ALBERT

Description: Background: Bortezomib-containing combination chemotherapy regimens are effective in non-Hodgkin's lymphoma (NHL), although there are limited data on toxicity in the front-line setting for indolent NHL when combined with reduced-dose vincristine-containing chemotherapy. Our group (Sinha et al, Cancer 2012) reported outcomes from a phase I study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (VR-CHOP) and found a maximum tolerated dose (MTD) of bortezomib (V) of 1.6mg/m2 with vincristine capped at 1.5 mg with an overall response rate (ORR) of 100%. Herein we report the results of our phase II study of this regimen. Patients and Methods: Eligible patients had untreated indolent NHL (small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], or follicular lymphoma [FL] grades 1-3) meeting standard criteria for treatment or with FL international prognostic index (FLIPI) ≥3. Patients received V administered at a dose of 1.6mg/m2 on days 1 and 8 as well as rituximab (R) 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (capped at 1.5mg/dose) on day 1 and prednisone 100mg on days 1-5 of a 21-day cycle. Patients received at least 6 cycles and up to 8 cycles of therapy at the discretion of the treating physician. Patients who achieved a complete response (CR) after induction were assigned to receive maintenance R 375mg/m2 every 12 weeks for 2 years while patients with a partial response (PR) or stable disease received R 375mg/m2 along with V 1.6mg/m2 (VR), both administered weekly for 4 weeks every 6 months for up to 2 years. Response was assessed by Cheson 1999 criteria, and toxicity assessed by CTCAE version 3.0. One FL patient discontinued study therapy after cycle 2 when a central pathology review revised the diagnosis to diffuse large B-cell lymphoma. This patient was not included in the efficacy analysis but is included in the safety reports. CR rate and ORR were determined at the conclusion of induction therapy, and progression-free survival (PFS) and overall survival (OS) were evaluated by the Kaplan-Meier method from the date of study entry. Results: Thirty patients received at least 1 treatment of VR-CHOP, including 16 males and 14 females. The median age was 58 (range: 31-71), and histologies included MZL (n=5), SLL (n=4), and FL (Grade 1, n=7; Grade 2, n=12; Grade 3, n=2). FLIPI score for patients with FL were 1 (n=2), 2 (n=4), 3 (n=12), and 4 (n=3). Twenty-nine were evaluable for response, including 19 patients with CR and 10 patients with PR at the conclusion of induction therapy (CR rate of 66%; ORR of 100%). For 20 evaluable patients with FL, the CR rate was 75%. Twenty-five patients proceeded with maintenance therapy, including 6 patients who received VR and 19 patients who received R alone. Three patients with PR to induction converted to CR after maintenance with VR. Four patients received no maintenance due to refusal/lost to follow-up (n=2), toxicity (n=1), and progression (n=1). Three patients with PR received only R due to neuropathy. Four patients have relapsed or progressed on therapy, including 1 patient prior to starting maintenance, 2 patients during VR maintenance, and 1 patient who achieved a PR but was receiving R maintenance. One additional patient progressed after completing R maintenance. With a median follow-up of 39 months, 3-year PFS rate is 85.8%, and the 3-year OS rate is 96.4% (Figure). Grade ≥3 peripheral neuropathy was noted in 2 patients (7%), while grade 1-2 neuropathy occurred in 17 patients (57%). Grade 3-4 hematologic toxicities included neutropenia (n=14, 47%), thrombocytopenia (n=3, 10%), anemia (n=1, 3%), and febrile neutropenia (n=1, 3%). Eight patients experienced additional grade 3 non-hematologic toxicities, including the following which occurred in more than 1 patient: vomiting (n=3, 10%), abdominal pain (n=2, 7%), fatigue (n=2, 7%), hyperglycemia (n=2, 7%), hypokalemia (n=2, 7%), and nausea (n=2, 7%). Conclusion: VR-CHOP is highly efficacious in the front-line setting for management of patients with untreated indolent NHL, and toxicities are expected and manageable. Incidence of grade 3 peripheral neuropathy is low with incorporation of a decreased dose of vincristine, and the PFS compares favorably with previously reported outcomes in FL and indolent NHL for R-CHOP, R-Bendamustine, and R-CHOP plus maintenance R. Figure 1 Figure 1. Disclosures Cohen: Janssen: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Off Label Use: Bortezomib is not currently approved for follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma and is being evaluated in combination with a standard induction regimen.. Kaufman:Millennium: Consultancy; Janssen: Consultancy. Nastoupil:TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Lechowicz:Millennium: Consultancy. Lonial:Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Flowers:Gilead, Spectrum, Millennium, Janssen: Research Funding; Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy.

