ALBERT

Description: Predictive policing is the use of analytical techniques to identify targets for police intervention with the goal of preventing crime, solving past crimes, or identifying potential offenders and victims. These tools are not a substitute for integrated approaches to policing, nor are they a crystal ball. This guide assesses some of the most promising technical tools and tactical approaches for acting on predictions in an effective way.

Description: Background. Lenalidomide (Len) is an immunomodulatory drug with single agent activity in patients (pts) with treatment-naïve (TN) CLL, (overall response rate (ORR) 56-65%, Chen JCO 2011, Ferrajoli Blood 2011). Given the encouraging results of the combination of Len and rituximab (R) in relapsed CLL, we explored this combination as initial therapy. TN pts could derive greater benefit than relapsed pts from Len + R given their less compromised immune function. Methods. Fifty-eight pts were enrolled between 01/2012 and the present time. All patients had treatment indications per IWCLL 2008 criteria, WHO performance status ≤2 and adequate hepatic and renal function. Patients with HIV, hepatitis B or C infection were excluded. Treatment consisted of R 375 mg/m2 IV given weekly for 4 weeks then monthly during months (mo) 3-12 and Len 10 mg PO/day from day 9 for 24 mo. Allopurinol 300 mg PO daily was given for the first 2 weeks. No pts received antibiotic or DVT prophylaxis. Use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at mo 3, 6 and every 6mo thereafter. Results. Forty-eight patients are evaluable for response and toxicity (8 too early, 1 lost to follow-up and 1 diagnosed with metastatic colonic adenocarcinoma within 1 week of study entry). Median age was 66 yrs (42-79). 29 (59%) pts were ≥age 65. 22 pts (46%) had Rai stage III-IV disease. Median β2M level was 3.8 mg/dL (1.4-10.5). 24/37 pts (65%) had unmutated IGHV gene and 31 pts (65%) expressed ZAP-70. 4 pts (8%) had del(17p) and 15 pts (32%) del(11q). Forty pts responded (ORR 83%). 7 pts (14.6%) achieved CR (1 MRD negative) and 33 (68.8%) achieved PR (including 7 nodular PRs). Median time to CR was 11mo (range 5-27). 5 pts discontinued therapy before the 3mo evaluation (4 due to toxicity and 1 due to unrelated co-morbidities). Six pts discontinued between 3 and 6mo (4 for refractory disease and 2 for toxicity after achieving PR). ORR was similar for patients with mutated and unmutated IGHV gene (85 vs 83%, p=0.96), age ≥65 and

Description: Introduction: Richter’s syndrome (RS) is a rare complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The clinical outcome is generally poor. The purpose of this study was to assess the presenting characteristics, treatment outcomes, and prognostic factors in patients with RS. Methods: An electronic database search of patients with CLL/SLL or RS who presented at U. T. M. D. Anderson Cancer Center between 1/75 and 6/05 was performed. Results: Among 3,986 patients with CLL/SLL, 204 patients (5.1%) had possible RS and 148 patients (3.7%) had biopsy- or fine-needle aspiration-proven RS. The median age was 61 years (range, 29–83 years); and 70% were men. Among 148 patients with RS, 53% were ≥ 60 years, 79% had Zubrod performance status 0–1, 47% had lactate dehydrogenase (LDH) levels ≥ 1.5 x the upper limit of normal, 57% had platelets ≥ 100 x 109/L, 57% had β 2-microglobulin ≥ 6 mg/dL (3 x the upper limit of normal), and 45% had tumor size 〉5 cm. Treatment included chemoimmunotherapy, such as rituximab with fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (R-hyper-CVAD) or cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and chemotherapy. A total of 135 patients were treated and 130 patients were evaluable. The overall response rate was 39% (chemoimmunotherapy, 47%; chemotherapy, 34%, p=0.2). In multivariate analysis (MVA), factors predicting response were platelet counts ≥ 100,000 (p=0.02), hemoglobin levels ≥ 11g/dL (p=0.036), performance status (PS) 0 or 1 (p=0.037), and β 2-microglobulin

Description: In murine models, transgenic chemokine–cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation. The safety and immunologic effects of this approach in humans were tested in 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections of a vaccine combining lymphotactin (Lptn)– and interleukin-2 (IL-2)–secreting allogeneic neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were limited to reversible panniculitis in 5 patients and bone pain in 1 patient. Injection-site biopsies revealed increased cellularity caused by infiltration of CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the vaccine produced a 2-fold (P = .035) expansion of CD4+ T cells, a 3.5-fold (P = .039) expansion of natural killer (NK) cells, a 2.1-fold (P = .014) expansion of eosinophils, and a 1.6-fold (P = .049) increase in serum IL-5. When restimulated in vitro by the immunizing cell line, T cells collected after vaccination showed a 2.3-fold increase (P = .02) of T-helper (TH2)–type CD3+IL-4+cells. Supernatant collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P = .021) and IL-5 (8.7-fold;P = .002). Six patients had significant increases in NK cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that bound to the immunizing cell line. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient. Hence, allogeneic tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little toxicity in humans and can induce an antitumor immune response.

