A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.

Retrospective histologic comparison of Helicobacter pylori infection in gastric carcinoma, ulcerous disease and non-ulcerous dyspepsia.

Although a number of epidemiological, biological and clinical studies have been published, the effective role of Helicobacter pylori infection in gastric carcinogenesis remains unclear. In the present work we retrospectively compared Helicobacter infection rate, by means of histologic examination of gastric bioptic samples, in 70 patients affected by gastric carcinoma, 70 with ulcerous disease and 70 with non-ulcerous dyspepsia. The analysis was carried out by a single pathologist. The differences between the 3 groups were not statistically significant. From our present and previously reported data, the Helicobacter infection cannot be considered per se a significant risk factor for malignant gastric disease and further studies are needed to evaluate the role of Helicobacter infection in the development of some preneoplastic conditions such as chronic atrophic gastritis and intestinal metaplasia.

Is there an association between Helicobacter pylori cytotoxin Cag A seropositivity and risk for gastric cancer?

BACKGROUND: Since discovered in 1990, Cag A, a protein expressed by specific strains of Helicobacter pylori, was thought able to explain why only a few Helicobacter infected patients develop peptic diseases and gastric cancer. However, clinical trials provide discordant results. MATERIALS AND METHODS: In this study we evaluate Helicobacter pylori and Cag A seropositivity in 35 cancer affected patients, in 36 gastritis affected patients and in 40 healthy blood donors by means of two commercially available fluorescence enzyme-immunoessay (ELISA). RESULTS: Odds ratios determination strongly suggests that Cag A bearer Helicobacter strains play a pathogenetic role in gastric diseases (OR 4.23, 95% CI 3.22-5.24 for cancer versus healthy volunteers, OR 3.2, 95% CI 2.19-4.21 for gastritis versus asymptomatic patients), but is unable to demonstrate a direct carcinogenic activity (cancer-gastritis difference is not significant: OR 1.32, 95% CI 0.39-1.25). CONCLUSIONS: Cag A seropositivity can be considered a risk factor for peptic disease, and only indirectly for gastric carcinoma. The paper also discuss some sampling, laboratory and statistical bias that can explain a wide eterogenity of the results reported in the literature.

Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy.

Hepatitis B virus (HBV) reactivation of various degrees of severity, including fulminant hepatitis, may develop in 20-50% of hepatitis B virus surface antigen (HbsAg)-positive patients undergoing immunosuppressive or cytostatic treatment. Lamivudine is a nucleoside analogue that can directly suppress HBV replication. We have performed a pilot study to test the efficacy and tolerability of lamivudine as a primary prophylaxis of HBV reactivation in 20 consecutive patients treated for haematological malignancies, mainly of lymphoid origin. Lamivudine, 100 mg/d, was given orally from the start until 1 month after the end of chemotherapy, which included corticosteroids and/or purine analogues in 85% of cases. It was well tolerated and did not cause any unexpected reduction of cytostatic drugs dosages. The chemotherapy programme was completed in all patients without modifications. A transient threefold increase in serum amylase was observed in one case. HBV-DNA levels decreased in six out of six patients (P = 0.039) and ALT levels in five out of six patients (P = 0.057) whose serum levels were abnormal at the onset of therapy. Two patients developed transient hepatitis. HBV reactivation was documented in only one of these patients who had stopped lamivudine 1 month before. No signs of HBV reactivation were detected both during and after treatment in 18 patients with a median follow-up of 6 months (range 3-12). Thus, primary prophylaxis with lamivudine may be a well tolerated and effective method to reduce the frequency of chemotherapy-induced HBV reactivation in chronic HBsAg carriers.

Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients.

The biological and clinical importance of cytogenetic analysis in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly recognized. Recently, cytogenetic similarities were noted between elderly de novo AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the present study we analyzed the cytogenetic similarities between patients with AML of different age and patients with MDS consecutively diagnosed during a 5-year period at a single, primary referral, hematologic center. Of 246 patients aged <86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML. Patients were classified according to FAB criteria and were subdivided into four groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65 years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic similarities both in the frequency of normal karyotypes (31% and 27%), single abnormalities (14% and 13%), double abnormalities (17% and 14%), complex karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7 (27% and 27%). The only difference between the two groups was found in the median number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic features resembled otherwise those of 'late MDS' and 'old AML', and any significant difference disappeared when patients with chronic myelomonocytic leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML and AML with trilineage dysplasia shared the same cytogenetic features of 'late MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups, particularly in the higher frequency of balanced translocations (29%; P<0.001) and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%; P<0.01) involvement. We conclude that in a population-based series of patients, the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical to that of elderly patients with AML both in the frequency and in the type of chromosomal abnormalities. These results support the possibility that MDS and AML of elderly patients may represent the same disease seen at different stages of evolution.

