ALBERT

Description: Abstract 1402 Poster Board I-424 Introduction: Anatomic imaging using contrast-enhanced computed tomography (CT) is essential for management of lymphomas. Functional imaging using 18FDG-PET (PET) improves detection of certain lymphomas, specifically, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Currently, PET imaging is performed with co-registration of low-dose non-contrast enhanced CT images used for anatomic correlation and attenuation correction of PET images (PET/CT). It has been suggested that the low-dose non-enhanced CT cannot substitute for diagnostic contrast-enhanced CT imaging since the arterial and venous phases of contrast enhancement improve detection of lesions. Given the differential sensitivity for detection of specific lymphomas by PET imaging, we hypothesized that FDG could substitute for intravenous contrast in imaging of certain lymphomas, and that PET/CT or PET imaging could potentially obviate the need for contrast-enhanced CT. To test this hypothesis, we performed an independent and blinded radiology review of these imaging studies in patients (pts) with DLBCL, FL, small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL/SLL) or marginal zone lymphoma (MZL) who had contrast-enhanced CT, PET, PET/CT, and low-dose non-enhanced CT available for retrospective review. Patients and Methods: Pts with a diagnosis of DLBCL, FL, CLL/SLL, or MZL with PET/CT and contrast-enhanced CT studies performed at the Hospital of the University of Pennsylvania within 6 weeks of each other without intervening therapy were studied. Pts with clinically suspected progression of lymphoma between studies were excluded. Radiologists, blinded to clinical information or other imaging results, separately interpreted image sets of low-dose non-enhanced CT, PET, fusion PET/CT, and contrast-enhanced CT studies. The presence or absence of disease at 44 nodal and 48 (female) or 49 (male) extranodal sites was recorded for each site for each imaging modality. Concordant findings across imaging modalities were defined as positive for involvement by lymphoma; discordant findings were reconciled using all available clinical and radiologic information with follow-up for progression or regression of abnormality, or by biopsy. Results: Between May 2006 and January 2008, 55 pts with either DLBCL (n=31), FL (n=13), CLL/SLL (n=5), or MZL (n=6) had complete images sets available for review. All patients had at least 18 months of clinical follow-up after imaging. A total of 282 sites met criteria for involvement by lymphoma. The rates of detection for specific lymphomas by each imaging modality are shown below: Conclusions: Our results suggest that combined PET/CT imaging is more sensitive than contrast-enhanced CT imaging for detection of DLBCL and at least as sensitive as contrast-enhanced CT imaging for detection of FL. In comparison, contrast-enhanced CT imaging appears superior to PET/CT imaging for CLL/SLL; while further studies are needed to confirm superiority of contrast-enhanced CT imaging in MZL. The routine use of both contrast enhanced CT and PET/CT modalities for staging of lymphoma may be unnecessary, potentially increasing both the cost of medical care and radiation exposure. Additional studies are needed to determine which imaging modality is optimal for each type of lymphoma. Disclosures: No relevant conflicts of interest to declare.

Description: Fludarabine-based chemotherapy combinations are highly effective in patients (pts) with low-grade follicular lymphoma (FL), but cause severe and long-lasting immunosuppression due to depletion of normal CD4 T-cells. Aside from increasing the risk of serious infections, this toxicity may limit the ability of the immune system to eliminate minimal residual disease. Adoptive immunotherapy using autologous CD25-depleted, CD3/CD28-costimulated T-cells expanded ex vivo (ACTC) may enhance immune reconstitution and improve disease control. We initiated a phase I study in pts with purine analog-naive relapsed/refractory FL (grades 1 and 2). After leukapheresis, pts receive 4 cycles of fludarabine (25 mg/m2) days 1 – 3 and cyclophosphamide (250 mg/m2) days 1 – 3. Four weeks after last chemotherapy, responding patients (CR, CRu, PR) receive escalating doses of ACTC prepared from autologous T-cells collected prior to chemotherapy. Thirteen pts have been enrolled to date. Median age is 49 y (range: 32 – 68). Median number of prior therapies is 2 (range: 1 – 3). Two pts were withdrawn from the study due to hematologic toxicity related to chemotherapy, one patient was withdrawn for progressive disease during chemotherapy, and one patient has not completed first response assessment after ACTC infusion. For 9 assessable pts completing chemotherapy and ACTC infusion, 7 pts achieved a CR and 2 pts achieved a PR; 5 pts received 1 – 5 x 109 and 4 patients received 5 – 10 x 109 CD3+ ACTC. There have been no adverse events related to T-cell infusions. Median follow-up after ACTC infusion is 20 months (range: 2 – 42 months). CD4 counts increased in all patients by 1 month after T-cell infusion, with a median increase of 3.8 fold (n = 8; range: 1.5 – 71). For patients at dose level 1, the median increase was 2.2 fold (n = 4; range: 1.5 – 21); at dose level 2, it was 4.2 fold (n = 4; range: 3.8 – 71). CD8 counts also increased, with a median increase of 8.1 fold (range: 1.0 – 30). All 9 pts receiving ACTC were anergic to candida antigen by delayed type hypersensitivity (DTH) skin testing before chemotherapy; 5 pts developed a positive DTH response to candida antigen 60 days after ACTC infusion. From the start of therapy for patients receiving T-cells, median follow-up is 24 months (range: 6 – 47) with median progression-free survival of 18 months, which is significantly longer than the time to progression from last therapy (median 11 months) (p = 0.01, log-rank test). Thus, ACTC results in more rapid CD4+ lymphocyte recovery in pts after cyclophosphamide-fludarabine chemotherapy compared to historical controls and results in reconstitution of recall immunity. These encouraging clinical responses provide the rationale for clinical trials to test ACTC as a way to enhance cellular immunity to tumor-specific antigens after chemotherapy.

