ALBERT

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: Engagement of the high-affinity IgG Fc receptor (FcγRI) activates a signal transduction pathway involving tyrosine phosphorylation of associated kinases. We compared the activation of the related protein tyrosine kinases (PTKs), Syk and ZAP-70, in FcγRI-mediated signaling. Cross-linking of the FcγRI multimeric receptor in monocytic cells results in tyrosine phosphorylation of the FcεRIγ subunit and association of Syk with this complex. We stably introduced ZAP-70 via a retroviral vector into two monocytic cell lines, U937 and THP-1, which normally do not express ZAP-70. Neither Syk nor MAP kinase activation was affected by the presence of ZAP-70. Although transduced ZAP-70 had in vitro kinase activity and associated with FcεRIγ after receptor aggregation, it was not tyrosine phosphorylated. In contrast, both ZAP-70 and Syk were phosphorylated in a T-cell line in which their respective levels of expression were similar to those detected in U937/ZAP-70 cells. Therefore, these results suggest that requirements for Syk and ZAP-70 phosphorylation are distinct in a monocytic cell context.

Description: Combination chemoimmunotherapies with purine analogues are frequently used as initial therapy of patients with CLL. We investigated the efficacy and tolerability of the combination of FCR plus GM-CSF (sargramostim, Leukine) as initial therapy of patients with CLL based on the following rationale: high response rates of FCR in frontline CLL as previously reported; ability of GM-CSF to stimulate granulocyte and macrophage natural cytotoxicity and therefore to potentiate antibody-dependent cellular cytotoxicity (Voso MT, Haematol. 2002); ability of GM-CSF to increase surface CD20 expression on CLL cells making them a better target for rituximab (Venugopal P, Leuk. Res. 2000); and the potential to reduce the myelosuppressive effect of the FCR combination. Patients with untreated CLL, who met NCI-WG criteria for initiation of therapy, were eligible for this trial. We limited accrual to patients with standard risk disease as determined by beta-2-microglobulin ≤ to 4 mg/dL. Patients received fludarabine 25 mg/m2 i.v. days 2–4, cyclosphosphamide 250 mg/m2 i.v. days 2–4, rituximab 375 mg/m2 i.v. day 1. GMCSF was given sc at 250 mcg/m2 on day -1 and days 5–11. For courses 2–6, FCR started day 1 together with rituximab 500 mg/m2, and GM-CSF was given sc at 250 mcg/m2 on day -1 and days 5–11 or until neutrophil recovery. Courses were repeated every 4–6 weeks. Patients were trained to self-administer GM-CSF during course 1 and therefore required to receive course 1 at our center. Local oncologists administered courses 2–6. All patients received standard anti-viral and PCP prophylaxis throughout the duration of therapy. Sixty patients were enrolled of whom 46 are evaluable for response and toxicity. The median age was 55 years (range 35–77). Twelve patients (20%) had Rai stage III–IV. Median beta-2-microglobulin was 2.8 mg/L (1.7–4.2). Seventeen patients (28%) had 11q deletion and 2 patients (3%) had 17p deletion by FISH. Unmutated IgVH occurred in 57% of the patients and ZAP-70 immunohistochemistry was positive in 53%. Thirty-three patients (72%) achieved CR, 5 patients (11%) nPR, and 8 patients (17%) PR, with an OR rate of 100%. Twenty-four patients (52%) had 〈 1% CD5/CD19+ cells in the marrow at the end of therapy. Twenty-four patients were evaluated for minimal residual disease (MRD) by PCR and 15 patients (63%) achieved MRD negativity at the end of therapy. Grade 〉/= 3 neutropenia occurred in 35 (76%) of the patients, thrombocytopenia in 8 (17%). Infectious episodes were seen in 5 patients (11%) including one patient who died after 4 cycles because of pneumonia. Nine patients (20%) discontinued GM-CSF after 1 (2 patients), 3 (3 patients) and 4 (4 patients) courses, because of pain/erythema at the injection site (7 patients), fever (1 patient) and syncope (1 patient). Thirty-nine patients (85%) completed all 6 planned courses and only 2 patients (4%) received less than 4 courses. In conclusion, FCR plus GM-CSF has a high CR rate in symptomatic frontline patients with CLL. This regimen has a favorable toxicity profile and was easily administered in the community setting. This study has completed accrual and time-to-event parameters and a comparison with FCR will be presented.

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: Abstract 2679 Introduction. Subsequent malignancies are a leading cause of morbidity and mortality among Hodgkin lymphoma (HL) survivors. Stomach cancer is one of the more common second malignancies occurring after HL, yet few studies have quantified stomach cancer risk in relation to radiation dose, and only one investigation has evaluated potential risks associated with chemotherapy. Methods. We conducted a nested case-control study of stomach cancer among 17,447 ≥5-year survivors of HL from six European and North American population-based cancer registries during 1953–2005. Patients included 71 cases diagnosed with HL and subsequent stomach cancer, and 142 individually-matched controls diagnosed with HL only. Data were pooled with a previous hospital-based case-control study from The Netherlands (18 cases, 48 controls), resulting in a total of 89 cases and 190 controls. For all patients, detailed data were abstracted from medical records on HL diagnosis and treatment and, for cases, stomach cancer diagnosis. Based on detailed radiotherapy information, the radiation dose was estimated to the area of the stomach where the case patient's tumor developed and to the comparable location in matched control patients. Chemotherapy data included specific drugs, doses, and number of cycles. The relative risk of stomach cancer was estimated using odds ratios (ORs) derived from conditional logistic regression analyses. Results. Median ages of case patients at HL and stomach cancer diagnosis were 32 years (range, 11–83 years) and 50 years (range, 26–89 years), respectively, with a median interval between HL and stomach cancer of 16 years (range, 5–36 years). Most patients received combined modality treatment (chemotherapy + radiotherapy, 56% cases, 44% controls) or radiotherapy alone (36% cases, 43% controls), whereas few patients received chemotherapy alone (8% cases, 13% controls). Stomach cancer risk increased with increasing radiation dose to the stomach tumor location (Ptrend