Idarubicin and cytosine arabinoside in the induction and maintenance therapy of high-risk myelodysplastic syndromes.

BACKGROUND AND OBJECTIVE: Recently, the results of a few pilot studies have shown the efficacy of the association of idarubicin (IDA) and cytosine arabinoside (Ara-C), already successfully employed in acute myeloid leukemia (AML), for remission induction in patients with myelodysplastic syndrome (MDS). We set out to evaluate in a multicenter study the efficacy and tolerability of an intensive therapy with IDA and Ara-C in patients with RAEB and RAEB-t, the rate and duration of CR and the overall survival in adults treated with full doses and in the elderly treated with lower doses; furthermore, we investigated the efficacy of low-dose maintenance chemotherapy. METHODS: Pretreated adult patients with de novo RAEB and RAEB-t, meeting at least one of the following criteria, were included: neutrophils < 0.5 x 10(9)/L or moderate neutropenia with infectious episodes, platelets < 30 x 10(9)/L or moderate thrombocytopenia but with bleeding symptoms, transfusion > 4 red cell units/months, rapid increase of bone marrow blasts. Induction treatment consisted of a cycle with IDA and Ara-C. Adult patients less than 65 years old were treated with the following doses: Ara-C 1 g/m2/day i.v. 6-hour infusion, on days 1-4, IDA 10 mg/m2/day i.v., on days 1-3. Elderly patients (> or = 65 yrs) were treated with lower doses: Ara-C 1 g/m2/day 6 hours infusion, on days 1 and 2, IDA 10 mg/m2/day i.v., on days 1 and 2. Responders followed a consolidation course identical to induction. RESULTS: From February 1994 to February 1997, 25 patients were enrolled, 20 males and 5 females aged between 22 and 76, 10 were > or = 65 years old, 7 had RAEB and 18 had RAEB-t. Twelve cases (48%) achieved complete remission (CR), 7 cases (28%) achieved partial remission, 4 patients were resistant and two patients (8%) died during the aplastic phase. A significantly higher CR rate was found in younger patients (p = 0.036), while gender, FAB subtype, presence of Auer rods, cytogenetic findings, and the interval from diagnosis to treatment did not significantly influence CR achievement. INTERPRETATION AND CONCLUSIONS: Our results show that in de novo RAEB and RAEB-t, the employed treatment with IDA and Ara-C is associated with satisfactory frequency of response with acceptable toxicity.

Idarubicin and cytosine arabinoside in the induction and maintenance therapy of high-risk myelodysplastic syndromes.

BACKGROUND AND OBJECTIVE: Recently, the results of some pilot studies have shown the efficacy of the association of idarubicin (IDA) and cytosine arabinoside (Ara-C), already successfully employed in acute myeloid leukemia (AML), for remission induction in patients with myelodysplastic syndrome (MDS). We set out to evaluate in a multicenter study the efficacy and tolerability of an intensive therapy with IDA and Ara-C in patients with RAEB and RAEB-t, the rate and duration of complete remission, and the overall survival in adults treated with full doses and in the elderly treated with lower doses; furthermore, we investigated the efficacy of low-dose maintenance chemotherapy. METHODS: Pretreated adult patients with de novo RAEB and RAEB-t, meeting at least one of the following criteria, were included: neutrophils < 0.5 x 10(9)/L or moderate neutropenia with infectious episodes, platelets < 30 x 10(9)/L or moderate thrombocytopenia with bleeding symptoms, transfusion > 4 red cell units/months, rapid increase of bone marrow blasts. Induction treatment consisted of a cycle with IDA and Ara-C. Adult patients less than 65 years old were treated with the following doses: Ara-C 1 g/m2/day i.v. 6-hour infusion, on days 1-4, IDA 10 mg/m2/day i.v., on days 1-3. Elderly patients (> or = 65 yrs) were treated with lower doses: Ara-C 1 g/m2/day 6 hours infusion, on days 1 and 2, IDA 10 mg/m2/day i.v., on days 1 and 2. Responders followed a consolidation course identical to induction. RESULTS: From February 1994 to February 1997, 25 patients were enrolled, 20 males and 5 females aged between 22 and 76, 10 were > or = 65 years old, 7 had RAEB and 18 had RAEB-t. Twelve cases (48%) achieved complete remission (CR), 7 cases (28%) achieved partial remission, 4 patients were resistant and two patients (8%) died during the aplastic phase. A significantly higher CR rate was found in younger patients (p = 0.036), while gender, FAB subtype, presence of Auer rods, cytogenetic findings, and the interval from diagnosis to treatment did not significantly influence CR achievement. INTERPRETATION AND CONCLUSIONS: Our results show that in de novo RAEB and RAEB-t, treatment with IDA and Ara-C is associated with satisfactory frequency of response with acceptable toxicity.