ALBERT

Description: SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below: CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of 〉365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21% Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Description: Abstract 2868 Poster Board II-844 Background and Objective: In newly diagnosed multiple myeloma (MM), the combination of lenalidomide plus high-dose dexamethasone (RD) is superior to high-dose dexamethasone (Zonder JA et al, Blood 2007;110:77). Preliminary results show that lenalidomide plus low-dose dexamethasone (Rd) has better 2-year overall survival (OS) compared with RD (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The addition of clarithromycin (Biaxin) to lenalidomide and low-dose dexamethasone (BiRd) has been investigated in a phase II study, demonstrating a high response rate and 2-year OS (Niesvizky R at al, Blood 2008;111:1101-1109). However, the additive value of clarithromycin is not known. No randomized trials have compared Rd versus BiRd, none are planned. The objective of this case–matched study was to compare the efficacy and the toxicity of BiRd vs Rd as initial therapy for newly diagnosed MM. Patients and methods: Data from 72 newly diagnosed MM patients treated at the New York Presbyterian Hospital–Cornell Medical Center, from December 2004 to December 2006, with BiRD, were analyzed. For comparison, an equal number of pair mates were selected among newly diagnosed patients seen at the Mayo Clinic who received Rd, from March 2005 to December 2008. Case matching was performed with respect to age, gender, and transplant status. Patients treated with BiRd received oral lenalidomide (25 mg/day, days 3-21 of cycle 1; days 1-21 of subsequent cycles); dexamethasone (40 mg days 1, 2, 3, 8, 15, 22 of cycle 1; days 1, 8, 15, and 22 of each subsequent cycle); clarithromycin (500 mg twice daily, from day 2 of cycle 1). Patients treated with Rd received oral lenalidomide (25 mg/day, days 1-21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22). In both groups patients were allowed to discontinue treatment to pursue transplant, but treatment until progression, relapse or unacceptable toxicity was permitted at the physician's discretion. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method; comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: Median duration of treatment was 11.8 months in the BiRd group vs 6 months in the Rd group. On intention-to-treat analysis, complete response was significantly higher with BiRd compared to Rd (45.8% vs 13.9%, respectively, p

Description: Abstract 1249 Poster Board I-271 Purpose B-cell receptor (BCR) signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking BCR signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in pre-clinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Experimental Design Fresh CLL B cells were treated with dasatinib and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of BCR signaling molecules as well as with molecular and cytogenetic prognostic factors. Results and Conclusions Among 44 CLL cases, dasatinib treatment reduced cell viability by 2-90%, with an average reduction of 48% on day four of culture. The drug induced CLL cell death via the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good as well as poor responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and PLCγ2, correlate well with the apoptotic response of CLL cells to dasatinib. Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with PLCγ2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment. Disclosures Lee: Bristol-Myers Squibb Research & Development: Employment. Coleman:Bristol-Myers Squibb Research & Development: Consultancy.

Description: Splenectomy is frequently performed for diagnostic purposes in patients with suspected or known lymphoma, including assessment for possible transformation. The ability to predict splenectomy findings (and potentially avoid associated morbidity and mortality) would be valuable. The purpose of this study was to determine whether preoperative18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results correlate with pathologic diagnosis from splenectomy. Methods: One hundred sixty-five patients who had undergone a splenectomy at New York Presbyterian Hospital from January 2004 to July 2006 were identified from the pathology database. Records of these patients were searched and 11 with suspected or known lymphoma as an indication for splenectomy and who had a pre-splenectomy PET scan were identified. A nuclear medicine physician performed a blinded review and assigned each PET scan to one of the following categories based on splenic FDG standardized uptake values (SUV): low splenic metabolic activity (correlated with maximum SUV range 2-3.7), intermediate splenic metabolic activity (maximum SUV range 6–7), and high splenic metabolic activity (maximum SUV range 26–29). Findings were correlated with splenectomy pathologic diagnosis. Results: Subjects (n=11, 4 female, 7 male) had a median age of 48 years (range 21–72); four had suspected lymphoma pre-splenectomy, while 7 had a prior diagnosis and had splenectomy for diagnostic (to rule out transformation) or other purposes. Median time between PET and splenectomy was 1.25 months. Of 5 patients with low metabolic activity on PET; three had benign findings at splenectomy and two had splenic involvement of previously known mantle cell lymphoma. Three patients had intermediate metabolic activity on PET; all subsequently demonstrated marginal zone lymphoma at splenectomy. Three patients had high metabolic activity on PET; all were found to have diffuse large B cell lymphoma at splenectomy. Conclusions: This study to our knowledge comprises the largest series to evaluate splenic FDG-PET uptake in patients with suspected or known lymphoma, followed by subsequent pathologic confirmation. Patients with low splenic SUVs appear to be less likely to have splenic involvement of lymphoma, while intermediate and high values may correlate with lymphoma histology. Our findings support a potential role for FDG-PET as a tool for use, in conjunction with clinical and laboratory assessment, in consideration of the need for splenectomy in these settings.