Description: Key Points Histologically aggressive CLL differs from histologically indolent CLL. Patients with different CLL phases but similar SUVmax have similar outcomes. FDG/PET is a useful diagnostic tool for patients with CLL and suspected transformation.

Description: Key Points FCR-treated chronic lymphocytic leukemia patients with mutated IGHV gene achieve long-term PFS, with a plateau on the PFS curve. MRD-negativity posttreatment is highly predictive of long-term PFS, particularly in patients with mutated IGHV gene.

Description: Background. Ibrutinib is active in relapsed/refractory (R/R) CLL, including patients (pts) with del(17p); pts with del(17p) have similar response rate to pts without, but have shorter progression-free survival and a pattern of continuous relapses. (Byrd NEJM 2013). It is unknown whether subpopulations of pts with del(17p) with distinct clinical courses can be identified. Del(17p) is frequently associated with a complex metaphase karyotype (CKT), defined as ≥3 distinct chromosomal abnormalities. CKT has been associated with inferior outcomes in treatment-naïve and R/R CLL, but its prognostic significance in ibrutinib-treated pts is unknown. Methods. We reviewed 100 pts treated for R/R CLL at MD Anderson Cancer Center with investigational ibrutinib-based regimens from 2010-2013. 50 pts received ibrutinib (Ib) monotherapy, 36 Ib plus rituximab and 14 Ib + bendamustine and rituximab (BR). All pts provided informed consent and studies were conducted according to the declaration of Helsinki. Pre-treatment FISH and CpG-stimulated metaphase cytogenetic analysis was performed on bone marrow. Results. Pt characteristics are shown below: Table Characteristic Age, median (range) 65 (35-83) # prior therapies, median (range) 2 (1-12) FISH hierarchy, n (%) (n=95) del(11q) 26 (28) del(17p) 46 (49) Complex karyotype, n (%) (n=72) 26 (36) Unmutated IGHV gene, n (%) (n=98) 80 (81) Fludarabine-refractory, n 19 β2-microglobulin ≥4.0, n (%) 48 (56) 22/26 pts with CKT had del(17p), [OR 19.2 (4.9-76.4) compared to non-del(17p) pts, p

