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Abstract Multiple myeloma is a highly radiosensitive malignancy but, at the present time, radionuclide-based interventions have no proven place in disease management. Bone-seeking radionuclides such as 153-Sm-EDTMP and 166-Ho-DOTMP are promising agents for systemic delivery of ionizing radiation to sites of myeloma disease activity, but they are associated with significant myelosuppression at therapeutically effective doses and have therefore been used only in the context of myeloma stem cell transplantation protocols. We previously reported that the proteasome inhibitor PS-341 potently and selectively sensitizes myeloma cell lines and primary myeloma cells to the lethal effects of ionizing X-irradiation (Goel et al, Exp Hematol. 33, 784, 2005). To determine whether PS-341 is equally effective in sensitizing myeloma cells to ionizing beta-radiation and to extend our initial observations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP. In vitro clonogenic assays were performed using a panel of myeloma cell lines and demonstrated synergistic killing following co-treatment with PS-341 and 153-Sm-EDTMP. Using the orthotopic, syngeneic 5TGM1 myeloma model, the median survivals of mice treated with saline, two doses of PS-341 (0.5 mg/kg), or a single non-myeloablative dose of 153-Sm-EDTMP (22.5 MBq) were 21, 22 and 28 days, respectively. In contrast, mice treated with combination therapy comprising two doses of PS-341 (0.5 mg/kg), one day prior to and one day following 153-Sm-EDTMP (22.5 MBq) showed a greatly prolonged median survival of 49 days. Correlative studies indicated that, compared to single-agent therapy, combination treatment with PS-341 and 153-Sm-EDTMP rapidly reduced the clonogenicity of bone-marrow resident 5TGM1 cells, slowed the elevation of serum myeloma-associated paraprotein levels, and was associated with longer term preservation of bone mineral density. The myelotoxicity of single agent and combination therapies was evaluated by comparing peripheral blood cell counts in each of the treatment groups, and by clonogenicity assays of hematopoietic progenitors isolated form normal mice receiving identical treatment regimens. Treatment with 153-Sm-EDTMP led to significant, but transient, myelosuppression which did not differ between animals treated with 153-Sm-EDTMP alone versus those treated with the combination of PS-341 plus 153-Sm-EDTMP. In summary, PS-341 is a potent in vivo radiosensitizer that greatly enhances the therapeutic potency, without increasing myelotoxicity, of skeletal targeted radiotherapy in the syngeneic, orthotopic 5TGM1 myeloma model. Based on these findings, we propose to conduct a phase I clinical trial at Mayo Clinic to evaluate the combination of PS-341 plus non-myeloablative skeletal targeted radiotherapy (using 153-Sm-EDTMP) in patients with advanced or treatment-refractory multiple myeloma.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. Methods: We studied the toxicity and efficacy of lenalidomide in patients with symptomatic AL. Patients received single agent lenalidomide. If progression by 3 months or no evidence of hematologic response after 3 cycles, dexamethasone was added. Originally, twenty-three patients (Cohort 1) were enrolled according to study design. Because of a significant early drop out rate and notable activity of the regimen, the trial was modified to include an additional 15 patients (Cohort 2). Baseline characteristics and adverse events are available for all enrolled patients, but at the time of this writing, response data are available for Cohort 1 patients due to short follow-up of Cohort 2, but will be updated by the time of the meeting. Results: Median age was 64 years, with 69% male. Twenty-three were previously treated. Organ involvement was cardiac (67%), renal (64%), hepatic (17%), nerve (17%). Thirty-three, twenty-two, and forty-four percent of patients were cardiac biomarker stage 1, 2, and, 3 respectively. Of the 37 patients, one was a cancel, and 6 have not yet made it through 3 months of protocol treatment and event monitoring. The respective median follow-ups for Cohorts 1 and 2 are 17 and 3.4 months. Of the remaining, 30 patients, within the first 3 cycles of therapy fifteen patients discontinued treatment: 7 early deaths and 8 adverse events or other causes. Three additional patients died 0.5 to 2 months after stopping treatment. The best predictor for early withdrawal and/or death was baseline NT-proBNP and cardiac biomarker staging system (cut-offs for serum troponin T <0.035 ng/ml and NT-proBNP <332 pg/ml--Stage I neither above cut-off; Stage III, both above cut-off; and Stage II, one above cut-off). Figure1 Figure1. Figure 2 Figure 2. Of the twenty 22 patients assessed for response ten patients responded to treatment for an overall response rate of 45%, including 23% organ responders. Among the patients with organ responses, there were four renal responses, two cardiac responses and two liver responses. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3−4 adverse events at least possibly attributable to lenalidomide were neutropenia (38%), thrombocytopenia (21%), fatigue (15%), and rash (12%). Conclusions: Lenalidomide and dexamethasone has significant activity in patients with AL with an overall response rate of 45%. Baseline NT−proBNP may be an effective eligibility screening strategy for subsequent trials.