Description: Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range

Description: Abstract 1862 Poster Board I-887 Background: Biotest AG (Dreieich, Germany) is developing the immunoconjugate BT062, which comprises the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent maytansinoid (DM4). Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4. At present, CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. Preclinical investigations demonstrated significant in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in relapsed or relapsed/refractory MM. Clinical response was assessed as per the international working group criteria (Durie et al., 2006). Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulating agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients are enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: To date 20 patients have been treated with BT062 at 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has not been defined to date with continued enrollment at 200 mg/m2 dose. None of the patients treated experienced serious hypersensitivity reactions or humoral responses (HAHA) against BT062. The most frequently reported adverse events to date cover primarily events expected for the underlying disease. Nevertheless, a few adverse events have also been observed involving skin and mucosa (tissues of epithelial origin with CD138 expressing cells). No grade 4 toxicity has been reported. Preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase at dose levels up to 120 mg/m2, whereas a more typical clearance profile was observed for all 3 patients at the 160 mg/m2 dose. Interestingly, even in phase I study decreased urine M-Protein or serum FLC levels have been observed in 2 patients. One of these patients showed a decrease in urine M-Protein by more than 50% after administration of 8 repeated low doses. At a high dose level another patient without detectable M-Protein levels, showed a decrease of serum FLC by more than 50% after having received the second dose of BT062. Furthermore, evidence of clinical benefit has been observed in at least 6 patients with early stabilization of M-protein levels (and light-chain burden) in serum and /or urine. Conclusion: Development of a monoclonal antibody in MM remains an important therapeutic option and BT062 is an exciting possibility. Preliminary data from this phase I study, demonstrate an acceptable toxicity profile of BT062 in the clinics. Even in phase I study, evidence of clinical activity is observed. These encouraging results and the unique PK observed support investigation of a more frequent dosing regimen for optimizing anti-MM responses. Updated data on safety, PK and efficacy of BT062 from this clinical trial will be presented at the meeting. Disclosures: Jagannath: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding. Lutz:Immunogen, Inc.: Employment. Haeder:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Uherek:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Biotest AG: Consultancy, Research Funding.

Description: Targeted therapy is increasingly incorporated into the chemotherapy regimens of adult ALL. While the prognosis of BCR/ABL + (Philadelphia) ALL is well recognized; the significance of CD 20 postivity is unknown. We report the characteristics of 76 patients treated at Emory University between January 1999 and March 2005, divided into 2 groups based on CD 20 expression, as determined by flow cytometry. The CD 20+ patients presented with a higher WBC count and LDH, and lower platelet counts (table). In the CD 20+ group, 65% had pre B cell ALL and 8% had high grade B cell leukemia/lymphoma, whereas the CD 20- group consisted of 30% pre B cell ALL, 24% T cell ALL, and 10% had high grade leukemia/lymphoma. Of the 35 Ph+ ALL patients, 27 were CD20+ (20%) and 18 CD20- (51%). Patients were treated on clinical trials L20, ALL2, and more recently with the Hyper-CVAD regimen (n=32). Only 5 of the CD 20+ patients received rituximab in addition to chemotherapy. With a median follow-up of 320 days, 46% of patients in each group are alive, 35% and 38% relapsed in the CD 20+ and CD 20- group, respectively. In summary, we found that CD 20+ ALL patients present with higher WBC count and LDH, and a lower platelet count; although, due to our small sample size, these differences were not significant. Further follow up is needed to provide mature results on survival and remission. CD 20+ CD 20- p= Total numbers 26 50 Median Age (yrs) 45.2 (18–74) 44 (19–76) NS Median WBC (103/μl) 29.1 10 0.09 Median Platelet (103/μl) 35 65 0.11 Median LDH (IU) 894 500 0.05 Normal Cytogenetics 13 (50%) 21 (42%) NS Ph+ ALL 7 (26%) 18 (35%) NS CR within 60 days 20 (77%) 27 (54%) NS Primary Refractory 2 (8%) 6 (12%) 0.7 Relapse 9 (35%) 19 (38%) NS Alive at last follow up 12(46%) 23 (46%) NS Expired by d270 8 (36%) 11 (25%) NS

