (38-155). As a consequence of leukaphereses, platelets progressively decreased, reaching the nadir after the last procedure (84-205 x 10(9)/l). A mean of two aphereses (1-3) were performed between day +4 and +7 during which 10 liters of blood were processed each time by a cell separator. Conditioning regimens were: fractionated total body irradiation (FTBI) plus either HDAra-C (2 g/m2 x 2/day for 6 days) (n=5) or melphalan (110 mg/m2) (n= 1) and busulfan (4 mg/kg/day for 4 days) and melphalan (110 mg/m2) in two patients relapsed after a previous FTBI-based allogeneic or autologous BMT. At transplantation, a median of 6.9 x 10(6) CD34+ cells/kg (4.2-16.5) and 279 x 10(6) CD3+ cells/kg (161-786) were infused. Engraftment of both neutrophils (> or v=1.5 x 10(9)/l) and platelets (> or v=20 x 10(9)/l) was observed in all patients after a median time of 18 days (range: 11-20 and 10-26, respectively). The evaluation of engraftment after transplantation was accomplished by PCR analysis of four hypervariable genomic regions (VNTR) (ApoB, ApoC2, YNZ-22, and MCT 118) which allowed to demonstrate the condition of donor chimaera in all patients after transplantation. As far as the clinical outcome, two patients died of interstitial pneumonitis at day +243 and +69 and two patients died at day +62 and +152 of pulmonary aspergillosis. Four patients remain alive in remission between day +88 and +287 with grade 0-l GVHD. Allogeneic PBPC transplantation is associated with a complete hematologic recovery and despite the infusion of a large amount of mature CD3+ lymphocytes, apparently acute GVHD is not worse than expected after transplantation of bone marrow progenitors.

Adolescent↗