Abstract Background: Angiogenesis has been found to be an important regulator in the disease progression of both solid tumors and hematologic malignancies. In solid tumors, the balance of pro and anti-angiogenic factors appears to be a critical factor in tumorigenesis, with disturbance in favor of angiogenesis promoting tumor growth and metastasis. This observation led to the concept of an “angiogenic switch” where pro-angiogenic influences outweigh anti-angiogenic factors. Patients with CLL have detectable levels of plasma and cellular pro and anti-angiogenic cytokines as well as abnormal neovascularization in the marrow and lymph nodes. Limited studies of pro-angiogenic cytokines have suggested that inter-patient variation in serum/plasma and cellular levels of these markers may have prognostic implications. We evaluated pro- and anti-angiogenic cytokines in a large sample of patients with CLL to evaluate the presence of angiogenic switching and its implications for disease progression. Methods: In a prospective, longitudinal study, we analyzed the serum/plasma, intracellular(determined by flow cytometry), and CLL B cell secreted (24 hour medium values) levels of pro-angiogenic cytokines (VEGF, bFGF) and an anti-angiogenic cytokine (Thrombospondin [TSP]) in 311 patients with previously untreated CLL. VEGF:TSP and bFGF:TSP ratios were calculated to evaluate for evidence of angiogenic switching (higher ratio suggests a pro-angiogenic phenotype). The relationship of angiogenic cytokines to Rai stage, IgVH gene mutation status, % CD38 protein expression, and time to treatment (TTT) from the date of sample were evaluated (median follow-up=11 months). Sequential samples were available on >90% of patients and were evaluated to assess if changes in levels of angiogenic cytokines occurred in patients requiring treatment. Results: Serum, cellular, and secreted levels of VEGF, bFGF, and TSP showed no correlation with Rai stage, IgVH gene mutation (continuous variable), or % expression of CD38 (continuous variable). However, among patients with Rai stage 0-II disease, individuals with lower TSP levels (<75 percentile, p=0.007) or higher bFGF:TSP ratios (continuous variable; p=0.003) had shorter TTT (Figure 1). Similar relationships for a shorter TTT were also observed for secreted TSP levels (p=0.007) and the cellular bFGF:TSP ratio (p=0.009). On analysis of sequential samples, no clear difference in serum, cellular, or secreted levels of VEGF, bFGF, TSP, VEGF:TSP, or bFGF:TSP occurred among those who required treatment. Conclusions: Angiogenic cytokines appear to have prognostic significance in patients with previously untreated early stage CLL. Importantly, we report the original observation that the ratio of bFGF (pro-angiogenic) to TSP (anti-angiogenic) correlates with time to treatment as a continuous variable. This result provides further evidence that angiogenic switching relates to clinical progression in CLL. Longer follow-up of this cohort is needed to fully define the prognostic implications of angiogenic cytokines in CLL and determine if integration of these markers with other prognostic parameters improves risk stratification for early stage patients. Survival According to Serum Thrombospondin Level Survival According to Serum Thrombospondin Level

