ALBERT

Description: The occurrence of additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph’) positive cells, a phenomenon termed clonal evolution (CE), reflects an increased genetic instability of the leukemic population which progressively acquires a highly malignant phenotype. Few data are available regarding the therapeutic effects exerted by imatinib mesylate on Ph’ cells bearing ACAs. Herein, we report the activity of imatinib mesylate employed as single agent or in combination with recombinant interferon (rIFN)a2 in inducing cytogenetic and molecular responses in 14 CML patients (F:M=5:9, median age: 58 years) with CE already present at diagnosis (5) or occurring later during the course of the disease (9) as the sole sign of accelerated phase (AP) (12) or associated with other AP features (2). Overall, the analysis of ACA rate showed the presence of i(Ph’) in 4, +8 in 3, -Y in 3, variant translocation in 2 (t(9;19;22) and t(3;9;22)), -17 in 1, 17p- in 1, 3p- in 1, 22q- in 1, and additional translocations involving chromosomes other than 9 and 22 in 3 other instances. Of note, the two cases with variant translocation showed at diagnosis the classical t(9;22). The t(9;19;22) or t(3;9;22), which was documented later in the course of the disease was therefore a proven second event. Imatinib was given at 400mg po/daily in all, but 2 patients with signs of AP in addition to CE who received a daily dose of 600 mg. rIFNa2 was given at a daily dose of 1 to 3x106UI, according to patient’s tolerance. An overall cytogenetic remission rate of 64% (9/14) was documented in response to imatinib mesylate employed as single agent (6/10) or in combination with rIFNa2 (3/4). Suppression of the ACA population was documented within an interval of 3–14 months from the beginning of imatinib treatment and it was timely coincident with the occurrence of CCR in 6 patients, irrespective of the entity of the ACA population in the context of the entire Ph’ positive one. In 2 of them, a “biphasic” response to imatinib was observed. Initially, suppression of i(Ph’) and t(9;19;22) with re-emergence of the original t(9;22) hemopoiesis was documented 4 and 7 months after treatment initiation, respectively, and then CCR occurred after further 10 and 9 months of treatment, respectively. In the last patient, a mixture of non-clonal and clonal +8 Ph’ negative hemopoiesis was noted at the time when CCR was documented. All 9 CCR patients tested negative for BCR/ABL gene at FISH analysis. Six of the 9 CCR obtained a major or complete molecular remission 3–29 months from treatment initiation. In 3 additional patients, who never achieved a CCR, suppression of the secondary clones was documented. In 1 case, the clone bearing 17p- was no more detected from the 6th to the 42nd month of therapy, when a new clone showing the i(17q) was recorded. In the other 2 cases, the leukemic population bearing the 3q- and 22q- or -17 marker was suppressed 6 and 3 months after the beginning of imatinib mesylate treatment, respectively. After a median follow up of 70 months, 8 patients are still alive and in continuous CCR. Such a long follow up, along with the rate, quality and duration of the responses observed, suggest that CE does not compromise the therapeutic activity of imatinib alone or combined with rIFNa in CML.

Description: Abstract 4899 Treatment of central nervous system (CNS) lymphoma remains challenging, and balance between therapeutic effectiveness and toxicity is difficult to find. The addition of systemic chemotherapy to whole brain radiotherapy has significantly improved the outcome of these patients. However, this combined strategy is burdened with possible acute and/or delayed severe neurotoxicity, particularly in elderly patients. Chemotherapy-only approaches, with or without concomitant intrathecal (IT) therapy, for CNS lymphoma have been explored. Moreover, deferring radiotherapy to the time of first or subsequent relapse may reduce the risk of severe neurotoxicity, without altering outcome. Recently, high-dose methotrexate and temozolomide (HD-MTX-TMZ) without IT CNS prophylaxis have been studied in PCNSL elderly patients. This regimen appears effective, while substantially decreasing acute and/or delayed neurotoxicity. Conflicting data exist regarding the safety of combining IT liposomal cytarabine (LC) and systemic CNS-penetrating therapy. We report our preliminary experience with HD-MTX-TMZ plus IT LC used