PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet.

In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P<0.0001, P=0.003), respectively.

Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia.

Fluorescence in situ hybridization and comparative genomic hybridization characterized 6p rearrangements in eight primary and in 10 secondary myeloid disorders (including one patient with Fanconi anemia) and found different molecular lesions in each group. In primary disorders, 6p abnormalities, isolated in six patients, were highly heterogeneous with different breakpoints along the 6p arm. Reciprocal translocations were found in seven. In the 10 patients with secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), the short arm of chromosome 6 was involved in unbalanced translocations in 7. The other three patients showed full or partial trisomy of the 6p arm, that is, i(6)(p10) (one patient) and dup(6)(p) (two patients). In 5/7 patients with unbalanced translocations, DNA sequences were overrepresented at band 6p21 as either cryptic duplications (three patients) or cryptic low-copy gains (two patients). In the eight patients with cytogenetic or cryptic 6p gains, we identified a common overrepresented region extending for 5-6 megabases from the TNF gene to the ETV-7 gene. 6p abnormalities were isolated karyotype changes in four patients. Consequently, in secondary AML/MDS, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/or congenital genomic instability.

Treatment of aplastic anaemia with granulocyte-colony stimulating factor and risk of malignancy. Italian Aplastic Anaemia Study Group.

Granulocyte-colony stimulating factor (G-CSF) is being increasingly used in healthy volunteers to harvest haemopoietic stem cells. A possible role of G-CSF in the development of clonal disorders or leukaemia has been suggested. We analysed 144 patients with aplastic anaemia treated with immunosuppression protocols with or without G-CSF, with normal cytogenetics at diagnosis or immediately after immunosuppression. Our findings indicated that the risk of developing myelodysplasia or leukaemia was similar in patients with aplastic anaemia on immunosuppressive treatment with or without G-CSF. Therefore, it seems unlikely that G-CSF causes leukaemia in healthy volunteers.

Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia.

Between July 1992 and June 1996, 3934 new cases of acute leukaemia were registered in the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Archive of Adult Acute Leukaemia. Two hundred cases (5.1%) presented with a history of primary malignancy (PM), 179 of which were acute myeloid leukaemia (AML). The median age of these cases was significantly higher than that of other primitive AML (63 years vs. 57 years; P < 0.001). The number of men was significantly lower than the number of women [74/1544 (4.8%) vs. 105/1420 (7.4%); odds ratio (OR) 0.63, 95% confidence interval (CI) 0.46-0.87; P < 0.002], as was the number of patients aged <65 years [104/1963 (5.3%) vs. 75/1001 (7.5%); OR 0.69, 95% CI 0.50-0.95; P < 0.01]. An increased incidence of cancer was observed among first-degree relatives of patients with AML occurring after a PM (secondary AML; sAML) [66/179 (36.9%) sAML vs. 757/2785 (27.2%) de novo AML, age adjusted; OR 2.62, 95% CI 1.07-6.42; P < 0.005]. Prevalent types of PM were breast cancer, lymphoma and Hodgkin's disease. sAML occurred after a median latency of 52 months (range 2-379). Of the 122 patients who received chemotherapy for sAML, 67 patients (55%) achieved a complete remission (CR), three a partial remission, 15 (12%) died in induction and 37 (30%) were unresponsive. The median duration of CR was 30 weeks (range 4-250). The median overall survival was 7 months (range 1-196). Comparing acute promyelocytic leukaemia with all other French-American-British (FAB) groups, a significant increase in CR achievement was observed [14/18 (77.7%) vs. 53/101 (52.4%), P < 0.046] as well as in median CR duration (55 vs. 24 months, P < 0.02). The analysis of our data suggests that not only previous chemotherapy but also genetic predisposition could play a role in the pathogenesis of sAML.

Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia.