Abstract Background: Castleman Disease (angiofollicular hyperplasia) is a rare, lymphoproliferative disease. There has been no large study describing the natural history of this disease. Hypothesis: A retrospective analysis of clinical, pathologic, and laboratory factors predictive of outcome should be identifiable. Methods: During the period from 3/30/48 to 6/18/2002, 114 patients with Castleman Disease were seen at the Mayo Clinic (Rochester, 56; Jacksonville, 19; Arizona, 13) and at the University of Nebraska (26). Pathology, laboratory and clinical characteristics analyzed included: the presence of unicentric or multicentric disease, the pathologic variant (hyaline vascular versus plasma cell variant), co-existing POEMS syndrome, age, serum albumin, alkaline phosphatase, AST, sedimentation rate, the presence of cytopenias, organomegaly (hepatomegaly or splenomegaly), papilledema, peripheral neuropathy, sclerotic bone lesions, renal disease, B-symptoms or respiratory symptoms. The impact of these variables on overall survival from time of diagnosis was evaluated using univariate analyses, where their significance was determined based on the logrank statistic. To derive the multivariable model, the score-based model-building method was used. Based on this approach, a 3-variable model was designed, adjusting for age at diagnosis. Patients were then assigned a risk score corresponding to how many of these risk factors they possessed. A final proportional hazards model was constructed based on this risk score. Results: The median age at diagnosis was 43 (range: 5 – 78), and 48% of patients were male. Fifty-five patients had multicentric disease. Median follow-up of living patients was 5.8 years (range: 0.02 – 27). On univariate analysis, factors that predicted for overall survival included: age at diagnosis, presence of multicentric disease, presence of a monoclonal protein in the urine, co-existing POEMS syndrome, serum albumin, presence of cytopenias, organomegaly, neuropathy, thrombocytosis, and respiratory symptoms. The final multivariable model included 98 patients. Adjusting for age, the model included organomegaly, respiratory symptoms, and thrombocytosis. Patients were assigned 1 point for each risk factor they possessed based on clinical relevance and similarity of the hazard ratios for each of these 3 variables (ranging from 3.1 to 4). A final prognostic survival model was constructed using this assigned risk score. These scores were collapsed further based on observed similarities (0 factors vs. 1 or more factors). This final model yielded a hazards ratio of 5.5 (95% CI 2.3–13.4). The 10 year survival rates were 80% (95% CI: 65–98%) and 41% (95% CI: 28–59%) for the 0 factor and 1+ factor groups, respectively. The 20 year survival rates were 71% (95% CI: 52–87%) and 31% (95% CI: 19–51%), respectively. Conclusion: The most distinguishing prognostic clinical, laboratory, and pathological characteristics of Castleman’s Disease are orgnaomegaly, respiratory symptoms, and thrombocytosis. This prognostic scoring system should aid in individual cases and in assessing results of therapeutic interventions.

