Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age.

We used nonpegylated liposomal doxorubicin (NPLD) in cytostatic drug combinations to treat 37 patients with non-Hodgkin's lymphoma and pre-existing cardiac disorder or elderly patients with reduced physical state who were ineligible for conventional anthracycline-containing therapy. High remission rates were observed in this poor-risk population: Complete remission rates were 75% for diffuse large B cell lymphoma (DLBCL) and 55% for T/NK cell neoplasm (overall response rate of 80% and 89%, respectively). Twenty-seven patients (73%) are still alive after a median observation time of 14 months. No major cardiac or gastrointestinal toxicity was observed. Extravasation of NPLD in two patients resulted in mild inflammation without tissue damage. Hematologic toxicity was comparable to that of conventional anthracycline-containing regimens. We conclude that NPLD is highly active in combination chemotherapy for lymphoma with low cardiac toxicity in patients with pre-existing cardiac disorders or higher age. Moreover, we also observed remarkable efficacy in T/NK cell lymphomas.

Autoimmune conditions and chronic infections in chronic lymphocytic leukemia patients at diagnosis are associated with unmutated IgVH genes.

Few data are available concerning the prevalence of autoimmune disease or chronic infections in chronic lymphocytic leukemia patients at diagnosis as well as their clinical outcome. We studied the frequency of such chronic conditions in relation to prognostic markers. A history of autoimmune disease or chronic infection was found in 21% of 186 chronic lymphocytic leukemia patients (12% in autoimmune diseases, 9% in chronic infections). Patients with a history of chronic stimulation were more likely to have unmutated IgV(H) genes (p<0.002), unfavorable or intermediate risk cytogenetics (11q, 17p deletions, trisomy 12) (p<0.001), and higher CD38 expression (p=0.004). Autoimmune conditions (n=22) were characterized by female predominance (55.0%) with a high frequency of unmutated IgV(H) (53,8%). Median time to first treatment was 83 months for the chronic stimulation group compared to 128 months for the non-chronic stimulation group (n.s.). Patients suffering from chronic conditions at chronic lymphocytic leukemia diagnosis are likely to have poor prognostic markers, particularly unmutated IgV(H) genes.

MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia.

PURPOSE: A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has been negatively associated with onset and outcome of disease in solid tumors. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL. PATIENTS AND METHODS: The frequency of SNP309 T/T, T/G, or G/G genotypes and the p53 status (wild type, mutated, or deleted) were assessed and correlated with clinical outcome in 140 B-CLL patients and a second independent cohort. In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 protein expression level in B-CLL cells was evaluated by immunoblotting. RESULTS: A significant negative association of the SNP309 T/G and G/G genotypes with overall survival was seen (T/G genotype, relative risk = 3.7; 95% CI, 1.2 to 11.5; P = .02; G/G genotype, relative risk = 9.1; 95% CI, 2.4 to 35.1; P = .001), but no correlation with incidence or onset of B-CLL was observed. The influence of the heterozygous SNP309 T/G genotype on treatment-free survival depended on the p53 status but not on the CD38, Zap-70, or IgVH mutational status or Rai stage of B-CLL patients. The unfavorable SNP309 T/G and G/G genotypes were associated with a gene-dosage-dependent increase of MDM2 expression. CONCLUSION: The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL.

Antibody responses to pneumococcal and hemophilus vaccinations in splenectomized patients with hematological malignancies or trauma.

In this study we addressed the question of whether an underlying hematological malignancy may affect the immune response to vaccination against bacterial polysaccharide antigens (e.g. Haemophilus influenzae type b, Streptococcus pneumoniae) in splenectomized patients. Between 1993 and 2003, 44 splenectomized adults from the outpatient clinic for infectious diseases were prospectively included in the study: 23 patients suffered from hematological malignancies (HM) and had undergone splenectomy; 21 were splenectomized following trauma (T) and served as the control group. Each patient received an intradeltoid injection with 0.5 ml of a single lot of a 23-valent pneumococcal polysaccharide vaccine, and 0.5 ml of a polyribosyl ribitol phosphate capsular polysaccharide vaccine of H. influenzae type b (Hib) into the opposite arm. Blood samples for determination of pneumococcal and Hib antibodies were taken prior to vaccination and again 6-8 weeks later. In assessing responses to the 23-valent pneumococcal polysaccharide vaccine, we found significant differences in antibody titer increase between the HM and T groups (median IgG increase 1.27 [0.7; 2.39] vs. 3.9 [2.1; 15.3], P < 0.001; and median IgM increase 1.33 [1.0;2.67] vs. 5.25 [2.3; 7.78], P < 0.001). In the HM group, only 8/23 and 6/23 showed a titer increase of twice or more the base value for IgG and IgM respectively, whereas in the trauma group an adequate response was shown by 16/21 and 16/20 respectively. Patients with splenectomy and hematological malignancies responded poorly to the 23-valent polysaccharide vaccine. Response to the conjugated Hib vaccine was slightly better, but still significantly lower than in individuals with posttraumatic splenectomy. Data suggest that vaccination response to the polysaccharide vaccines should be evaluated at least in the high-risk group.