In an attempt to define mechanisms by which B-cell non-Hodgkin lymphoma (NHL) may escape rituximab immunotherapy, we developed several rituximab-resistant cell lines (RRCL) generated from the rituximab-sensitive cell lines (RSCL) Raji and RL. Rituximab resistance was associated with CD20 downregulation and upregulation of CD52 and the complement inhibitory proteins (CIPs) CD55 and CD59. No significant alemtuzumab-associated complement-mediated cell lysis (CMC) or antibody-dependent cellular cytotoxicity (ADCC) was demonstrated in RSCL. In contrast, in vitro exposure of RRCL to alemtuzumab resulted in a significant degree of CMC and ADCC. Of note, in vitro blocking of CD52 with anti-CD52 F(ab')(2) fractions in RRCL improved rituximab-associated CMC as compared to unblocked RRCL. Our current data provides a basis for further evaluation of alemtuzumab-based clinical trials for patients with rituximab-resistant NHL.
Myelodysplastic syndromes (MDS) traditionally have been grouped together as a disease entity based on clinical phenomena seen in association. Despite the similarities, there is great heterogeneity among the syndromes. Recent insights have shown, however, that there exists a biologically cohesive theme that unifies and thereby validates the conceptual interconnectedness. The first suggestion that such a relationship existed where biology could directly explain the observed cytopenias was the finding of excessive premature apoptosis of hematopoietic cells in MDS marrows. This apoptosis was mediated by paracrine as well as autocrine factors implicating both the seed and the soil in the pathology of the disease. Pro-inflammatory cytokines in the marrow microenvironment were mainly the paracrine mediators of apoptosis, but how the clonal cells committed suicide because of autocrine stimulation had remained a mystery for more than a decade. It has been shown now that deregulation of ribosome biogenesis can initiate a stress response in the cell through the p53 signaling pathway. Congenital anemias had been associated with mutations in ribosomal protein genes. The surprise came with the investigation of 5q- syndrome patients where haplo-insufficiency of the ribosomal protein gene RPS14 was found to be the cause of this MDS subtype. Similar ribosomal deregulation was shown to be present in all varieties of MDS patients, serving as another unifying characteristic. In addition to these findings, there are other DNA-related abnormalities such as uniparental disomy, mutations in the TET2 gene, and epigenetic phenomena that are associated with and occur across all types of MDS. This paper summarizes the themes unifying this heterogeneous group of diseases.
Cancer cells, including B-cell lymphoproliferative disorders, sculpt their phenotype in an attempt to escape not only immune-surveillance but also evade the anti-tumor activity of biological agents and/or chemotherapy drugs including rituximab. In an attempt to study the mechanisms that regulate the emergence of rituximab resistance, we developed several rituximab-resistant cell lines and demonstrated that the emergence of a rituximab-resistant phenotype was associated with global down regulation of CD20 antigen and unexpectedly an increase in CD52 antigen. Validation of our findings in more clinically relevant settings is important to support alemtuzumab-based clinical studies in rituximab-resistant B-cell malignancies. To this end, we retrospectively studied changes in CD20 expression over time in alemtuzumab treated-patients with rituximab-fludarabine (RF) refractory CLL. Patients were identified using the institute tumor registry and pharmacy electronic database. Demographic characteristics, treatment history, outcome data were obtained for each patient. In addition, CD20 expression in CLL cells obtained from flow cytometry analysis performed on peripheral blood, bone marrow and tissue was reviewed. A total of 16 patients with RF refractory CLL treated with alemtuzumab were included in the analysis, 13 males and 3 females, the median age at the time of diagnosis was 55.5 yrs +/− 10.47stv, and most of the patients had a good PS (0) at the time of treatment with alemtuzumab (81%). The response rate to alemtuzumab was 56.3%, with 7 (43.5%) patients achieving a complete response (CR). After a median follow up period of 88.5 months, 7 patients are still alive, 3 are free of disease. Complete flow cytometry data was available only for 9 patients. A down regulation of CD20 antigen expression was observed among 5/9 patients in blood, bone marrow and/or tissue over time when compared to baseline CD20 levels. Following alemtuzumab therapy, CR was achieved in 3/5 patients with CD20 down-regulation versus 1/4 patients with steady levels of CD20. Alemtuzumab-treated CLL patients with CD20 down-regulation had a longer overall survival (141 months) than alemtuzumab treated CLL patients with steady levels of CD20 antigen overtime (116 months, Log Rank P = 0.026). Our data suggest, that emergence of rituximab-fludarabine resistance is associated with changes in the expression of CD20 antigen. A response to alemtuzumab in this setting appears to be higher than historical controls (2% CR). Refractory CLL patients with decreased levels of surface CD20 appears to respond better to alemtuzumab and have a longer overall survival than patients with steady CD20 levels. Similarly to what we have observed in our pre-clinical models, an increase in CD52 expression in rituximab-fludarabine refractory patients with CD20 down regulation could explain the higher response rate observed in this small group of highly selected patients. Detailed monitoring of CD20 and CD52 levels in CLL patients before, during and after treatment with rituximab-based regimens is warranted in an attempt to identify patients that can benefit from almetuzumab-based therapies.