Abstract Background: CLL is still an incurable lymphoid malignancy. The current standard of care is to treat only patients with obvious clinical progression as defined by the National Cancer Institute Working Group in 1996 (NCI–WG 1996). High risk CLL can be identified at diagnosis by a variety of tests including fluorescence in situ hybridization (FISH), immunoglobulin heavy-chain variable region (IgVH) analysis, and expression of ZAP-70 or CD38. With this information we can identify patients with high risk, early stage disease who are candidates for novel low toxicity therapies that could alter the natural course of their disease. Our hypothesis was that combination monoclonal antibody (MoAb) therapy using alemtuzumab and rituximab would significantly reduce the high risk clone in early stage CLL. Methods: This phase II trial was conducted with IRB approval and accrued the planned 30 patients between January 2005 and July 2007 at Mayo Clinic Rochester. The study enrolled consenting patients with Rai stage 0–II CLL without NCI–WG 1996 criteria for treatment who had high risk CLL as defined as one or more of the following 17p13–, 11q22–, unmutated (UM) IgVH (< 2%) and expression of ZAP–70 (≥ 30%) and/or CD38 (≥20%). Treatment was one 30 day cycle (alemtuzumab 3 mg, 10 mg, 30 mg days 1–3 then 30 mg 3 × week × 4 weeks with all doses subcutaneously and rituximab at 375 mg/m2/week IV × 4 doses from day 8). Patients received 7 days of allopurinol and antimicrobial prophylaxis against PCP and herpes virus infections for 7 months. CMV testing by PCR was done weekly during treatment, then monthly × 6. Results: All 30 patients have completed therapy and 27 have been evaluated for response. The median age of these 27 patients was 62 yr (range 29–77) with 8 patients > 70 years. There was a male predominance (67%) with median time from diagnosis to treatment of 0.7 yr (range 0.1 – 6.1). Stage (Rai) at the start of therapy was 0 in 7 (26%), I in 19 (70%), and II in 1. High risk markers were 17p13– in 9 (33%), 11q22– in 7 (26%), UM IgV and expression of either ZAP–70 or CD38 in 11 (41%). All 27 patients completed therapy without interruption. Non hematological grade 3–4 toxicity occurred in 3 patients (2 drug reactions caused by SMX/TMP, 1 CMV reactivation responsive to IV therapy). Response evaluation at 2 months after completion of therapy using NCI–WG 1996 criteria showed an ORR of 93% with 12 (44%) CR, 8 (30%) nPR, and 5 (19%) PR. Two (7%) patients had disease progression. Median duration of follow up was 14.1 months (range 1.9 – 27.2). Median time to disease progression in the 25 responding patients was 14.4 months (95% CI 5.9 – 22.4). Seven (26%) patients have received subsequent treatment for CLL (median 5.2 months, range 2.4 – 20.1). A minimal residual disease assay using 3-color flow cytometry on peripheral blood was negative in 6 of the 7 patients with CR who had no evidence of residual CLL on immunohistochemical examination of the bone marrow. These 6 patients all remain in sustained CR (median follow up 15 months, range 2 – 27.2). Conclusion: Alemtuzumab and rituximab is an effective and tolerable therapy in patients with high risk early stage CLL. A randomized controlled trial is now required to test if this intervention is better than the standard observation approach. In addition, this combination MoAb regimen could be used as a platform to develop even more effective combination treatments for patients with CLL.

Abstract Introduction Antisense oligonucleotides are used to inhibit messenger RNA function and inhibit protein translation. Bcl-2 expression proteins have been implicated in mediating resistance to apoptotic cell death in Waldenstrom Macroglobulinemia (WM). Oblimersen sodium is a specific inhibitor of Bcl-2 expression and has shown activity in multiple myeloma and in Waldenstrom cell lines. The in vitro data led to the development of a phase I study for WM patients with relapsed or refractory disease. Materials and Methods Eligible patients had symptomatic WM who had failed prior cytotoxic chemotherapy. All patients had to have one of the following: a hemoglobin <11 g/dL, a platelet count <100,000/uL, bulky lymphadenopathy, or hyperviscosity syndrome. As a phase I study, the primary end point was toxicity assessment, but all patients were assessed for response, using monoclonal protein levels. Patients were enrolled and evaluated in cohorts of three. Drug was administered as a 24-hour continuous infusion for 7 days every 21 days, with intrapatient dose escalation each subsequent cycle beginning at 3 mg/kg/day up to a maximum of 7 mg/kg/day days 1–7 for a maximum of 8 cycles. Results To date 9 patients have been accrued, six at dose level one and three patients at dose level two. Data is available for the first six entered. Five women