ALBERT

Description: Abstract 1233 Poster Board I-255 Introduction Cytogenetic analysis has become a routine part of the evaluation of patients with chronic lymphocytic leukemia (CLL) because specific chromosomal aberrations have been shown to assist in predicting disease progression, treatment efficacy, and overall survival. One such abnormality is del(17p13.1), which has been found to be associated with a need for early therapy, poor response to conventional treatment, and shortened survival. Identification of recurring abnormalities in this region represents great interest to identify genes relevant to CLL progression and poor prognosis. Patients and Methods We performed an extensive review of 1213 patients undergoing metaphase cytogenetics study at our institution and identified 16 (1.3%) with a recurrent unbalanced translocation between the p arms of chromosomes 17 and 18 that results in a dicentric chromosome with loss of much of 17p and 18p. The clinical features of these patients were characterized. Results A total of 16 patients were identified to have dic(17;18)(p11.2;p11.2) representing a 1.3% occurrence rate. The median age at diagnosis of these patients was 57 years (range 37-68). The dic(17;18)(p11.2;p11.2) was associated with a complex (3 or more unrelated cytogenetic abnormalities) karyotype in 12 patients (75%) at the time that the abnormality was first identified, and eventually associated with a complex karyotype in 94% of patients. This abnormality was associated with trisomy 12 in 7 patients (44%) and with del(13q) in 5 patients (31%) with no overlap between these two abnormalities. IgVH mutational analysis was un-mutated in 88% of cases. Except for one patient who was diagnosed with CLL incidentally during a workup for metastatic tonsillar cancer, all patients identified with dic(17;18)(p11.2;p11.2) met criteria for disease treatment, with a median time from diagnosis to first treatment of 15 months. Of the 12 patients who received fludarabine-based therapy, 7 (58%) were refractory. Three patients have received stem cell transplant for recurrent/refractory disease, and 4 are currently undergoing chemotherapy. With a mean follow-up of 54 months, 4 patients have died, 21, 42, 49, and 92 months after diagnosis. Conclusions Our study combined with small series reported by others demonstrate that dic(17;18)(p11.2;p11.2) is a novel recurrent cytogenetic abnormality in CLL. Here we demonstrate the clinical significance of this recurring abnormality that is associated with young age at diagnosis, accelerated disease progression, decreased response to fludarabine, and shortened overall survival. The dic(17;18)(p11.2;p11.2) is frequently accompanied by other negative prognostic markers including a complex karyotype and unmutated IgVH status. Additional studies to further characterize the prevalence of this abnormality and genes that are disrupted by the translocation are warranted. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 539 Introduction: The addition of rituximab to fludarabine-based regimens in CLL has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, and development of secondary malignancies has been limited. Patients and Methods: We report the long-term follow up of the chemoimmunotherapy trial CALGB 9712 (Blood 2003;101:6-14). This trial randomized 104 untreated, symptomatic patients to receive either 6 monthly cycles of fludarabine plus rituximab (FR) followed 2 months later by 4 weekly doses of rituximab (concurrent arm) or 6 monthly cycles of single agent fludarabine followed by rituximab consolidation using 4 weekly doses (sequential arm). With a median follow up of 92 months (range: 60-107), we analyzed the updated CALGB database and flow sheets submitted by treating physicians. Results: The overall response rate (ORR) was 84% (95% CI: 77%-91%), with a 90% ORR in the concurrent group (95% CI: 82%-98%) and a 77% ORR in the sequential group (95% CI: 66%-89%). Complete response (CR) was seen in 38% of patients (95% CI: 30%-45%), and partial response (PR) in 46% (95% CI: 38%-54%). The median OS was 85 months (95% CI: 71-95), with 71% of patients alive at 5 years (95% CI: 61%-79%). The median PFS was 37 months (95% CI: 27-45), with 27% progression-free at 5 years (95% CI: 19%-36%). With long-term follow up, the estimated median OS and PFS for the concurrent group were 84 months (95% CI: 57-100) and 32 months (95% CI: 23-55), respectively; the median OS and PFS for the sequential group were 91 months (95% CI: 71-110) and 40 months (95% CI: 23-50), respectively. Patients with del(17p13.1)/del(11q22.3)(18 patients) and unmutated IgVH(43 patients) continue to have an inferior OS (P=0.01 and P=0.04, respectively) and PFS (P=0.03 and P=0.04, respectively) compared to those without these abnormalities. We next assessed the frequency of therapy-related myeloid neoplasms (t-MN) and other cancers occurring after this chemoimmunotherapy regimen. No patient has developed MDS or AML prior to relapse. One patient (1%) developed t-MDS following relapse and receipt of FCR 41 months after completing trial therapy; t-MDS was diagnosed 9 months later. Richter's transformation was noted in three (3%) of the CALGB 9712 patients with large cell (n=2) or Hodgkin lymphoma (n=1). Second malignancies have included localized basal cell or squamous cell skin cancer in 12 (12%) patients whereas 11 (11%) have developed other epithelial malignancies including 4 GI, 3 lung, 3 melanomas, and 1 prostate cancer. Conclusions: Long-term follow up of patients enrolled on CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab, given either concurrently or sequentially, with an estimated 17%(95% CI: 9%-27%) of responders still in remission 8 years later. Looking at other published data, patients treated with FR administered concurrently or sequentially do not appear to have an increased risk of t-MN or second cancers. These long-term data reaffirm that FR is one of several acceptable frontline treatments for symptomatic patients with CLL. Disclosures: Morrison: Genentech: Speakers Bureau.