upfront or as salvage in 4 primary or secondary CNS lymphoma patients, only one of which under the age of 60 (56). Treatment consisted of induction: MTX 3g/ms d 1, 10, 20, TMZ 100 mg/ms d 1–5; and maintenance for ≥SD patients, and for up to 5 additional cycles: MTX 3g/ms d 1, TMZ 100 mg/ms d 1–5, every month. Fifty mg IT LC were given concomitantly for up to 6 doses planned. LC doses were separated by at least 14 days from one another and at least 7 days from HD-MTX. Pt n. 1 (56 year-old male) had a history of testicular diffuse large B cell lymphoma (DLBCL), stage IVA. He received chemo-radiotherapy with 4 concomitant IT LC injections as CNS prophylaxis. Complete response (CR) was achieved. Two months later, he presented with headache and dizziness. MRI and PET revealed metabolically active righ cerebellar lesion. Karnofsky performance status (KPS) was 50%. Rituximab plus TMZ and IT MTX were initiated but soon discontinued due to a G4 CMV-related pneumonia. After complete recovery, HD-MTX-TMZ was started with concomitant 4 IT LC injections, and precautionary stem cell harvest. No significant G3-4 toxicities were observed during treatment. At 9 months of follow-up post-treatment, the lesion is stable with no contrast enhancement at MRI and PET is negative, suggesting a CRu. Pt 2 (76 year-old male) was referred in May 2009 with a diagnosis of CNS peripheral T-cell lymphoma not otherwise specified with MRI- and PET-documented multiple brain localizations (i.e. hypophyseal infundibulum, cavernous sinus, cerebellum). KPS was 60%. He was treated with systemic steroids and TMZ 150 mg/ms d 1–5/28. In August 2009 disease progressed after two cycles, and HD-MTX-TMZ was started. IT LC was added as CNS prophylaxis with 4 drug injections. Toxicity consisted of G2 renal insufficiency and G3 steroid-induced diabetes mellitus, both resolved. Treatment resulted in marked shrinkage of all lesions, with no contrast enhancement and PET is negative, indicating CRu, which is stable at 5 months of follow-up. Pt 3 (68 year-old female) was diagnosed with PCNSL, DLBCL, with left cerebellar localization. KPS was 50%. HD-MTX-TMZ and concomitant IT LC injections were initiated as first-line therapy. Four maintenance cycles and 5 IT LC injections have been performed so far. Toxicities included G3 atrial fibrillation. Interim MRIs documented very good partial remission of the disease. Pt 4 (71 year-old female) was diagnosed with DLBCL stage IIIE (i.e. subcutaneous facial localization) in July 2009, and treated with R-COMP (liposomal doxorubicine in lieu of the free formulation) for 8 cycles. She obtained CR, but in July 2010 presented with aphasia and facial hemiparesis. Brain MRI showed multiple subcortical lesions in both hemispheres, biopsy-confirmed to be lymphoma. The first IT LC injection and HD-MTX dose were given without significant toxicity. All patients completed induction and 5 maintenance cycles. HD-MTX-TMZ and concomitant IT LC therapy appeared feasible and overall well tolerated. No acute neurologic complications were observed. Follow-up is too short to make comments on delayed neurotoxicity. Increasing the number of LC injections might be reasonable and at least 7 days should be interposed between systemic and IT therapy. HD-MTX-TMZ plus IT LC deserves further evaluation in a larger prospective setting. Disclosures: No relevant conflicts of interest to declare.

Description: The incidence of chronic lymphocytic leukemia (CLL) is significantly lower in African Americans than whites, but overall survival is inferior. The biologic basis for these observations remains unexplored. We hypothesized that germline genetic predispositions differ between African Americans and whites with CLL and yield inferior clinical outcomes among African Americans. We examined a discovery cohort of 42 African American CLL patients ascertained at Duke University and found that the risk allele frequency of most single nucleotide polymorphisms known to confer risk of development for CLL is significantly lower among African Americans than whites. We then confirmed our results in a distinct cohort of 68 African American patients ascertained by the CLL Research Consortium. These results provide the first evidence supporting differential genetic risk for CLL between African Americans compared with whites. A fuller understanding of differential genetic risk may improve prognostication and therapeutic decision making for all CLL patients.