and 1 man have been accrued with a median age of 74.5 years, ranging from 58 to 81. Four patients had relapsed from prior therapy, 2 were refractory. Three had a history of transfusions. The median number of prior regimens was 4 (range 2–7). One patient had a dose-limiting toxicity on the first cycle of therapy, which was grade 3 fatigue and anorexia, and the dose for this patient was reduced. Two patients had non-hematologic grade 3 toxicity, possibly related to therapy. Five out of six patients on dose level one had grade 3 or greater hematologic toxicity. These toxicities occurred after cycle 1 was completed, during the toxicity observation period and were not considered dose limiting toxicities influencing dose escalation. Three patients required dose reductions in subsequent cycles. To date one patient has had a partial response with her serum M spike falling from 3.6 to 1.1 g/dL. Her quantitative IgM fell from 6,000 mg/dL to 1,000 mg/dL(figure). Conclusion Oblimersen was well tolerated at the first dose level in patients with WM. Hematologic toxicity is frequent in this cohort with heavily involved bone marrows when the dose was escalated during successive cycles. Dose reductions with subsequent cycles were frequently required. Evaluation of the maximum tolerated dose continues. Data on response for this dose level is promising, where efficacy will be fully evaluated in the phase II portion of this trial. Figure Figure

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell dyscrasia with limited therapeutic options. Based on the observed 25 to 50% partial response rates in myeloma patients, thalidomide has been tried in patients with AL. Two reports (Dispenzieri et al, Amyloid10:247; 2003; Seldin et al, Clinical Lymphoma3:241; 2003) have demonstrated that standard dose, single agent thalidomide (≥ 200 mg per day) has a higher than expected rate of adverse events in AL patients without hematologic or organ response, potentially due to rapid patient attrition. We therefore performed a prospective clinical trial using low dose, single agent thalidomide in patients with AL. Methods: In August 2001, we began accrual to a phase II trial of low dose thalidomide for patients with AL. Eligibility included: age ≥ 18 years, creatinine <3mg/dL, total bilirubin < 3 mg/dL, ANC ≥ 1 x 10(9)/L, left ventricular ejection fraction of >45%, histochemical proof of amyloid and a monoclonal plasma cell dyscrasia, symptomatic organ involvement, and ability to supply informed consent. Patients were started with thalidomide 50 mg per day, with a dose escalation to a maximum dose of 400 mg per day over a 19 week period as tolerated. Patients were evaluated monthly by their physician. These office visits were staggered with telephone toxicity checks monthly by the primary investigator. The endpoint of the study was hematologic and organ response by 12 months. Results: Eighteen patients were treated. The median age was 66 years (range 43–83). Eight were male. Twenty-eight percent had an ECOG performance status of 2 or 3. Five patients (28%) had received no prior therapy. Five had received one prior regimen; 6, two prior; and 2, ≥ three. Three had received prior PBSCT. Sixteen patients had a monoclonal lambda plasma cell disorder; two, monoclonal kappa. Immunoglobulin heavy chains were IgG (n=9), IgM (n=5), IgA (n=1), and none (n=3). Twelve patients (67%) had cardiac involvement; twelve (67%) renal; two liver; two symptomatic gastrointestinal; one pulmonary; and two nerve involvement. Study participants had significant symptomatology at baseline with dyspnea (n=12), light-headedness (n=6), and edema (n=13). Median number of organs involved was 1, range (1 to 4). Median time on study drug was 5.6 months, range 0.7–24 months. Reasons for discontinuation included: progression, 7 (39%); 3 each (17%) for adverse events, death, and patient refusal; and other causes in 2. The median tolerated dose was 100 mg. There were no hematologic responses observed. The overall organ response rate was 11%. There was one renal response at 1 year and a gastrointestinal response at 3 months with 24 hour fecal fat changing from 21 to 8.7 grams. The most common adverse effects attributable to thalidomide were: constipation (78%), edema (44%), sinus bradycardia (17%), dyspnea (11%), and paresthesias (11%). Light-headedness, rising creatinine, thrombosis, infection, syncope, and rash was attributed to the thalidomide in 5.6% of patients. Conclusions: Low dose thalidomide is tolerable in this fragile group of patients, but as a single agent efficacy is limited. Further study of combination therapy of thalidomide and low dose dexamethasone may be warranted. A study using the next generation immune modulatory drug Revlimid is scheduled to open to accrual. Funded by NIH grant CA 91561 and Celgene.