Description: BACKGROUND: Fludarabine-based chemotherapy combinations are highly effective in patients (pts) with low-grade follicular lymphoma (FL), but cause severe and long-lasting immunosuppression due to depletion of normal CD4+ T-cells. Aside from increasing the risk of serious infections, this toxicity may limit the ability of the immune system to eliminate minimal residual disease. Adoptive immunotherapy using autologous CD25-depleted, CD3/CD28-costimulated T-cells (ACTC) expanded ex vivo may enhance immune reconstitution and improve disease control. METHODS: We initiated a phase I study in pts with purine analog-naive relapsed/refractory FL (grades 1 and 2). After leukapheresis, pts receive 4 cycles of fludarabine (25 mg/m2) days 1–3 and cyclophosphamide (250 mg/m2) days 1–3. Four weeks after the last cycle, responding patients (CR/CRu, PR) receive escalating doses of ACTC prepared ex vivo from autologous T-cellss collected prior to chemotherapy and depleted of regulatory CD4+/CD25+ cells, then expanded and activated using anti-CD3 and anti-CD28. RESULTS: Eleven pts have been enrolled to date. Median age is 49 y (range: 33–64y). Median number of prior therapies is 2 (range: 1 – 3). Two pts were withdrawn from the study due to hematologic toxicity related to chemotherapy, one patient was withdrawn for progressive disease during chemotherapy, and one patient has not yet completed chemotherapy. Of the 7 pts completing chemotherapy and proceeding to T-cell infusion, 5 pts achieved a CR/CRu and 2 pts achieved a PR; 5 pts received 1 – 5 x 109 CD3+ cells and 2 patients received 5 – 10 x 109 CD3+ cells. There have been no adverse events related to T-cell infusions. Median follow-up after ACTC infusion is 19 mos (range: 3 – 26 mos). CD4+ counts increased in all patients by 1 month after T-cell infusion, with a median increase of 3.2 fold (range: 1.5 – 70, p= .028)(see figure). For patients at dose level 1, the median increase was 2.2 fold (n=4; range: 1.5 – 3.3); at dose level 2 it was 37 fold (n=2; range: 3.8 – 70). CD8+ counts also increased, with a median increase of 8.1 (range: 1.0 – 30, p= .046)(see figure). All 7 pts receiving ACTC were anergic to candida antigen by delayed type hypersensitivity (DTH) skin testing before chemotherapy. Four pts developed a positive DTH response to candida antigen 60 days after ACTC infusion. For patients receiving ACTC, median follow-up is 24 mos (range: 7 – 31 mos) with a median progression-free survival of 18 months which is significantly longer than the time to progression from last therapy (p= .024). CONCLUSIONS: ACTC infusion results in significant CD4+ and CD8+ numerical and functional lymphocyte recovery after cyclophosphamide-fludarabine chemotherapy in pts with low-grade FL. This compares very favorably to historical controls treated with fludarabine-based regimens. T-cell dose escalation is ongoing. Figure Figure