Introduction: Relapsed/refractory B-cell lymphomas are a constant treatment challenge. High- dose chemotherapy and stem cell transplant (HDC-SCT) continues to be the backbone of treatment for such patients. Adequate cytoreduction with salvage chemotherapy is necessary prior to HDC-SCT and its achievement has been demonstrated to correlate with post-transplant outcomes. Various non-cross resistant salvage regimens have been developed to treat patients with relapsed/refractory B-cell lymphoma. In this report we present our institution’s experience with DHAC±R in patients requiring salvage therapy prior to HDC-SCT. Methods: The DHAC regimen consists of Dexamethasone at 15mg/m2/dose po every 6 hours × 10 doses, High-dose Ara-C at 3gr/m2 (1.5gr/m2 if >50 yrs old) iv over 3 hrs every 12 hrs for 4 doses and Carboplatin at 200mg/m2 iv every 24 hrs for 2 doses. When utilized, patients received rituximab at the standard dose of 375mg/m2, 48 hrs prior to each cycle of DHAC. Growth factor support and anti-microbial prophylaxis was implemented 24 hours after completion of chemotherapy. The regimen was repeated every 21 days for 2-3 cycles prior to HDC-SCT. We treated 37 patients with relapsed/refractory lymphomas, the median age of the entire cohort was 47 years (range 18 – 78); 25 were male and 19 females. While most of the patients treated had diffuse large B-cell lymphoma (DLBCL), various histological subtypes were included (DLBCL (n=16); follicular lymphoma (n=10); marginal zone lymphoma with blastoid features (n=1); small lymphocytic lymphoma (n=1) and Hodgkin’s lymphoma (n=8). The majority of the patients presented with advance stage at the time of DHAC therapy-Stage III (n=43%), Stage IV (n=39%). Seventeen patients were treated with R+DHAC, and 20 were treated with DHAC, either as second line or third line therapy. 19 out of the 37 patients proceeded to Stem cell transplant (SCT). Results: The overall response rate (ORR, CR+PR) for all patients was 61%(CR (n=16); and PR (n=7). The remaining 14 patients had either stable disease (n=10) or progressed (n=4). Complete responders (43%) had a longer mean survival of 107 (range 78 – 136) months compared to 66 months (range 49 – 83) for partial responders (19 percent) and non-responders who had a mean survival of 30.8 months (range 9–54), [P = 0.008]. Patients who proceeded to SCT had an overall response rate of 79% [CR (n=11) and PR (n=4)] compared to only 44% in those who did not [CR (n=5) and PR (n=3)]. The median survival in patients transplanted was longer than non-transplanted patients (92 vs 68 months). Response rates and median survival was similar between patients receiving R-DHAC or DHAC. As expected grade 3&4 hematologic toxicities were seen and effectively managed with appropriate supportive care. Conclusions: DHAC with or without rituximab appears to be an effective salvage treatment for patients with relapsed or refractory advanced-stage B-lymphoma undergoing HDC-SCT. An overall response of 61% which increases to 79% when followed by autologous SCT were demonstrated. Median survival was longer in patients experiencing CRs compared to partial or non-responders suggesting that the quality and quantity of the cytoreduction after salvage chemotherapy is an important predictor factor of post-SCT survival. Data looking at prognostic factors predicting response to DHAC±R treatment are being analyzed and will be reported at the ASH annual meeting.
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