E. Thiel

To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.

In a prospective multicenter study, 368 acute lymphoblastic leukemia (ALL) patients aged 15 to 65 years were treated with an intensified induction and reinduction regimen; 272 (73.9%) achieved complete remission (CR). The median remission duration (MRD) is 24.3 months, and the probability of being in continuous CR (CCR) at greater than 5 years is .37. The median survival for all 368 patients is 27.5 months, and the probability of being alive at 5 years is .39. For the 272 patients in remission the median survival is 58.4 months, and the probability of being alive at 5 years is .49. A lower CR rate was seen for patients with bleeding at diagnosis or with splenomegaly/hepatosplenomegaly. The prognostic factors unfavorable for remission duration were time to CR greater than 4 weeks v less than 4 weeks (P = .0002), age greater than 35 years v less than 35 years (P = .0008), leukocyte count greater than 30,000/microL v less than 30,000/microL (P = .0112), and null ALL v common ALL (c-ALL)/T cell ALL (T-ALL) (P = .05). The remission duration correlated strongly (P = .0001) with the number of these independent prognostic factors. In patients with none of these adverse factors the MRD has not yet been reached, with one adverse factor the MRD is 21.9 months, and with two or three adverse factors the MRD is only 9.6 months. For the immunologic subtype T-ALL, the probability of being in CCR at greater than 5 years is .55; for c-ALL, .34; and for null ALL, .24. According to these results, patients were stratified into a low-risk group with a CCR rate of .62 and a high-risk group with a CCR rate of .28, with the latter now allocated to either further chemotherapy or bone marrow transplantation in first remission.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

One hundred seventy adult patients with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL) were entered into a prospective multicenter therapy trial at 25 hospitals. The aim of the trial was to improve remission duration by using a modified form of an intensified induction regimen that was successful in childhood ALL, to define immunologic subtypes of ALL by use of cell-surface markers, and to extract other possible prognostic factors. The overall complete remission rate was 77.8%. The median overall survival time was 26 months, being 4 months for nonresponders and 32 months for responders. The median remission duration for the 126 patients with complete remission was 20 months. Prognostically favorable factors for remission duration were response to chemotherapy within 4 weeks, age less than 35 years, a low initial leukocyte count, and the immunologic subtypes c-ALL with early response to therapy and T-ALL, where 61% and 58%, respectively, are still in complete remission at 3 years. An adverse influence on remission duration was observed for the subtype null-ALL, with a median survival of 13 months, and for patients with a delayed response to induction therapy, independent of phenotype.