Description: Background Waldenstrom Macroglobulinemia (WM) is a hematological malignancy that affects 1500 people each year in the United States. Due to lack of literature on era comparative population-based analysis, we have analyzed Surveillance Epidemiology and End Results (SEER) data to evaluate the changes in incidence and survival patterns in the new millennium where modern therapeutic agents such as rituximab, immunomodulatory drugs and proteasome inhibitors were offered to WM patients; in contrast to the earlier period when they were non-existent. Methods The SEER 18 registry which includes data from 1973-2010 from 18 geographic areas including 28% of US representative population was used in analysis. ICD-O-3 code 9761 was used for identifying patients for this analysis. SEER* Stat 8.0.4 is used to calculate age-adjusted incidence and mortality rates based on race, gender, and age for patients. Age adjusted rates were used in this anlaysis to avoid confounding variables when comparing rates over time. Results We have included 4304 patients in the analysis (1244 patients diagnosed before 2000 and 3060 patients after 2000). The incidence rate of WM increased with age. The 10 year cumulative incidence rate per 100,000 by age stratification (80) are 0.02%, 0.40%, 1.01%, 2.14% and 2.98% respectively. Over the last decade the trend of incidence rate in WM has been steadily decreasing across all age groups (Figure 1). Median survival for all WM patients is 74 months (m) (70.2-77.8). Significant survival improvement was seen in the current era (median survival ≥2000 vs.

Description: Abstract 1628 Introduction: Historically, relapsed DLBCL and HL has been associated with a high cure rate with salvage regimens followed by high dose chemotherapy and stem cell transplant (ASCT). However, patients (pts) who relapse early following upfront chemotherapy and pts who fail to respond to salvage have a poor overall response rate (ORR) with additional salvage regimens and a poor prognosis even when consolidated with ASCT (von Tresckow & Engert, 2011; Gisselbrecht et al., 2010). At present there is no standard therapy in the third-line setting for pts with DLBCL and HL. We designed a regimen: vinorelbine (30mg/m2) & paclitaxel (175mg/m2) given on day 1; etoposide (100mg/m2) & cisplatin (20mg/m2) given on days 2–5; and cytarabine (2000mg/m2) on days 4 and 5 (VTEPA) for treatment of lymphoma pts with 1° refractory disease or relapse following salvage. In phase 1, VTEPA was safe with a 33% ORR following 1 cycle (Lonial et al, 2006). Design and Methods: To examine the effectiveness of VTEPA, we conducted an IRB approved retrospective review of consecutive cases of relapsed/refractory DLBCL and HL identified from our database from 1999–2011. All pts had evidence of primary refractory disease or stable or progressive disease following first line salvage therapy. Responses following salvage VTEPA were retrospectively assessed using International Working Group Criteria (JCO 1999) for all pts. Responding pts proceeded to ASCT. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 74 pts (44 DLBCL and 30 HL) with a median age at diagnosis of 30 years (range 18–63) for HL and 49 years (range 20–68) for DLBCL were included. 67% of HL pts had primary refractory disease and 33% of pts had relapsed disease; 60% were stage III/IV at diagnosis. 75% of DLBCL pts had primary refractory disease and 25% of pts had relapsed disease; 73% stage III/IV. Pts received a median of 2 prior therapies (range 1–4). 63% pts with HL received prior salvage therapy with ifosfamide, carboplatin, and etoposide (ICE) and 13% with other regimens. 16 pts with HL received 1 cycle of VTEPA, 13 received 2 cycles and 1 pt received 3 cycles of VTEPA. 70% pts with DLBCL had received prior salvage therapy with rituximab (R) + ICE and 16% received other salvage regimens. 32 pts with DLBCL received 1 cycle of R-VTEPA and 12 pts received 2 cycles. The most common reported grade 3/4 toxicities were pancytopenia (97%), nausea/vomiting (58%), fatigue (30%), infectious complications (26%), diarrhea (24%), electrolyte imbalance (19%), and mucositis (16%). 70 pts (43 DLBCL and 27 HL) were evaluable for response. The ORR for DLBCL pts was 44% (9% CR and 35% PR) while that for HL pts was 70% (26% CR and 44% PR, p=0.04). 4 DLBCL pts had treatment related mortality. 34 pts went on to collect ≥2 × 106 CD34+ cells/kg; 3 pts had inadequate stem cell collection. In 23 pts collection was not attempted, and 14 pts collected stem cells prior to R+/−VTEPA. 37 pts (47%) went onto planned ASCT, and 4 pts underwent allogeneic transplantation. The PFS at 2 years for pts with HL was 68% vs. 49% for pts with DLBCL (p