Description: Fludarabine-based chemotherapy combinations are highly effective in patients (pts) with low-grade follicular lymphoma (FL), but cause severe and long-lasting immunosuppression due to depletion of normal CD4 T-cells. Aside from increasing the risk of serious infections, this toxicity may limit the ability of the immune system to eliminate minimal residual disease. Adoptive immunotherapy using autologous CD25-depleted, CD3/CD28-costimulated T-cells expanded ex vivo (ACTC) may enhance immune reconstitution and improve disease control. We initiated a phase I study in pts with purine analog-naive relapsed/refractory FL (grades 1 and 2). After leukapheresis, pts receive 4 cycles of fludarabine (25 mg/m2) days 1–3 and cyclophosphamide (250 mg/m2) days 1–3. Four weeks after last chemotherapy, responding patients (CR, CRu, PR) receive escalating doses of ACTC prepared ex vivo from autologous T-cells collected prior to chemotherapy and depleted of regulatory CD4+/CD25+ cells, then expanded and activated using anti-CD3 and anti-CD28. Eight pts have been enrolled to date. Median age is 40.5 y (range: 32–64). Median number of prior therapies is 2 (range: 1–3). Two pts were withdrawn from the study due to hematologic toxicity related to the chemotherapy; one patient has not completed chemotherapy. Of the 5 pts completing chemotherapy, 3 pts achieved a CR and 2 pts achieved a PR; 4 pts received 5 x 109 and 1 patient received 1 x 1010 CD3+ ACTC. There have been no adverse events related to T-cell infusions. Median follow-up after ACTC infusion is 9 months (range: 2–15 months). Median time to CD4 count 〉200 /uL was 29 days following T-cell infusion (range 28–127 days). CD4 counts increased in all patients by 1 month after T-cell infusion, with a median increase of 126% from baseline (range 50 to 484%). CD8 counts also increased, with a median increase of 82% (range −4 to 976%). All 5 pts receiving ACTC were anergic to candida antigen by Delayed Type Hypersensitivity (DTH) skin testing before chemotherapy. Three pts developed a positive DTH response to candida antigen 60 days after ACTC infusion. From the start of therapy for patients receiving T-cells, median follow-up is 14 months (range 7–20 months) with median progression-free survival not reached; 4 pts remain in remission and 1 patient had progression of disease. ACTC results in significant CD4+ lymphocyte recovery in previously treated pts receiving cyclophosphamide-fludarabine chemotherapy and compares very favorably with historical controls. T-cell dose escalation is ongoing.

Description: Background: Recent studies have prospectively established that concurrent or sequential addition of rituximab (R) to conventional therapies improves the overall survival rate (OS) for patients with low-grade follicular lymphoma (FL). However, there is little information regarding the prognosis of patients considered R-resistant. Subjects/Methods: We examined the records of 305 subjects with a diagnosis of FL seen at our institution between 1995 and 2007. To better define the prognosis for R-resistant subjects, we identified 133 subjects (grade 1, N=75; grade 2, N=41; grade 1 or 2, N=17) who completed an R-containing treatment (R alone, N=61; R combination, N=72) and had at least six months of follow-up from start of R-containing therapy. For the purposes of our study, we define R-resistance as progression of lymphoma within 6 months of the first R dose (i.e., the dose defining R-resistance) of the R-containing regimen followed by progression. Overall survival rates were evaluated for all subjects from first dose of R to last follow-up or death and, for R-resistant subjects, from the dose defining R-resistance to last follow-up or death. R-resistant subjects (N=62 [47%]) were subdivided into primary refractory (R-resistant after first R-containing treatment; N=30) or acquired resistant (R-resistant after at least one prior R-containing treatment without progression within 6 months; N=32). Median age at first treatment with R was 55 years (range: 21–87) for all subjects and 54 years (range: 21–87) for R-resistant subjects (for primary refractory, median=54 years [range: 28–87]; for acquired resistant, median=55 years [range 30–81]). The median number of prior non-R-containing treatment regimens was 1 (range: 0–4) for resistant subjects, and 0 (range: 0–3) for non resistant subjects. The median number of R-containing regimens for subjects with acquired resistance was 2 (range: 2–4). The frequency of large cell transformation did not differ between R-resistant and non R-resistant cohorts (N=7/71 [10%] and N=8/62 [13%], respectively). Results: Of 20 deaths observed for all subjects with FL receiving R or R containing regimens, 19 deaths occurred after R-resistance. At a median follow-up of 56 months (range 6–115) for all subjects receiving R, the median OS was not reached with 5-year Kaplan-Meier OS estimate = 81%. For R-resistant subjects, median OS from first dose of R defining R-resistance was 64 months (range: 6–100) with 5-year Kaplan-Meier OS estimate = 58%. Median rates of OS from R dose defining R-resistance were not significantly different between primary refractory and acquired resistant subjects. For subjects with acquired R-resistance, median time from first dose of R to first dose of R defining R-resistance was 10.4 months (range: 9–83). Conclusion: The OS estimate for subjects with R-resistant FL (5-year estimate OS = 58%) appears worse than survival estimates reported for unselected subjects with FL (5 year estimate OS = 80% for grade 1; 76% for grade 2 [SEER Survival Monograph, Non-Hodgkin Lymphoma]). This inferior prognosis seems unrelated to large cell transformation. Survival is similar for subjects with primary refractory and acquired resistance when survival is measured from the R dose used to define R-resistance.

