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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-a (PML–RARa) 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–RARa 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–RARa 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.

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 × 109/L (range, 0-0.5 × 109/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 × 109/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 × 109/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.

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 × 109/L (range, 0-0.5 × 109/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 × 109/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 × 109/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.

The consistency in time of responses to separate desmopressin (DDAVP) infusions in patients with von Willebrand's disease (vWD) and mild or moderate hemophilia A has been the subject of limited investigation. We report here the results of a clinical study undertaken to test the consistency of responses to repeated DDAVP administrations in 22 patients with vWD and 10 with mild or moderate hemophilia A (time interval between first and last infusion ranging from 1 to 77 months; median, 13 months). In patients with vWD, 80% of cases showed a departure of less than 20% from the average VIII:C peak level calculated after the two infusions. A similarly consistent pattern was observed for bleeding times recorded 30 minutes after each infusion. In patients with hemophilia A, some infused on more than two instances, the departure from the average VIII:C peak level was less than 20% in nearly 70% of cases. A good within-family consistency was also demonstrated by analyzing data obtained from seven kindreds with vWD and two with hemophilia A. In conclusion, our study suggests that the pattern of responsiveness observed after a DDAVP test-infusion can be reliably used to decide the future clinical management of the individual patient and that a similar pattern of response is usually observed within the same kindred.

Summary. 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.

The occurrence of a sMDS in patients potentially cured from a previous APL has been recently reported. To evaluate the real incidence and the clinical characteristics of sMDS/sAML post APL, the follow-up of 336 patients with newly diagnosed APL enrolled by 22 GIMEMA Centers in the LAP AIDA 0493 protocol has been revised. After the induction, 314 patients (93.4%) achieved complete remission (CR): of them, 225 (71.6%) are still alive in 1st CR, 12 (3.8%) died in CR and 71 (22.7%) relapsed. The remaining 6 patients (1.9%) developed a sMDS while in 1st morphological CR, after a median time from CR achievement of 42 months (range 27 - 75). Among the 71 relapsed patients, 15 had no further data and 41/56 (73.2%) achieved a 2nd CR after salvage treatments: 2 of them (4.8%) developed a sMDS while in 2nd morphological CR, after 48 and 27 months from 1st CR, respectively. Furthermore, another patient showed a sMDS while in 3rd CR. As to clinical and biological characteristics of these 9 sMDS patients, there were 3 male and 6 female with a median age at sMDS diagnosis of 57 years (range 31 – 71): cytogenetic analysis failed in 2 patients, was normal in 1 patient and revealed abnormalities of chromosomes 5 or 7 in the remaining 6 patients, with a complex karyotype in 4 of them. One patient underwent allogeneic BMT soon after sMDS and is still alive after 57 months, 2 patients are in stable myelodysplastic phase after 25 and 63 months respectively. An evolution in sAML occurred in the remaining 6 patients, after a median sMDS duration of 7.6 months (range 2 – 45): 5 sAML patients received only supportive care +/− palliative chemotherapy, 1 patient underwent intensive chemotherapy but was resistant. All sAML patients died after a median time from AML evolution of 4 months (range 0.8 – 5) In conclusion, the incidence of sMDS post APL seems low in 1st molecular CR, but increases in patients achieving 2nd or subsequent CR: clinical characteristics and prognosis are similar to those observed in other sMDS. A longer follow-up will help us to define the late occurrence (> 5 years from CR) of this severe complication. In addition, the availability of prognostic score systems at initial diagnosis and residual disease monitoring by PCR might allow better tailoring of treatment intensity in APL, in an attempt to spare unnecessary toxicity and minimise the risk of sMDS/sAML development for patients who have low risk disease.

The occurrence of a sMDS in patients potentially cured from a previous APL has been recently reported. To evaluate the real incidence and the clinical characteristics of sMDS/sAML post APL, the follow-up of 336 patients with newly diagnosed APL enrolled by 22 GIMEMA Centers in the LAP AIDA 0493 protocol has been revised. After the induction, 314 patients (93.4%) achieved complete remission (CR): of them, 225 (71.6%) are still alive in 1st CR, 12 (3.8%) died in CR and 71 (22.7%) relapsed. The remaining 6 patients (1.9%) developed a sMDS while in 1st morphological CR, after a median time from CR achievement of 42 months (range 27 - 75). Among the 71 relapsed patients, 15 had no further data and 41/56 (73.2%) achieved a 2nd CR after salvage treatments: 2 of them (4.8%) developed a sMDS while in 2nd morphological CR, after 48 and 27 months from 1st CR, respectively. Furthermore, another patient showed a sMDS while in 3rd CR. As to clinical and biological characteristics of these 9 sMDS patients, there were 3 male and 6 female with a median age at sMDS diagnosis of 57 years (range 31 – 71): cytogenetic analysis failed in 2 patients, was normal in 1 patient and revealed abnormalities of chromosomes 5 or 7 in the remaining 6 patients, with a complex karyotype in 4 of them. One patient underwent allogeneic BMT soon after sMDS and is still alive after 57 months, 2 patients are in stable myelodysplastic phase after 25 and 63 months respectively. An evolution in sAML occurred in the remaining 6 patients, after a median sMDS duration of 7.6 months (range 2 – 45): 5 sAML patients received only supportive care +/− palliative chemotherapy, 1 patient underwent intensive chemotherapy but was resistant. All sAML patients died after a median time from AML evolution of 4 months (range 0.8 – 5) In conclusion, the incidence of sMDS post APL seems low in 1stmolecular CR, but increases in patients achieving 2ndor subsequent CR: clinical characteristics and prognosis are similar to those observed in other sMDS. A longer follow-up will help us to define the late occurrence (> 5 years from CR) of this severe complication. In addition, the availability of prognostic score systems at initial diagnosis and residual disease monitoring by PCR might allow better tailoring of treatment intensity in APL, in an attempt to spare unnecessary toxicity and minimise the risk of sMDS/sAML development for patients who have low risk disease.