ALBERT

Description: Ninety ET patients diagnosed according to the PVSG criteria entered a phase II study designed to identify a treatment with PEG Interferon α-2b (PEG Intron, Schering-Plough Corp) safe and able to obtain and to maintain for a long time the Hematological Response (HR, PLTs 〈 500x 109/L). The patients, 30 Males and 60 Females, median age 45 years (18–72), judged at risk and in the majority of cases pre-treated with cytoreductive drugs (60%), at study entry showed a mean PLT count of 1093 ± 357 x 109/L (〉1000 in 49% of cases). During the first year (part 1 of the study) the PEG Intron starting dose of 25 μg/week was gradually increased if necessary at week 13, 26 and 39 till a maximum of 100 μg/week to reach the HR. The HR at the end of the 1st year (primary endpoint) was registered in 64 patients who represented the 71% of the 90 enrolled subjects (analysis on Intent-to-Treat, ITT) and the 79% of the 81 patients still receiving PEG Intron. The PEG Intron effective dose had a mean value of 50 ± 22 μg/week resulting very low (25μg/week) in 33% of cases. The primary endpoint was reached independently by sex, age, cytoreductive pre-treatment and baseline PLT count. Nevertheless, the HR was more frequent in the patients with true ET respect those with false ET (WHO criteria, HR 93% vs. 68%). In the 64 responder patients admitted to the part 2 of the study according to the protocol, the HR at the end of the 2nd year was registered in 75% of cases on ITT and in 87% of the 55 patients still on treatment, with a PEG Intron maintenance dose gradually reduced to a mean level of 27 μg/week. No thrombotic or hemorrhagic events occurred during the study and, moreover, a decrease of splenomegaly (from 22% to 6%) and of disease related symptoms (from 42% to 2%) was registered. The unmaintained HR, in 29 valuable patients who discontinued the PEG Intron treatment after two years, had a median duration of 11 weeks (4–52). Eighteen patients discontinued PEG Intron treatment (9 during the 1st year and 9 during the 2nd year) as consequence of PEG Intron toxicity and side effects (n 7), loss of compliance (n 5) and drug unrelated reasons (n 6). Toxicity and side effects (WHO grading) were never of grade 4, in very few cases of grade 3 and in the majority of patients of grade 1 or 2 (mainly flu-like syndrome, leukopenia, hypertransaminasemia). The ECOG Performance status (PS) was of grade 0 in all but few patients who showed a transitory grade 1 PS. In conclusion, PEG Intron treatment performed at relatively low dose seems safe and able to induce and to maintain the HR for a long time in the majority of at risk ET patients.

Description: From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts 〉 or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event-free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+, and 17+ months from the second CR. These results indicate that (1) the AIDA protocol is highly effective in treating APL; (2) after 3 consolidation courses, the majority of patients who achieved CR are RT-PCR- for the hybrid gene PML-RAR alpha; (3) the persistence of an RT-PCR positivity for the PML- RAR alpha hybrid gene after 3 consolidation courses is indicative of early relapse, thus these patients still require additional treatment. These results have prompted the Gruppo Italiano Malattie Ematologiche Maligne dell′Adulto (GIMEMA) to initiate, in cooperation with the Associazione Italiana di Ematologia ed Oncologia Pediatrica and some European Organization for Research and Treatment of Cancer (EORTC) centers, a new multicentric clinical trial named AIDA LAP 0493 for the treatment of adult and pediatric APL patients. All patients are considered eligible if APL diagnosis is confirmed with molecular or cytogenetic studies for PML-RAR alpha hybrid gene or t(15;17) and are enrolled to receive the same induction and consolidation therapy of this pilot study. After consolidation, patients who are RT-PCR- for PML- RAR alpha hybrid gene are randomized to four arms, whereas patients who are RT-PCR+ after consolidation undergo, if eligible, an allogenic transplantation procedure.

Description: It has been recently hypothesized that the hepatitis C virus (HCV) might be involved in the pathogenesis of malignant B-cell non-Hodgkin's lymphomas (NHL). On the basis of this observation we sought to determine the prevalence of HCV infection in the patients affected by B- cell NHL and extended our analysis to all the patients affected by lymphoproliferation disorders seen at our institution in the last 30 months. Five hundred and thirty-seven unselected, consecutive patients were studied. HCV infection was investigated through detection of anti- HCV antibodies and HCV-RNA. HCV genotyping was performed on HCV-RNA positive specimens. The risk of being infected by HCV was compared with that of the general population of our area. Among all lymphoproliferative disorders, the prevalence and the relative risk (RR) of being infected by HCV were increased only among B-cell NHL (9%; RR 3.24; p 〈 .0001). Among these, a strong prevalence of HCV was found only in the subgroup of immunocytomas (30%; RR 10.27; P 〈 .0001), while other histotypes were associated with it only occasionally. Because HCV- positive lymphomas clinically behave as essential mixed cryoglobulinemia (EMC), the close association between HCV infection and EMC is confirmed, and evidence is provided that the pathological substrate of EMC corresponds to the immunocytoma. HCV genomic sequences were found in 84% of patients analyzed. Viral genotypes were those more frequent in our area.