Description: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients (pts) with relapsed or primary refractory lymphoma that is responding to salvage chemotherapy. Limitations of ASCT include significant morbidity, cost, restriction of further treatment options, and frequent relapse of lymphoma. To define the ability of FDG-PET to predict clinical outcome after ASCT, we conducted a retrospective analysis of lymphoma pts in our institution who received salvage chemotherapy followed by ASCT for relapsed or primary refractory lymphoma between 1999 and 2005. We identified 47 lymphoma pts (19 with diffuse large B-cell, 18 with Hodgkin, 4 with mantle cell, 3 with follicular and 3 with other lymphomas) who had an FDG-PET scan after at least two cycles of salvage chemotherapy and prior to ASCT. Three pts were excluded from the analysis because their FDG-PET scan results were non-conclusive. The remaining 44 pts (median age 44 yrs, range: 19–65) were categorized into FDG-PET scan negative (26 pts) and positive (18 pts) groups. Each group was evaluated for event-free survival (EFS), which was defined as the interval between the date of the transplant to the date of relapse after complete remission (CR) or the date of progression for pts without CR or the date of death from any cause without a documented relapse. The overall median follow-up was 14 mo (range: 2–58). There were no statistically significant differences in the distribution of lymphoma subtypes between the two groups. In the FDG-PET negative group, the median EFS was 18 mo (range: 3–58) with 14 pts (54%) remaining in CR. In the FDG-PET positive group, the median EFS was 5 mo (range: 1.5–19) with only 1 pt (6%) remaining in CR. Comparison between the two groups confirmed that the difference in the median EFS was highly statistically significant (p

Description: Abstract 1700 Poster Board I-726 Introduction Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond to or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continue during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results To date, 22 pts have started therapy; diagnoses included: follicular (n = 17), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 72); male: female ratio was 5:6; median number of prior therapies was 3 (range: 1 - 7); LDH was increased in 23%. For 21 pts with at least one follow-up visit, there were 2 deaths and 2 episodes of disease progression. One death due to myocarditis occurred during Part I treatment; one death due to lymphoma occurred in a patient removed from study due to grade 3 rash, which subsequently resolved. Both episodes of disease progression occurred in pts with follicular lymphoma, one of whom had been removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. For all patients, at a median follow-up of 5.0 months (range: 0.3 - 12.3), progression-free survival (PFS) is 81% (95% CI: 51-94). For 10 pts with response assessments after Parts I and II, overall response rate (ORR) after Part I was 30% (3 CR; 6 SD; 1 PD) and ORR after Part II was 70% (5 CR; 2 PR; 2 SD; 1 PD). At a median follow-up of 7.8 months (range: 5.0 - 11.9), PFS is 89% (95% CI: 43-98) for these 10 pts. For pts who completed Parts I and II, grade 3 or 4 non-hematologic toxicities included hypokalemia (2/10 pts), hypophosphatemia (1/10 pts), and hypocalcemia (1/10 pts); grade 1 tumor flare occurred in one pt with follicular lymphoma. Conclusions Based on these preliminary data in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with relatively durable responses. Additional follow-up and correlative studies will be presented. Disclosures Off Label Use: Lenalidomide is used in this trial for treatment of lymphoma.. Downs:Genentech: Honoraria; Celgene: Honoraria. Nasta:Genentech: Speakers Bureau. Schuster:Celgene: Consultancy, Research Funding.