Description: Galiximab is a PRIMATIZED®, anti-CD80, monoclonal antibody with human IgG1 constant regions and macaque variable regions. CD80 is an immune costimulatory molecule that is constitutively expressed on the surface of follicular lymphomas. Modest single-agent clinical activity was demonstrated in a Phase I study in relapsed or refractory, follicular NHL (ORR=11%). Preclinical data show that galiximab + rituximab may be more effective than either antibody alone. Here we report updated results from the Phase II part of a multicenter study (Study 114–21) evaluating galiximab + rituximab for relapsed or refractory, follicular NHL. Patients (pts) were administered galiximab (500 mg/m2 qwk x 4) concurrently with a standard course of rituximab (375 mg/m2 qwk x 4). Rituximab-refractory pts (no response or a response with TTP

Description: The majority of indolent B-cell lymphoma patients [pts] receive R, either as a single agent or in combination with chemotherapy. Recently, “biologic” agents (e.g. GM-CSF, Interferon-alpha, other monoclonal antibodies [mAbs]) are being combined with R in an attempt to increase its anti-tumor activity. Compared to R-chemo, these “purely” immuno-therapies avoid chemotherapy-associated non-specific toxicities while introducing unique mechanisms-of-action [MOA] against drug-resistant cells. G is a primatized anti-CD80 mAb with single-agent activity and excellent safety profile in prior psoriasis and previously treated FL trials. CD80 (i.e. B7.1) is a transmembrane glycoprotein present on the surface of various lymphoma subtypes, but also on a number of immuno-effector cells (e.g. activated macrophages, activated B-cells, dendritic cells). MOA of G includes the ability to induce ADCC on targeted malignant B-cells, but also possible immunomodulatory effects by altering cellular composition and/or cytokine profile within the tumor microenvironment. Objectives of CALGB 50402 were to determine ORR and time-to-progression [TTP] from an “extended” induction schedule of G + R (i.e. G + R weekly x 4, then every 2 months x 4) in previously untreated FL pts (WHO grades 1–3a). The base-line characteristics of 61 evaluable pts are: 61% M: 39% F; median age = 57 years (range: 22–85) with 48% of pts 〉60; 23% with elevated LDH; FLIPI: good risk = 20.3%, intermediate-risk = 42%, high-risk = 37%; histology: 44% grade 1, 46% grade 2, 10% grade 3a; 93% stage III/IV; 24% bulky (〉7 cm) disease. Therapy was very well tolerated with only 13% grade 3 adverse events. ORR is 70% (95% CI: 57% – 81.5%) and includes 44% CR/CRu, 26% PR. Greater than 10% of pts had “delayed” initial responses (i.e. 8–14 months after starting therapy) and more than 15% of pts converted from PR to CR after at least 9 months or more of therapy. Of particular interest is an apparent association of FLIPI score to ORR and CR rate: ORR (p=0.059) CR (p=0.03) FLIPI Score 0–1 11 (92%) 9 (75%) 2 20 (80%) 12 (48%) 3–5 12 (55%) 6 (27%) In further analyses, ORR was not associated with stage, gender, bulky disease, marrow involvement or age 〉 60. At a median follow-up of 2.17 years, 41 of 61 (67%) pts remain progression-free. Notably, PFS also is impacted by FLIPI score (p=0.0012): % Progressed Median PFS FLIPI Score 0–1 0 Not reached 2 24% Not reached 3–5 59% 1.62 years In conclusion, upfront extended induction G + R immunotherapy was well tolerated and achieved a current (i.e. continue to monitor for “late” responders) ORR of 70% (44% CR/ Cru). Although the FLIPI was originally developed in pts receiving chemotherapy alone, our data strongly suggest that it has applicability to a purely upfront immunotherapy (i.e. G + R) treated group of FL pts. G + R combination immunotherapy is an extremely well-tolerated and promising regimen in previously untreated FL pts with low- and intermediate-risk FLIPI status. An update, including “delayed” response rate, durability of therapeutic response, TTP, and analysis of Fc receptor polymorphisms versus response to dual monoclonal antibody therapy will be presented at the annual meeting.

