PURPOSE To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

Tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment-naïve CLL. Patients received 6 months of continuous daily thalidomide with standard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sensory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median follow-up of 15+ months none of the patients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen.

CLL is an incurable disease. Standard treatment with F results in an ORR of 63% (CR 20%). Improved RR are noted when F is combined with biologic agents such as rituximab. All pts eventually relapse with limited salvage options. TNF-a is an important cytokine in the pathogenesis of CLL. T is an immunomodulatory drug with anti- TNF-a, anti-VEGF and immunostimulatory activity. We have completed a phase I study combining T with F as an immunochemotherapeutic approach to enhance anti-CLL activity of F. Treatment-naïve pts requiring therapy for CLL were eligible for this study. T was started at D1 and continued for 6 months stepwise in 3 cohorts of T (100,200,300 mg). Standard dose F (25mg/m2 x 5 D every 4 wks) was given for 4–6 cycles starting on D7. Antitumor activity of T alone was assessed at D7 prior to the first F dose. Low-dose coumadin (1 or 2 mg po qd) was used for prophylaxis against venous thromboembolism (VTE). Thirteen pts (9M, 4F; median age 65,range 38–74 yrs) have been enrolled on 3 dose levels (cohort #1 n =6, #2 n=3, #3 n=4). All pts are available for toxicity analysis. Pts were considered evaluable for response if they completed the intended 6 months of T. 3 pts were removed from study for toxicity (2VTE, 1 in the 1st week of therapy prior to F infusion, 2nd during the 4th cycle, 1 Hep C reactivation presumably secondary to F), without evidence of disease progression. 9 pts completed 6 months of therapy and are available for response (5CR and 4PR, ORR of 100%) median follow-up of 12+ (range 6–18+) months. Response to T alone, assessed on D7 of cycle 1, was noted at all dose levels, and no dose-limiting toxicity was noted. Flare reaction (tender swelling of lymph nodes) was noted in 5/13 pts (38%) and was the most common side effect. Rash, fatigue and constipation were noted in 30%, 23% and 15% of the pts, respectively. Of the 60 cycles given on this study, 9 (15%) and 3 (5%) episodes of Grade III and IV non-hematologic toxicities were noted, respectively. In this phase I study, the combination of T with F was well tolerated with improved ORR over F. T alone appears to be active in CLL with clinical activity noted as early as D 7 at all dose levels studied. The combination does not appear to increase the incidence of VTE compared to T alone. Ongoing phase II portion of this study will further establish the potential role of FT in CLL.

Recent understanding of MM biology suggests that MM cells rely on their microenvironment for disease progression and dissemination. MM cell interaction with stromal cells in the bone marrow microenvironment fosters chemotherapy resistance. Targeting the microenvironment with novel biologic agents such as thalidomide (T) has shown encouraging clinical results in patients with previously untreated as well as relapsed/refractory MM. We have previously shown here that VAD plus low dose T (t) is an effective salvage regimen for VAD refractory pts. We report the preliminary results of an ongoing phase II trial studying a combined chemoimmunotherapeutic approach - standard VAD plus t (200 mg) in treatment-naïve MM pts. This regimen was designed to target concurrently the malignant cell and its microenvironment. MM pts, ≥ Stage I with no prior therapy were eligible for study. Monthly infusional VAD (standard dose) was given for 4 cycles every 28 days concurrently with t for 4 months. t (100mg) was started 1 wk prior to VAD and was escalated in 1–2 wks to 200mg. Pts were evaluated for response after each cycle and after cycle 4 using SWOG criteria. Pts characteristics include: enrolled n=16, 8M, 8F; median age 58 yrs range 46–77; Stage III disease n=11, Stage II, n=3 and Stage 1, n=1; and Median B2M, 1.9 mg/L (range 1.2–11.5). Low dose coumadin (1–2 mg) was used for venous thromboembolism (VTE) prophylaxis, t was also held during the 4 days of each infusion of VAD. All pts are evaluable for toxicity and 11 are evaluable for response after completing 4 cyc. 10/11 (91%) responded clinically; CR, n=3, PR, n=7. One pt had progressive disease. Three pts with responding disease were removed from study for Grade III toxicity (1 adriamycin associated cardiomyopathy, 1 pulmonary hypertension and 1 recurrent infections) but are not included in response evaluation. Toxicities: fatigue (Gr. II) was the most common side effect (25%) and DVT was noted in 2 (12%). All pts eligible for stem cell (SC) transplant (n=7), were able to collect adequate amount of SC post VAD-t. Preliminary results of this study suggest that VAD-t is an effective and well-tolerated regimen with improved ORR compared to standard VAD regimen in pts with treatment naïve MM. No increase in incidence of VTE was noted with the combination. Adequate SC collection was achieved in transplant eligible pts. Accrual is ongoing on this study and updated results will be presented at the annual meeting.

Abstract Introduction: Bortezomib, a first in class proteasome inhibitor, has become a standard of care in the treatment of relapsed and refractory MM. A recent randomized Phase 3 trial showed an improvement in time to progression (TTP) and overall survival relative to dexamethasone (dex) in patients with relapsed MM and 1–3 prior lines of therapy. In relapsed MM, the rate of treatment -emergent significant peripheral neuropathy (PN) with bortezomib was higher in patients with baseline neuropathy. The incidence and severity of PN in front-line treatment will be important to define. This multi-center, Phase 2 study was planned to evaluate the activity and toxicity (in particular PN) of single agent bortezomib in previously untreated pts. Methods: Response rate, TTP, tolerability, incidence and severity of PN, and the effect of dose modification, symptomatic treatment and nutritional supplements on PN were evaluated in previously untreated, symptomatic MM pts. Pts received bortezomib 1.3 mg/m2 on D 1, 4, 8, and 11 of a 21-d cycle and response to treatment was assessed every 2 cycles. Dex was not permitted. Neurologic evaluation was required before and after treatment, and if significant PN developed during therapy. Results: 28 pts with symptomatic MM have been treated with a median age of 60 yrs, IgG isotype in 68% and Stage III disease in 52%. Analysis of best paraprotein response after ≥ 2 cycles revealed CR in 1 (5%) pt and PR in 8 (36%), for an ORR of 41% in 22 evaluable pts. An additional 5 pts (23%) achieved MR, with stable disease in 6 pts (27%); 2 pts progressed (9%). The most commonly reported adverse events included PN, fatigue, GI symptoms and rash. Neurological evaluation has been performed in all pts, including nerve conduction studies (NCS), assessment of autonomic function and skin biopsy for EM imaging of small fibers in a subset (n=19). Six of 28 pts (21%) so far have developed PN with most being G2: 1 pt experienced G3 PN and drug was discontinued. Dose modification was required in 4 pts and supplements have been used in all pts with PN. Preliminary results of neurological testing and NCS have indicated subclinical PN at baseline prior to therapy in 6/19 (30%) of pts evaluated by NCS, with small fiber, axonal PN documented in 1 pt with treatment-emergent PN. Bortezomib-related toxicity has otherwise been manageable. Conclusion: Single agent bortezomib is a promising approach for newly diagnosed pts and is without the complications of high-dose dex. The incidence of subclinical PN by NCS at baseline prior to therapy is currently 30%; G2 or greater treatment-emergent PN has occurred in 21% of pts and was G3 in only 1 pt (4%) to date. Further assessment of PN including analysis of skin biopsies is ongoing.