Description: Abstract 720 Based on the demonstrated activity of ofatumumab and lenalidomide as monotherapy in patients (pts) with CLL and on the activity of rituximab in combination with lenalidomide in pts with relapsed CLL, we conducted a phase II study to investigate efficacy and tolerability of a combination regimen of ofatumumab and lenalidomide in patients with relapsed CLL who had received prior treatment with purine analogs. Thirty-six pts entered this study between January 2010 and January 2011. All pts had an indication for therapy. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2 and adequate organ function (creatinine clearance 〉 30ml/min, total bilirubin 〈 to 2 mg/dl, ALT 〈 2 X ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets 〈 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Treatment consisted of ofatumumab IV given weekly for 4 weeks (300 mg week 1; 1,000 mg weeks 2 and thereafter), monthly during months 2–6 and every other month during months 7–24, and lenalidomide 10 mg PO/day started on day 9 and continued for 24 months. Allopurinol 300 mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at months 3 and 6 and every 6 months thereafter. Thirty-four pts are evaluable (one pt withdrew consent prior to treatment with lenalidomide, and one was excluded because of concomitant MDS at study entry). Median age was 64 yrs (34–82). Twenty-two pts (65%) had Rai stage III-IV disease. Median β-2M level was 4.1 mg/dL (1.7–16). Twenty-two pts (65%) had unmutated IgHV and 23 pts (68%) expressed ZAP-70. Nine pts (26%) had del(17p), and 4 pts (12%) had del(11q). Median number of prior treatments was 2 (1–8). All pts had been previously treated with FCR and 13 pts (38%) were fludarabine-refractory. Three pts (9%) had relapse following SCT.Twenty-three pts achieved a response, for an overall response (OR) rate of 68%. Eight pts (24%) achieved a complete response (CR), including 3 MRD-negative CR, and 15 pts (44%) achieved a partial response (PR). Median duration of response is 22 months (4–30), with a median follow up of 24 months. Among the 9 pts with del17p, 5 (55%) achieved a PR. The average daily dose of lenalidomide was 10 mg in 9 pts (26%), 7.5 mg in 4 pts (12%), 5 mg in13 pts (38%) and 5 mg in 8 pts (23%). Seventy-six % of the pts are alive. No pt deaths occurred while on therapy. Eight deaths occurred after discontinuation of therapy: progression of CLL despite subsequent therapy (5 pts), complications of HSCT (1 pt), CLL/lung cancer (1 pt) and causes unrelated to CLL(1 pt). Seven pts are still on therapy and 10 pts have an ongoing response. Six pts discontinued therapy despite an ongoing response due to transition to HSCT (3 pts), toxicity (2 pts) and physician choice (1 pts), and 7 pts discontinued therapy because of loss of response [after 12 (1 pt), 16 (2 pts), 19 (2 pts), 22 (1 pt) and 29 (1 pt) months].The most common grade 3–4 treatment-related hematological adverse events consisted of neutropenia in 16 pts (47%), thrombocytopenia in 3 pts (9%) and anemia in 2 pts (6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 infectious episodes occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), cellulitis (2), HZV (1) and CNS toxoplasmosis (1). No G3-4 tumor lysis syndrome or tumor flare reaction (TFR) was observed. G1-2 TFR was observed in 8 pts (24%), In conclusion, the combination of ofatumumab and lenalidomide induced responses in 68% of pts with relapsed CLL, including pts with del17p, all of whom had received prior chemoimmunotherapy. This treatment was well tolerated and neutropenia was the most common toxicity. The severity of TFR with this combination was less than with single agent lenalidomide, possibly due to attenuation by the addition of treatment with ofatumumab. Several studies are currently investigating the combination of anti-CD20 mAb and lenalidomide used both as initial and salvage therapy of CLL. Disclosures: Ferrajoli: Celgene Corporation: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene Corporation: Consultancy. Wierda:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Keating:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction The combination of lenalidomide and rituximab is an active treatment for patients (pts) with relapsed Chronic Lymphocytic Leukemia (CLL), with 66% Overall Response Rate (ORR) and a median Progression Free Survival (PFS) of 17.4 months (JCO 2013). We therefore sought to evaluate its efficacy and tolerability in untreated pts. Methods Twenty-five pts with untreated CLL have been enrolled. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle 1 and on day 1 of cycles 3 to 12. Lenalidomide was started on day 9 of cycle 1 at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely. Response was assessed every 3 cycles by 2008 NCI-WG criteria. Treatment-related toxicity was assessed using Common Terminology Criteria for Adverse Events (version 3.0). The primary end point of this study was ORR. Secondary objectives included PFS and Overall Survival (OS). PFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. Categorical variables were compared using Fisher's exact test (two tailed). Differences were considered significant if p≤.05. Results Baseline characteristics of the 25 pts are shown in Table 1. Twenty-four pts are evaluable for toxicity (one pt was taken off study after only 7 days due to the diagnosis of widely metastatic pancreatic cancer) and 20 for response (2 pts too early, 3 pts early discontinuation). So far 5 pts received 1 cycle, 1 pt received 2 cycles, 6 pts received 3 cycles, 5 received up to 6 cycles and 8 received 12 or more cycles of therapy. ORR by 2008 NCI-WG criteria is 85%, including 2 (10%) complete remission (CR) and 15 (75%) partial remissions (PR). No significant association between ORR and baseline characteristics was observed. At the latest follow-up, the median dose of lenalidomide was 5 (2.5-10) mg and 14 (56%) pts needed at least one interruption because of toxicity. Grade 3-4 toxicities are summarized in Table 2. No episodes of grade 3-4 tumor flare were observed and 7 (29%) pts experienced a grade 1 or 2 tumor flare. Eight (32%) pts have so far discontinued treatment: 1 because of metastatic pancreatic cancer diagnosed after only 1 week on study, 2 because of progressive disease (after 4 months and 13 months), and 5 because of toxicity (skin rash in 3 pts, a deep venous thrombosis in 1 pt, and persistent neutropenia in 1 pt). Two of the 5 pts who discontinued treatment have required subsequent therapy. Twenty-four pts are alive, 1 pt died of metastatic pancreatic cancer after treatment discontinuation. At a median follow-up of 9 (1-17) months, median PFS and median OS have not been reached. Conclusions Our initial experience with the combination of lenalidomide and rituximab as front-line treatment of CLL indicates that this combination is tolerated by the majority of pts and responses are seen in 85% of them. Enrolment in this study is ongoing. Disclosures: O'Brien: CELGENE: Consultancy. Ferrajoli:CELGENE: Research Funding.