Description: Chronic lymphocytic leukemia (CLL) is characterized by phenotypical and functional alterations of different host immune components. Lenalidomide is an immunomodulatory agent which exerts both a direct antitumor effect and a pleiotropic activity on the immune system. Single-agent lenalidomide is active in patients with relapsed and refractory CLL, and the addition of an anti-CD20 monoclonal antibody to lenalidomide has shown synergism in vitro, as well as improved clinical responses in vivo. We designed a phase II study with the aim of determining the efficacy and tolerability of combined ofatumumab and lenalidomide for the treatment of relapsed or refractory CLL. We also wanted to investigate whether immune system and tumor microenvironment characteristics, such as circulating T and NK cell number and function, and plasma levels of chemokines, cytokines, and angiogenic factors could be correlated with the response to treatment and could be modulated during the course of the therapy. Ofatumumab was administered at a dose of 300 mg on day 1, 1000 mg on days 8, 15, and 22 during course 1, 1000 mg on day 1 during courses 3-6, and once every other course on day 1 during courses 7-24 (28-day courses). Lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed. Thirty-four patients were enrolled. The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade 〉2 in 18% of the 574 patient-courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). For the correlative studies, peripheral blood mononuclear cells and plasma samples were collected at baseline and after 3, 6, 9, and 12 months of therapy. Lymphocyte subsets were analyzed by flow cytometry. T and NK cell function was evaluated on 9 patients based on the expression of CD107a, IFNγ, TNFα, and IL-2 after the exposure to CD3/CD28 magnetic beads and K562 cell line, respectively. Chemokines, cytokines, and angiogenic factors were quantified through a multiplex bead-based immunoassay. Thirty-four age-matched healthy donors (HD) were used as controls. Treatment with ofatumumab and lenalidomide decreased the number of circulating T and NK cells. The greatest decrease was observed after 3 months of therapy as compared to baseline (p≤0.02 for all comparisons). We found that the baseline number of CD4+ T cells and CD57+ CD56+ NK cells was higher in CR patients as compared to non responder (NR) patients (median absolute number 1595/μl vs. 715/μl, p=0.04, and 358/μl vs. 70/μl, p=0.02). We also compared baseline T and NK cell populations of CR patients to HD, and found that the former had significantly higher numbers of CD16+ CD56+ and CD57+ CD56+ NK cells (median 356/μl vs. 80/μl, p=0.03, and 358/μl vs. 29/μl, p=0.0008). Interestingly, baseline numbers of CD16+ CD56+ and CD57+ CD56+ NK cells were comparable between NR patients and HD. We also observed that patients who achieved CR had significantly better T and NK cell function at baseline, whereas T and NK cell function was impaired in patients who only had partial or no response. Plasma levels of bFGF, VEGF and IFN-γ were significantly decreased at month 3 compared to baseline in all patients (p≤0.02 for all comparisons). Finally, significantly lower levels of circulating CCL2, CCL3, CCL4, IFNα, and IL-12p70 were detected during treatment in patients who achieved CR, compared to NR (p

Description: Background: Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation (ASCT) represent an unmet medical need. Allogeneic SCT can be curative, but is burdened with significant morbidity and mortality. Nivolumab and pembrolizumab are anti-programmed death (PD)-1 monoclonal antibodies and are referred to as immune checkpoint inhibitors (ICI). These agents have shown remarkable activity in patients with R/R cHL, but rarely induce complete response (CR). Studies on ovarian cancer cell lines have shown that exposure of tumor cells to the hypomethylating agent (HMA) 5-azacitidine, may induce transcription of latent endogenous retroviral genes, which then trigger a T-cell-mediated immune response. Therefore, HMA can act as "immunologic primers" and enhance the efficacy of ICI. We reviewed our experience with ICI in patients with R/R cHL, and compared responses between those who had been previously exposed to 5-azacitidine to those who had not. Methods: Twelve patients with R/R cHL received pembrolizumab at the dose of 2 mg/kg every 3 weeks (N = 9), or nivolumab at the dose of 3 mg/kg every 2 weeks (N = 3). Response was assessed by positron emission tomography/computerized tomography. For patients who were transplant candidate, ICI were used as a bridge to the procedure. Results: The patient median age was 35 years [range 25-79]. The median number of prior treatments was 11 [range 3-16] and 75% of patients had had ≥ 7 lines of therapy. All patients had received ASCT and Bv. Six had been exposed to 5-azacitidine for a median of 2.5 months [range 2-16] as part of a phase 1 study (NCT01998035). Four of them had received it immediately prior to ICI, the other two within 14 months of starting ICI. A total of 141 patient-courses were completed, with