Description: Abstract 3034 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate. The goal of the current trial is to improve on the CR rate compared with RVD by adding a novel targeted agent. Preclinical studies have demonstrated that vorinostat (Vor), an HDAC inhibitor, is synergistic with bortezomib, immunomodulatory (IMiD®) compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study is to determine the tolerability and preliminary efficacy of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (Pts) received the current standard RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5-8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. DLT (≥ G3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of ANC to ≥1,000/μL or platelets to ≥50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified EBMT and Uniform criteria. Pts with PR or better could proceed to autologous transplant after ≥ 4 cycles. Results: Eleven pts (median age 54, 82% men, 54.5% ISS Stage II/III) have been enrolled to date with n=4 pts each in cohorts 1 (Vor 100mg) and 2 (Vor 200mg), and 3 pts in cohort 3 (Vor 300 mg). One patient has completed 8 cycles, 1 pt completed 4 cycles and proceeded to transplant, 6 pts remain on study treatment and 3 pts have discontinued therapy (1 for significant peripheral neuropathy {grade 3}, 1 for patient choice unrelated to toxicity and 1 for non adherence). Two DLTs have occurred: syncope (cohort 1) and asymptomatic grade 3 elevation of ALT (cohort 2) with none in cohort 3.The episode of syncope was not related to cardiac arrhythmia. One study related SAE has occurred (syncope). One other episode of grade 3 elevation of ALT occurred in a pt in cycle 3 in cohort 1. Both episodes of increased ALT resolved and patients remained on study with dose modification. One patient developed grade 3 diarrhea in cohort 1. No patients have developed a grade 4 toxicity. Treatment emergent peripheral neuropathy occurred in 6 patients (4 grade 1, 1 grade 2 and 1 grade 3). No episodes of study related grade 3 fatigue, nausea, or vomiting have occurred. The MTD has not been reached. Eight patients are evaluable for response. All have responded to study therapy with 3 CRs, 1 VGPR and 4 PRs. Three patients went on to stem cell collection after 4 cycles and all collected an adequate dose for transplant of 〉5 ×106 CD34+ cells/kg. Conclusion: The combination of RVD with vorinostat has been generally well tolerated to date. No unexpected toxicity has been noted with side effects commensurate with prior experience with each of the drugs and no additive toxicity seen to date. While asymptomatic elevation of ALT has been seen and will require ongoing monitoring, grade 3 ALT elevation was a DLT in the original RVD study and related to dexamethasone, so may not be related to the addition of vorinostat. Early efficacy data is promising with 50% of patients achieving a VGPR or higher. Accrual is ongoing to determine the MTD. Disclosures: Kaufman: Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Off Label Use: Use of lenalidomide as upfront therapy. Use of vorinostat as upfront therapy. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding. Heffner:Millenium: Consultancy, Honoraria, Research Funding. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau.