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

7574 Background: Patients (pts) with relapsed aggressive NHL are usually treated with intensive platinum-based chemotherapy regimens prior to stem cell transplant (SCT). This study was designed to learn the toxicity and efficacy of adding 4 doses of rituximab to the standard DHAP salvage chemotherapy regimen. Methods: Eligible pts had biopsy-proven relapsed CD20+ NHL and were eligible for platinum-based chemotherapy. Pts were treated with rituximab 375 mg/m2 d1,8,15, and 22 as well as cis-platinum 100 mg/m2 d3, cytosine arabinoside 2 g/m2 IV q 12 hours x two doses d4, dexamethasone 40 mg PO/IV d3–6, and G-CSF d5–14. Pts were restaged after 1 and 2 cycles; responding pts could proceed to SCT or further cycles of DHAP at MD discretion. There was no provision for rituximab maintenance. The goal was to achieve an overall response rate (ORR) of ≥ 75%. Results: Fifty-eight pts were enrolled between 10/29/00 and 6/20/03. The median age was 63 years (range, 43–83). One pt was ineligible because the tumor was CD20-. All 57 eligible pts completed one cycle; 48 pts completed 2 cycles. The ORR was 70% (40/57) with 16 (28%) CR/CRu and 24 (42%) PR. For all 57 pts, the median TTP was 13.1 months (mos) (95% CI: 7.3–18.2) and the median OS 30.5 mos (95% CI: 17.8–52.5). Seventeen pts (30%) proceeded to SCT. The median duration of response (DR), time to progression (TTP) and overall survival (OS) for the SCT pts were 41.6, 42.3, and 43.6 mos, respectively. The median DR, TTP, and OS for the 25 pts who responded to RDHAP but did not proceed to SCT were 12.4, 13.1, and 38.8 mos, respectively. The incidence of grade 3 and 4 thrombocytopenia was 53% and 39%, respectively. The incidence of grade 3 and 4 neutropenia was 11% and 68%, respectively. Six pts (11%) had nephrotoxicity–five grade 3 and two grade 4 (one pt had both) and one pt required dialysis. Conclusions: The addition of rituximab to standard DHAP is safe with similar toxicity profile to DHAP alone. Despite a high ORR, the CR rate and the % pts proceeding to SCT in this cooperative group setting remain low. New agents are needed that can be added to these regimens to increase the effectiveness and reduce toxicity to allow more pts to proceed to SCT. No significant financial relationships to disclose.

7532 Background: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. Temsirolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly temsirolimus at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (JCO 23 (23); 5347–56, 2005). Thrombocytopenia was frequently observed and was dose limiting. The current study tested whether low-doses (25mg) of temsirolimus could produce a similar overall response rate (ORR) with less toxicity. Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received temsirolimus 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. The goal was to achieve an ORR of at least 20%. Results: Twenty-nine patients were enrolled between March and August 2005. Twenty-two patients have completed therapy. One patient with a major protocol violation on cycle-1 and one ineligible patient were excluded, leaving 27 evaluable patients. The ORR was 41% (11/27), with 1 CR and 10 PRs. Early evaluation of TTP showed a median of 5.5 months (95% CI: 3.3–7.7) and the duration of response for the 11 responders was 6.2 months (95% CI: 3.6 to not yet reached). These results compare favorably with the 6.5 months and 6.9 months, respectively, found in previous trials that used 250 mg. The median dose delivered per month was 80 mg (range, 10–100 mg). Sixteen (59%) of patients required a dose reduction. The median time on treatment was 4.4 months (95% CI, 3.3–7.7). The incidence of grade 3 and 4 thrombocytopenia was 12% and 0%, respectively. One patient experienced grade 5 infection without neutropenia, which was considered unrelated to CCI-779. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL similar to the 250 mg dose. This study indicates that combinations of temsirolimus with other agents should be feasible. [Table: see text]