a median of 7 courses per patient [range 1-39]. There were 6 grade ≥ 3 adverse events (AE): infusion reaction (N = 1), thrombocytopenia (N = 1), grade-5 respiratory failure (N = 1), myelodysplastic syndrome, (N = 2, one of which pre-existent, both evolved into fatal acute myeloid leukemia (AML)), and acute kidney injury (N = 1, pre-existent). Grade 1-2 AE included infusion reaction (5), elevated thyroid stimulating hormone levels (3), diarrhea (2), fatigue (1). Ten patients are evaluable for response: 7 (70%) achieved CR, one partial response, one a reduction of tumor burden and one stable disease. Five of the 6 patients who received 5-azacitidine prior to ICI achieved CR, while only 2 of 4 who did not receive prior 5-azacitidine achieved CR. One patient's evaluation is pending at this time. At a median follow-up of 14.2 months [range 0.5-17.7], 9 patients are alive and 7 are still receiving treatment. Two patients with radiographic progression continue to be treated given sustained clinical benefit. One patient transitioned to allogeneic SCT while in complete remission and one discontinued due to symptomatic progression. The median progression-free survival has not been reached as of this writing (7.9+ months). Conclusions: We report the largest cohort of patients treated with ICI after being exposed to HMA. In these patients with very heavily pretreated cHL we observed a higher-than-expected CRR. Most serious AE were not related to ICI therapy. The finding that most CR clustered in patients previously exposed to 5-azacitidine may reflect synergism between HMA and ICI and support the notion of HMA-mediated "immunologic priming". This hypothesis is being tested in prospective clinical trials at our institution. Disclosures Sawas: Gilead Sciences: Speakers Bureau; Seattle Genetics: Honoraria. Amengual:Acetylon Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding. O'Connor:Spectrum: Research Funding; Spectrum: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.

Description: Abstract 164 Background: The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives: To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods: Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results: A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was:

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: Introduction: PTCL may represent the prototypical epigenetic malignant disorder. First, recurring mutations in important epigenetic regulators, such as TET2, IDH2, and DNMT3, have been described across several PTCL subtypes, though especially in AITL. Second, HDACi have only been approved as single agents in patients with relapsed/refractory (R/R) PTCL, and exhibit T-cell lineage-specific activity across disease subtypes. Thirdly, preclinical evidence from our group suggests marked class synergism between HDACi and HMA. In addition, across a panel of diverse T-cell lymphoma lines, the combination of HDACi and HMA induced the expression of many cancer testis antigens and genes involved in the interferon pathway/viral antigen response. Based on this collective experience, a phase 1/2 trial of romidepsin (ROMI) and oral 5-azacitidine (AZA) was launched to determine if this activity is reproduced in patients with R/R PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, and included both R/R and treatment-naïve individuals. The dose-escalation portion of the study followed a 3+3 design with progressively increasing dose intensity across 7 cohorts. The phase 1 primary objectives were determination of the maximum tolerated dose and dose-limiting toxicity. Phase 2 primary objectives were overall response rate (ORR, i.e., complete response [CR] + partial response [PR]), progression free survival, and duration of response (DOR). Results: 36 patients have been enrolled to date, 26 in phase 1 and 10 in phase 2. In the intention-to-treat population the median age was 56 years [23-83] with 59% being males. Twelve patients had Hodgkin lymphoma, 8 had a B-cell lymphoma, and 16 had a T-cell lymphoma (6 enrolled in the phase 1 and 10 in phase 2). The median number of prior therapies was 6 [1-15] for the phase 1 population and 1 [0-6] for the phase 2. After a median of 2 cycles [0-16], all phase 1 patients have discontinued therapy, whereas 6 out of 10 patients in phase 2 are still on treatment after a median of 2.5 cycles [1-14]. No patient discontinued therapy due to adverse events (AE). The most frequent hematologic G3-4 AE included neutropenia (39%), lymphopenia (39%), and thrombocytopenia (28%). The most frequent non-hematologic G3-4 AE included febrile neutropenia (8%), hyponatremia (5%), and lung infection (5%). Other common G1-2 toxicities included hyperglycemia, hypoalbuminemia, nausea/vomiting, and fatigue. The recommended phase 2 dose for the combination was declared AZA 300 mg days 1-14 and ROMI 14 mg/m2 days 8, 15, and 22 on a 35-day cycle. Thirty-two patients are evaluable for response. Of these, 27 had measurable disease. The ORR and CR in the overall population are 41% and 22%, respectively. However, while only 2 (11%) patients