A total of 622 consecutive patients with acute promyelocytic leukaemia (APL) treated within the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group during 1989-97 have been reviewed to assess the clinical effectiveness of all-trans retinoic acid (ATRA) on the incidence of early haemorrhagic deaths and on APL-associated coagulopathy. Of them, 499 were treated with idarubicin plus ATRA (study A) and 123 with Idarubicin alone (study B). In both studies, similar guidelines for supportive treatment were used. Haemorrhagic symptoms were evaluated according to a reproducible score system. Deaths occurring within 10 d of starting treatment were 19 (3.8%) in study A and nine (7.3%) in study B (P = 0.09), with 15 (3%) and five (4.1%) (P not significant) due to haemorrhage. Overall, induction mortality was 7.6% and 16.2% respectively (P < 0.003). In study A, days with platelet counts 30 x 109/l (P < 0.001) in both studies, and by a haemorrhagic score of 3 in study A (P < 0.001). Although the reduction of early fatal haemorrhages was not significant, a substantial clinical improvement was evident in terms of reduction of the severity of bleeding symptoms, blood product consumption and overall induction mortality when ATRA was combined with idarubicin.

Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO).

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

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.

Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and effective alternative to horse ALG (h-ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2-67) not responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 microg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58-361 d). No relevant side-effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14-377). Nine patients (30%) achieved complete remission (neutrophils >/=2.0 x 109/l, haemoglobin >/=11 g/dl and platelets >/=100 x 109/l). The overall survival rate was 93% with a median follow-up of 914 d (range 121-2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA patients unresponsive to first-line IS treatment.

Characterization of 12p molecular events outside ETV6 in complex karyotypes of acute myeloid malignancies.

Acute myeloid disorders with rearrangements of 12p outside the ETV6 gene were characterized by fluorescence in situ hybridization (FISH) with a panel of DNA probes. Seven patients with de novo acute myeloid leukaemia (AML), one with secondary acute myeloid leukaemia (sAML), and one in the blast phase of chronic myeloid leukaemia (CML-BP) were enrolled in the study. All AML cases showed multiple karyotypic changes. Chromosome 5 and/or 7 deletions were the most frequent accompanying changes. FISH revealed amplification, cryptic translocation, and fragmentation of chromosome 12, not discernible at karyotypic level. Different karyotypic rearrangements of 12p showed a common molecular event. Among the seven cases in which breakpoints could be determined, six were telomeric and one centromeric to ETV6. In three AML cases a new recurrent breakpoint in the telomeric region was identified distally to locus D12S158 and to pac 922B22 which is the most telomeric probe available for 12p. Accompanying cryptic deletions were also detected in five patients and the commonly deleted region, of around 700 kb, included the ETV6 gene and the D12S391 locus.

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.

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.

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.

Acute promyelocytic leukaemia: epidemiology and risk factors. A report of the GIMEMA Italian archive of adult acute leukaemia. GIMEMA Cooperative Group.

Acute promyelocytic leukaemia (APL) exhibits peculiar epidemiological, clinical, cytogenetic and molecular features, compared to the other acute myeloid leukaemias (AML). Data on epidemiology and occupational risk factors for APL desumed from the GIMEMA archive are reported and compared with those of the other AML. An exploratory case-case study was designed on AML patients from 56 haematology centres in Italy. Overall, 4296 patients older than 15 yr with a new diagnosis of acute leukaemia were recorded between July 1992 and July 1997. Of these, 335 were classified as APL, and 2894 as other AML. The median age of APL patients was 43 compared to 59 yr for the other AML (p < 0.00001). In order to identify peculiar risk factors for APL development, different parameters were compared in the 2 groups. After adjusting by age no significant differences were observed with regard to education, lifetime prevalence of cancer among siblings and previous diseases in the patient's history. Occupational exposure as a possible risk factor for APL showed no increased risk compared to other AML among farmers, builders and leather workers. A significant association was found in electricians (OR=4.4, 95% CI=2.0-9.7) and a weak association was found in wood workers (OR=3.2, 95% CI=0.8-10.8). The proportion of APL with respect to other AML was significantly higher in the north east of Italy compared to the rest of the country (OR=1.7, 95% CI=1.3-2.2). These data confirm the younger age of APL patients compared to the other AML. A possible role of electromagnetic fields is suggested by the higher risk of APL in electrical workers and in the more industrialized areas of the country.