Description: Abstract 1788 Patients with relapsed CLL have limited effective treatment options, and new therapies are needed. We report the results of a phase II study which investigated the efficacy and tolerability of a combination regimen with ofatumumab and lenalidomide in patients (pts) with relapsed CLL. These agents were evaluated as a combination regimen for pts with relapsed CLL based on their documented single-agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicities. Furthermore, the combination of rituximab and lenalidomide was active in relapsed CLL (Badoux et al. 2010). Pts with symptomatic disease who met treatment indications were eligible. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2, and adequate organ function (creatinine clearance 〉 30ml/min, total bilirubin 〈 to 2 mg/dl, ALT 〈 2 × ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets 〈 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Pts received ofatumumab IV weekly for four weeks (300mg week 1; 1,000 mg weeks 2 to 4), monthly during months 2–6, and every other month during months 7–24. Lenalidomide 10 mg PO daily was started on day 9 and continued daily for a maximum of 24 months. Allopurinol 300mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was according to standard guidelines. Responses were assessed after 3, 6, 12, 18 and 24 months. Between January 2010 and January 2011, 36 pts were enrolled and 34 pts are evaluable (one pt withdrew consent prior to treatment and one was excluded because of concomitant MDS). The median age of the pts was 62 yrs (34–82). Twenty pts (59%) had Rai III-IV disease. The median beta-2M level at start of therapy was 4.4 mg/dL (1.7-16.5). The median number of prior treatments was 2 (1–8). All pts had received prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). Twelve pts (35%) were fludarabine-refractory. Twenty-two pts (65%) had unmutated IgHV genes, 9 (26%) del(17p) and 4 (12%) del(11q). Responses were evaluated according to the 2008 NCI-WG criteria: 5 pts (15%) achieved CR (including 1 CRi) and 17 pts (50%) PR, for an ORR of 65%. Of the 5 CR pts, 1 was MRD-negative by flow cytometry. Two of the PR pts achieved marrow CR and only had persistent lymphadenopathy. Of the 22 responders, 13 are continuing on therapy with ongoing response (median time on therapy 14 months, range 8–20 months). Despite ongoing response, 7 pts discontinued therapy due to: transition to HSCT (3 pts; after 3, 6 and 6 months, respectively), pulmonary embolism (1 pt; after 4 months), recurrent zoster infection (1 pt; after 17 months of therapy) and physician choice (2 pts; after 9 and 16 months of therapy). Two pts discontinued therapy because of loss of response after 12 and 18 months of treatment, respectively. Thirty-one pts (91%) are alive. There have been no deaths on therapy. Three deaths occurred after discontinuation of therapy due to refractory disease (1), following HSCT (1) and due to progressive disease and adenocarcinoma of the lung (1). The most common grade 3–4 treatment-related hematological adverse events included neutropenia (15 pts, 44%), thrombocytopenia (3 pts, 9%) and anemia (1 pt, 3%). Thrombotic events occurred in 2 pts (6%). One pt experienced grade 3 pulmonary embolism and another patient grade 2 superficial vein thrombosis. In both cases with thrombotic event, ESAs were concomitantly administered. One pt (3%) experience a grade 3 infusion reaction during the first ofatumumab administration. Eight grade 3 infectious episodes occurred: pneumonia (3), neutropenic fever (2), parotitis (1), LE cellulitis (1) and CNS toxoplasmosis based on radiological findings (1). Intermittent grade 1–2 diarrhea was reported by 8 pts (24%). Grade 1–2 lenalidomide-associated tumor flare reaction was seen in 8 pts (24%). The median tolerated daily dose of lenalidomide was 5 mg/day (2.5-10 mg). In conclusion, the combination of ofatumumab and lenalidomide is well tolerated. Neutropenia was the most common toxicity. This combination induced responses in 65% of pts with relapsed CLL, all of whom had received prior chemoimmunotherapy. Responses are durable and ongoing in some pts. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding; Celgene: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene: Consultancy. Wierda:GlaxoSmithKline: Research Funding.