Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

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Summary Previous studies have shown that haemorrhage in Lassa fever is associated with abnormal in vitro platelet aggregation and a high mortality. In Sierra Leone we studied platelet aggregation in healthy local subjects, patients with laboratory‐confirmed Lassa fever and febrile patients in whom Lassa virus infection was excluded. There were no significant differences in the mean platelet counts of these groups. Patients with fulminant Lassa virus infection showed a gross depression of in‐vitro platelet responsiveness to 1 and 5 μm ADP and 4 μg/ml collagen compared to other groups (P=0·0004–0·0008 when compared to healthy controls, P=0·002–0·0008 when compared to mild Lassa fever patients). When plasma samples from five of these patients were mixed 1:1 with control platelet‐rich plasma, a marked inhibition of ADP‐induced aggregation was observed. No inhibitory activity was detected in plasma obtained from healthy subjects or febrile control patients. The presence of inhibitor was strongly associated with the occurrence of haemorrhage (P=0·03), depression of platelet aggregation (P=0·004) and severity of Lassa fever (P=0·007).

For the past decade, survival (S) for adults with ALL has remained at 30–40% despite achieving high complete remission (CR) rates of 70–90%. CALGB 19802 was designed to test the hypothesis that dose intensification of daunorubicin (D) and cytarabine (Ara-C) could improve disease-free survival (DFS) and that aggressive high dose intravenous (IV), oral (PO) and intrathecal (IT) methotrexate (MTX) could replace cranial irradiation (RT) for central nervous system (CNS) prophylaxis. Treatment consisted of 6 monthly courses of intensive therapy followed by 18 mos of maintenance. In pts < 60 yrs, the D dose during induction and in post-remission therapy was increased in cohorts from 45 mg/m2 on days 1–3 (used in prior CALGB ALL studies) to 60 and then to 80 mg/m2/day X 3. In pts ≥ 60 yrs, D was increased from 30 to 60 mg/m2/day X 3. High-dose Ara-C and CNS prophylaxis with IV, PO, and IT MTX were given in post-remission modules for all pts with a goal of targeting serum methotrexate levels to be 1–2 μM at 30 hours following the IV MTX infusion. No cranial RT was given. From 1/99–1/01, 163 adults with untreated ALL were enrolled. Median age was 40 yrs (range, 16–82) and 33 (20%) were ≥ 60 yrs old; 61% were male. Of 127 centrally reviewed cases, 100 (79%) were precusor B-cell; 19 (15%) precursor T-cell; and 8 (7%) were bilineal or biphenotypic. A large proportion, 46 (46%) of 100 centrally reviewed and evaluable cases, had poor risk cytogenetics as defined in prior CALGB studies: 31 with t(9;22), 7 with t(4;11), 6 with −7 and 2 with +8. With a median follow-up of 4.4 years, the S and, especially DFS, for pts < 60 yrs was improved for those who received D at 80 mg/m2 vs 60 mg/m2. The outcome of all 163 evaluable pts is summarized below: CR (%) 3 yr DFS [95% CI] 3 yr S [95% CI] OVERALL 128 (78.5) 32% [24–41] 36% [29–44]     AGE/ D DOSE     < 60/ 60 mg/m2 36 (92%) 24% [11–39] 35% [20–50]     <60/ 80 mg/m2 72 (79%) 43% [31–54] 46% [35–56]     60+/ 60 mg/m2 20 (61%) 10% [2–27] 8% [2–21] Disease progression during treatment occurred in 43 (26%) and 20 (12%) were removed for alternative therapies including 16 pts who received allo-SCT in CR1. Relapses have occurred in 84 (66%) pts; of these, 10 (8%) were isolated CNS relapses. CNS relapses tended to occur more frequently in pts with hour 30 serum MTX levels of < 1μM during CNS prophylaxis. Age ≥ 60 was significantly associated with worse DFS and S. DFS was longer for precursor T-ALL (median S at 3 years not reached). Interestingly, neither WBC > 30,000/μl nor adverse cytogenetics were significantly associated with worse outcomes. Higher levels of minimal residual disease (MRD) using quantitative clone specific PCR following induction therapy was predictive of inferior DFS (p = .02). In conclusion, omission of CNS irradiation did not result in higher CNS relapse rates than what has been reported in prior CALGB studies; furthermore, adjustment of MTX dosing to achieve targeted serum MTX levels may reduce the risk of CNS relapse. Younger pts who received 80 mg/m2 D had improved DFS and S. However, in contrast to other reports, the differences were not statistically significant. Thus, risk-adapted approaches to eradication of MRD using new agents and/or biologically targeted therapies should be incorporated into front-line treatment of ALL.

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