Description: BACKGROUND: Epratuzumab, an anti-CD22 humanized monoclonal antibody, has shown clinical activity as a single-agent (Leonard et al, J Clin Oncol.2003; 21:3051–3059) and in combination with rituximab in relapsed/refractory B-cell NHL (Leonard et al, J Clin Oncol.2005; 23:5044–5051). To evaluate this combination regimen in a larger cohort of patients and to evaluate long-term efficacy, we conducted an international multicenter, open-label, single-arm study in patients with recurrent indolent NHL. METHODS: Forty-nine patients (23F/26M, median age: 61, elevated LDH: 25%, bone marrow involvement: 49%) with chemotherapy-relapsed or refractory follicular NHL (n=41) or small lymphocytic lymphoma (n=7) (as well as one enrolled patient with histological evidence of follicular and diffuse large B-cell lymphoma) were evaluated. Thirty-five (71%) were rituximab-naive, with the remainder having previously received and responded to then relapsed from rituximab (single agent or with chemotherapy). Patients received 360 mg/m2 IV of epratuzumab, followed by 375 mg/m2 IV of rituximab, weekly for 4 consecutive weeks. RESULTS: As preliminarily reported (Emmanouilides et al, Blood2003; 102/11:69a), the combination therapy was well tolerated, without notable additive toxicity over that expected with single-agent rituximab. Twenty-two of the 41 (54%, 95% CI: 37% – 69%) follicular NHL (FL) patients achieved an objective response (OR) using IWG response criteria, including 10 (24%) patients with complete responses (CR), half of whom remained in remission at the last evaluation with a median duration of follow-up of 44.3 months (range: 18.2 – 52.4 months). The median duration of response (DR) was 13.4 months (95% CI: 8.4 – 28.2 months) and the median progression-free survival (PFS) was 10.2 months (95% CI: 6.3 – 13.6 months), with a Kaplan-Meier estimated median DR of 33.4 months (range: 11.2 – 47.9 months) and an estimated median PFS of 35.1 months (range: 12.9 – 52.4 months) for the 10 patients who achieved CR. Importantly, 4/7 SLL patients (57%) experienced OR, including 2 CR, 1 CRu and 1 PR. Furthermore, while the rituximab-naive FL and SLL patients (n=34) showed an OR of 50% (26% CR/CRu, 24% PR), those patients who had responded to prior rituximab (n=14) had an OR of 64% (29% CR, 36% PR). CONCLUSIONS: Overall, this study confirms that the combination of epratuzumab and rituximab, in addition to being well tolerated, demonstrates promising anti-lymphoma activity for indolent NHL, and can result in durable complete remissions in a subset of patients. Further evaluation of this combination regimen as initial therapy for indolent NHL is planned (CALGB 50701), and in diffuse large B cell lymphoma (CHOP + epratuzumab + rituximab) is ongoing (NCCTG N0489).