Description: Copper deficiency has long been recognized as cause of hematopoietic dysfunction, and diagnosis is straightforward if it is pursued. Over a three year period, we diagnosed copper deficiency in seven pts referred to our university-based hematology and BMT outpatient clinics for evaluation and treatment of myelodysplastic syndrome (MDS) or neutropenia/anemia. This represents approximately 3% of new outpatient referrals carrying an ICD-9 code corresponding to MDS or neutropenia. Patient characteristics are shown in Table 1. Three of the seven pts carried a presumptive diagnosis of MDS, and one had received several months of decitabine therapy. Two patients were actually referred for consideration of stem cell transplantation; the others were referred for evaluation of cytopenias. Six of the seven patients had been evaluated by a hematologist prior to referral. Only 3 of 7 pts in our series had recognized risk factors for copper deficiency such as prior gastric bypass or other GI dysfunction; postulated risk factors in the other pts are included in Table1. All pts in our series were anemic and leukopenic, with absolute neutropenia at presentation. In contrast, platelet counts were normal or elevated in all pts, consistent with most previous reports. Five of the seven pts in our series had neuropathy or myelopathy of variable severity. The hematologic abnormalities responded rapidly and completely to oral and/or IV copper replacement in all pts, although neurologic recovery was slow and incomplete. Conclusions: Our experience indicates that copper deficiency is a relatively common cause of neutropenia and anemia, and the consequences of missing the diagnosis may be substantial, including performance of unnecessary transfusion, chemotherapy, and even stem cell transplantation. Normal or elevated platelet counts and concomitant neuropathy or myelopathy are important clues to the diagnosis. Furthermore, copper deficiency must be considered even in pts without obvious GI absorption abnormalities. Serum copper and ceruloplasmin assays should be incorporated into the routine evaluation of most pts with cytopenias and suspected MDS. Age/gender Ref. diagnosis Risk factor Associated symptoms Serum copper (80–155 mcg/dl) Ceruloplasmin (21–53 mg/dl 53F MDS–RAEB unknown Severe sensory-motor neuropathy 29 7 43F MDS–RA Excess carbonated soda intake? Severe sensory-motor neuropathy 2

Description: Background: High dose therapy and autologous transplant (HDT) clearly benefits many patients with myeloma, but the addition of other chemotherapeutics or TBI to high dose melphalan (HDM) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor that synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that the sequence of administration may be critical to the combination of B and HDM. We hypothesize that B followed by M is inferior to M followed by B. To test this hypothesis, we designed a randomized phase I trial combining escalating doses of B and Melphalan 200 mg/ m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration. Methods: Patients were randomized to receive either B 24 hours before Mel 200 (ARM A) or B 24 hours after Mel 200 (ARM B). Doses for B escalated from 1.0mg/m2 up to 1.6mg/m2 as defined using the Escalation with Overdose Control (EWOC) method, a Bayesian phase I design. Patients eligible for the study were required to have achieved no better than a PR following induction therapy, and to have measurable disease in the bone marrow. Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for annexin V staining, and myeloma cells were sorted for protein analysis. We compared the increase in annexin V and PI staining from the D-4 sample to D0 sample for each patient in order to determine which sequence was optimal for administration of B. Routine demographics, toxicity, and engraftment data were also collected. Results: 41 patients have been enrolled to date, with 34 evaluable for response assessment at day +100. B doses range from 1.0–1.6mg/m2 at both time points. Median age is 59 (44– 74). Median duration of ANC

Description: Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)