with non-T-cell lymphoma responded, of which one was a CR, 11 of 14 (79%) patients with T-cell lymphoma responded, including 6 (43%) who attained CR (see waterfall plot in figure). Notably, all 6 evaluable patients with AITL responded, and 3 achieved a CR. Two of these 3 achieved PR before reaching CR. Responses have been durable and the median DOR has not been reached [0.2-13.1+ months]. The AUC for ROMI at 10 mg/m2 (N = 15) and 14 mg/m2 (N = 20) were 2021.5 +/- 1461.3 h*ng/mL and 1565.7 +/- 5656.2 h*ng/mL, respectively, with a median half-life of 4.8 and 4.9 hours respectively, which is comparable to single-agent values. Conclusions: The combination of AZA and ROMI is well tolerated, with cytopenias being the most common G3-4 AE. The combination appears to exhibit marked T-cell lineage-specific activity. The 100% ORR in AITL patients is unprecedented and warrants detailed follow-up. Ongoing sequencing analysis will evaluate the impact of recurring mutations on the clinical activity of the combination. The study is actively accruing (NCT01998035). Figure Figure. Disclosures O'Connor: ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

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: Patients (pts) with Chronic Lymphocytic Leukemia (CLL) are known to have an increased risk of other cancers. Treatment with lenalidomide has been associated with an increased rate of solid tumors (ST) in pts with multiple myeloma (MM). However, the occurrence of ST in patients with CLL receiving therapy with lenalidomide remains unknown. Methods: We evaluated the development of ST in pts with CLL that received front-line treatment with lenalidomide as monotherapy or in combination with rituximab in clinical trials conducted at our institution. We report the characteristics and timing of ST, as well as patient outcome. All pts enrolled had indication for therapy according to the International Workshop on CLL guidelines and no history of malignancy for three years, with the exception of treated malignancy with indolent behavior such as prostate cancer that was treated with surgery or radiation therapy. Results: One-hundred twenty-one pts were enrolled in two consecutive phase II clinical trials of frontline therapy with lenalidomide (N = 61, 51%) or combination of lenalidomide and rituximab (N = 60, 49%). Baseline pts characteristics are shown in Table 1, median age was 66 yrs and 24% of patients were age 70 or older. At a median follow up after lenalidomide therapy of 41 months (range 1-102+), 7 (6%) pts developed a ST: renal cell carcinoma (RCC, 3 pts), localized breast cancer (LCIS and DCIS, 2 pts), pancreatic adenocarcinoma (1 pt) and colon adenocarcinoma (1 pt) (details are shown in Table 2). The median time interval between receiving lenalidomide-based therapy and the development of ST was 1.5 years (range 0-8.5). At the time of this report, 5 out of 7 pts with ST are alive and cancer-free. Two pts died: 12 months and 18 months after developing ST from progression of pancreatic adenocarcinoma and heart failure, respectively. Since pts with CLL have a high rate of non-melanoma skin neoplasms (NMSC), we also monitored patients for new diagnoses of skin cancers. Seven (6%) additional pts developed NMSC, 4 of these pts had prior history of NMSC. All cases of NMSC were superficial and did not require systemic therapy. Additionally, because of the high median age of this population, we reviewed prior history of malignancies. Eleven (9%) pts had history of ST [prostate cancer (N = 9), bladder cancer (N = 1), RCC (N = 1)]. Twenty-two pts (18%) had skin cancers (NMSC, (N = 21) and 1 pt had history of melanoma. None of them had received chemotherapy, two had radiation therapy [prostate cancer = 1, NMSC (basal cell carcinoma of the nose (1 pt)]. All ST were in remission before starting therapy with lenalidomide for more than 3 years as per the inclusion criteria. Conclusions: Seven cases of ST were observed in our population of 121 pts with CLL that received initial therapy with lenalidomide, after a median follow-up of 3.5 years. The most common neoplasm was RCC followed by in-situ breast cancer. In our limited experience the timing, number and type of malignancies do not appear to mirror what was seen in patients with MM. However, this comparison may be limited by the size of our patient population and length of follow-up. Our group reported the incidence of ST in patients treated with FCR. After a similar follow-up the incidence of second malignancies was similar (5.9%), but the type of malignancies was different, although NMSC remained the most common ST in both experiences. Reporting the incidence of other malignancies in patients with CLL enrolled in large studies, including those of novel targeted agents, will help understanding the expected incidence of ST and how novel treatments modulate such risk. Disclosures Jain: Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Servier: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; BMS: Research Funding; Novartis: Consultancy, Honoraria. Thompson:Pharmacyclics: Consultancy, Honoraria.