Description: Standard stem cell mobilization regimens for multiple myeloma patients include G-CSF alone or in combination with high dose cyclophosphamide. Given the known in vitro and in vivo synergy between alkylating agents and proteosome inhibitors, we sought to optimize the potential for concurrent cytoreduction by adding bortezomib to the mobilization regimen. Five evaluable patients, whose prior therapy consisted of six cycles of a 21-day treatment with bortezomib/dexamethasone +/− pegylated liposomal doxorubicin, were mobilized. They received IV push bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 in combination with high-dose cyclophosphamide at 3mg/m2 and MESNA on day 8. G-CSF was given for 10 consecutive days starting on day 9. One patient began this regimen in nCR, two were in PR, and two were in CR by urine and serum immunofixation and bone marrow evaluation. Stem cells were easily harvested from each of the five patients. The number of CD34+ cells collected far exceeded the amount normally mobilized with cyclophosphamide and/or G-CSF alone, with four out of 5 patients collected in a single day. The two patients who began the mobilization cycle in PR continued to respond positively. Their protein levels dropped an additional 8.9 and 14.6 percent respectively during the last cycle. The patient who began mobilization in nCR achieved a CR by the end of treatment. Some expected toxicities associated with high dose cyclophosphamide and G-CSF occurred. All patients experienced grade 3 and 4 cytopenias, however, they recovered and were able to continue on to transplant. Serious adverse events of grade 3 chest pain (non-cardiac), grade 4 pneumonia, and grade 4 febrile neutropenia also occurred. Bortezomib in addition to high dose cyclophosphamide followed by G-CSF is a novel, well-tolerated and efficacious combination for stem cell mobilization in patients with multiple myeloma. This regimen not only yields a high number of stem cells within a short collection time, but may further cytoreduce disease as well. Stem Cell Collection Patients Days Required for Collection CD34+ Stem Cells (million/kg) 1 1 21.2 2 1 47.4 3 1 22 4 1 17.9 5 4 40.6

Description: Introduction: Thalidomide and the IMiDs are rapidly becoming mainstays in the treatment of multiple myeloma. To improve the efficacy of thalidomide (T) or Revlimid (lenalidomide) (R), we have developed the BLT-D (Biaxin® (clarithromycin) (B), low dose T, and dexamethasone (D)), and the BiRD (B, R, D) regimens. These regimens have produced remarkably high responses, including complete and near complete remissions, with almost every patient not previously exposed to thalidomide. When the BLT-D regimen was initiated, an excessive number of thrombotic episodes were noted. Subsequent to this initial observation, others have also reported an inordinate number of thrombotic events, usually when T was combined with other biological or chemotherapy agents. Given the putative antiangiogenic properties of T or R, we postulated that endothelial damage may be responsible for the enhanced thrombosis and thus, subsequently initiated low dose aspirin (ASA), 81mgs, as prophylaxis in patients (pts) undergoing treatment. We report the effect of low dose ASA as a prophylactic treatment when given to pts receiving L/T containing regimens as follows: A retrospective analysis of pts receiving BLT-D before ASA prophylaxis compared to a similar group after ASA was instituted; An examination of the incidence of thromboembolic phenomena in pts receiving either D alone, not receiving ASA, compared to combined D and low dose T, receiving ASA, as part of a prospective sequential randomized study also studying the impact of subsequent B and 3) An evaluation of thrombosis in pts receiving the BiRD regimen with mandated low dose ASA. Results: Low dose ASA significantly reduced the incidence of thrombosis in pts receiving BLT-D. Of the 60 pts studied, 5 (8%) developed grade 1–2 thrombosis, primarily thrombophlebitis (DVT), and 9 pts (15%) developed grade ≥3 thrombosis, primarily pulmonary embolism (PE) and coronary thrombosis. All episodes of thrombosis occurred prior to the institution of ASA. Slightly less thrombotic events were recorded in pts receiving low dose ASA and the T-D combination with or without B (1/12) when compared to pts not receiving ASA and D with or without B (3/11). 3) Three of 22 pts treated with the BiRD regimen have developed thromboembolic complications, all while off the prescribed ASA. Patient 1, a 44 yo male discontinued (d/c’ed) ASA due to epistaxis. Exactly 7 days after d/c’ing ASA, and while remaining on BiRD, he developed a DVT and PE. Patient 2 underwent exploratory laparotomy to investigate a renal mass. ASA and BiRD were discontinued 7 days prior to surgery. Ten days after surgery, the patient developed DVT. Patient 3 underwent closure of a colostomy; ASA and BiRD were d/c’ed 7 days prior surgery. Two days after the surgery, despite low dose heparin, he suffered a fatal massive PE. No thrombotic episodes with BiRD have not occurred with pts remaining on ASA. Conclusions: Low dose ASA appears to reduce the incidence of thrombosis in pts receiving combination T or R therapy. Endothelial damage may persist beyond the residual salutary effects of discontinued ASA.