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.

Acquired haemophilia: experience of two Italian centres with 17 new cases.

Acquired haemophilia is a rare but often catastrophic haemorrhagic disorder associated with a high mortality rate. No single therapeutic approach has been consistently successful and clinical experience remains mainly anecdotal. This report describes 17 new cases diagnosed at two Italian haemophilia centres between 1979 and 1995. There was no difference in sex distribution. Mean age at diagnosis was 50 years. Fifty-nine per cent of cases had associated disorders and 29% developed an inhibitor post-partum. Eleven (64%) patients required substitutive therapy. Desmopressin was successfully used in five cases for minor bleeding. Immunosuppressive drugs (steroid, cyclophosphamide or experimental therapy) were used in 14 (82%) cases. Eight of 15 (52%) evaluable cases achieved complete remission (four post-partum). Fatal haemorrhage occurred in 2/15 (13%) of patients within 2 days from diagnosis. Acquired haemophilia is a severe coagulopathy. Prompt diagnosis with characterization and intensive treatment is usually required. However, particular subsets of patients such as those with inhibitor occurring post-partum or with low inhibitor titre at diagnosis usually show a more favourable clinical outcome.

A (15;17) translocation not associated with acute promyelocytic leukaemia.

We report a woman with acute myeloid leukaemia (AML) type M2 according to FAB classification, showing a t(15;17) apparently identical to that of acute promyelocytic leukaemia (APL) on conventional cytogenetic analysis. Fluorescence in situ hybridization (FISH) using cosmidic probes specific for RAR alpha and PML, regions did not show a fusion signal as in APL. The breakpoints were assigned to 15q24.3 and 17q21.1. Detailed molecular analyses did not reveal any involvement of RAR alpha and PML genes. The patient was resistant to several front-line AMI treatments and to all-trans retinoic acid (ATRA). These findings reinforce FISH and RT-PCR as useful tools for the characterization of a t(15;17) as the translocation specifically associated with APL.

Therapeutic impact of adult-type acute lymphoblastic leukemia regimens in B-cell/L3 acute leukemia and advanced-stage Burkitt's lymphoma.

BACKGROUND: Adult B/L3-ALL is a rare disease subset characterized by an aggressive clinical course and a poor response to conventional adult ALL-type chemotherapy. Recent data from the GMALL Group showed that prognosis can be improved with an innovative treatment regimen. In the current retrospective survey we focus on therapeutic results obtained at our Institutions during a 15-year period with ALL-type regimens in 34 adults with either B/L3-ALL or advanced-stage Burkitt's lymphoma. METHODS: Five successive ALL treatment programs were developed. They included a homogeneous induction phase with early intrathecal chemoprophylaxis, multidrug postremission consolidation followed by cranial irradiation (4 trials), high-dose chemotherapy plus autografting (2 trials), late consolidation (2 trials), and variable-length maintenance (4 trials). Early response and prolonged disease-free survival rates were analyzed according to selected clinical and therapeutic variables. RESULTS: Overall, a complete remission was achieved in 62%, with a median duration of 1.6 years and a 10-year remission rate of 49%. A diagnosis of B/L3-ALL (p = 0.007), the use of idarubicin instead of adriamycin during induction (p = 0.018), a serum creatinine < 1.6 mg/dL, and an uninvolved central nervous system were associated with higher response rates. As regards long-term disease-free survival, results were significantly better in patients with < 1 x 10(9)/L L3/blast cells in the peripheral blood (p = 0.0029) and/or aged < 50 years (p = 0.04), and in those consolidated with the most recent rotational high-dose plus peripheral blood stem cell autotransplant regimen. CONCLUSIONS: According to the results presented, ALL-like regimens may still represent a worthwhile therapeutic choice. The use of idarubicin during induction, the prognostic subclassification of patients, a careful control of dysmetabolic complications, the selection of the proper chemo-radioprevention for meningeal disease and perhaps the introduction of high-dose chemotherapy supported by autologous stem cell rescue appear to be the mainstay of further improvements.