All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia.

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.

Endothelium and bone marrow transplantation.

Thrombotic complications may occur early after marrow transplantation and many data suggest that endothelial injury plays a pivotal role in their pathogenesis. Since plasma thrombomodulin and P-selectin are thought to be of value as markers of vascular endothelial cell membrane injury, we investigated their plasma concentration in bone marrow transplant patients aiming better to clarify the degree of endothelial involvement. Plasma thrombomodulin and P-selectin were monitored in 25 patients without thrombotic complications before transplant, on day 0 and weekly for 1 month thereafter, while in three patients who developed VOD monitoring continued until day +52. These proteins were in the normal range in all the uncomplicated patients and in two with reversible VOD, while they were always very high in the only patient who developed very severe and lethal VOD. In conclusion, we suggest that endothelial activation/damage occurs rarely in the course of BMT for hematological malignancies; we were able to document endothelial injury in only one patient with very severe thrombotic complication.

Increased P-selectin plasma levels in patients with thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare vascular disorder of unknown etiology. There is evidence to support the hypothesis that platelets and endothelium play a pivotal pathogenetic role. Immunological assays for plasma thrombomodulin and P-selectin levels have recently been made available and they allow simple evaluation of endothelial damage and endothelial/platelet activation, respectively. In this study, we measured the plasma levels of thrombomodulin, P-selectin and von Willebrand factor in 9 TTP patients during active disease and at the time of complete remission (CR). METHODS: Thrombomodulin, P-selectin and von Willebrand factor were measured by enzyme immunoassay. RESULTS: Mean thrombomodulin and von Willebrand factor plasma values were always within the normal range. P-selectin plasma levels, both in the active phase of the disease and in CR (median 312 and 185 ng/mL, respectively), were significantly higher than in normal controls (mean 96 +/- 35 ng/mL, mean 88 ng/mL; p < 0.05). However, the mean value of P-selectin in CR (median 185 ng/mL) was significantly lower than that observed at diagnosis (p < 0.05). In addition, an inverse relationship between P-selectin plasma levels and platelet count (r = -0.526; p = 0.03) was observed. CONCLUSIONS: These findings suggest that activation of platelets and/or endothelium may play a relevant role in the pathogenesis of TTP.

Negligible hemostatic toxicity of intermediate-dose Erwinase in adult patients with acute lymphoblastic leukemia: preliminary data.

The hemostatic toxicity of low dose L-asparaginase from Erwinia carotovora (Erwinase) has been reported to be negligible in adult patients with acute lymphoblastic leukemia (ALL); conversely, no consistent data have been obtained when Erwinase is administered at intermediate doses. We report preliminary clinical and laboratory hemostatic data from 10 adult patients with ALL treated during induction phase with intermediate doses of Erwinase (20,000 IU/m2s.c. every other day, for a total of six administrations). No thrombotic or hemorrhagic events were registered and the mean values of PT, aPTT, fibrinogen, antithrombin and D-dimer did not change during treatment. Only one patient showed a decrease of antithrombin (48% on day 8) requiring temporary suspension of Erwinase therapy. These data suggest that intermediate doses of Erwinase also have negligible hemostatic toxicity in adult patients with ALL.