Citations

Abstract Background: Associations of medical history, lifestyle, and family history of hematological disorders with risk of chronic lymphocytic leukemia (CLL) have been previously established (1), but these exposures have not been well-studied as contributing factors to CLL prognosis. Here we investigate the association of these exposures with time to first treatment (TTFT) in 730 CLL patients. Methods: Newly diagnosed CLL patients seen at the Mayo Clinic between 2002 and 2012 were enrolled. CLL was defined according to the 1996 NCI-Working Group criteria (2). Risk factor data (including body mass index, smoking, alcohol use, sun exposure, having lived on a farm, any allergy, asthma, eczema, blood transfusion, diabetes, rheumatoid arthritis, and family history of hematological malignancy) were collected from self-administered questionnaires. Clinical and prognostic characteristics for CLL were extracted from medical records. Analyses were performed using Cox regression with first treatment as the event. Hazard ratios (HR) and 95% confidence intervals were estimated. We used Bonferroni correction for multiple testing with statistical significance at 0.004. Results: The median age at CLL diagnosis was 63 years (range 36 - 89); 65% were male, and 95% had a Rai stage< III. The median follow up time was 6.3 years, and 40% received treatment. In unadjusted analyses, patients with any history of allergies had significantly longer TTFT (HR = 0.66, 95% CI: 0.51-0.85, P = 0.001). We also observed borderline significance with history of asthma (HR = 0.53, 95% CI: 0.34-0.85, P = 0.008). These associations held after adjusting for important prognostic factors including age, sex, Rai stage, and IGVH mutational status. The other risk factors had non-significant associations (P>0.1). Conclusions: We observed an improved CLL prognosis in patients with a history of any allergies or asthma. These results were independent of other prognostic markers and suggest that an overactive IgE level from environmental exposures may provide insight into the progression of CLL. Literature Cited 1. Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, et al. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):41-51. 2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. Citation Format: Sara Beiggi, James M. Foran, O’Byrne Megan, Celine M. Vachon, Timothy G. Call, Neil E. Kay, Tait D. Shanafelt, James R. Cerhan, Susan L. Slager. Medical history, lifestyle, and family history exposures and chronic lymphocytic leukemia outcome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3453.

Abstract Introduction. First-line chemoimmunotherapy (CIT) has significantly increased the complete remission (CR) rate for patients with CLL; however, relapse is a common event and strategies aimed at eradicating disease more effectively are needed. Vascular Epithelial Growth Factor (VEGF) plays a crucial role in the cross talk between CLL B cells and their microenvironment. In addition low baseline VEGF levels predict a better response to CIT. Testing the combination of an anti-VEGF agent with CIT was therefore assessed by us in upfront CLL patients. Methods. Here we report the results of a phase II open-label randomized trial comparing the combination of bevacizumab, an anti-VEGF monoclonal antibody, with pentostatin, cyclophosphamide and rituximab (PCR-B) to PCR alone as front-line therapy in previously untreated patients with CLL. VEGF, b-fibroblast growth factor (FGF), thrombospondin (TSP)-1, chemokine ligand (CCL)-3 and CCL-4 plasma levels were measured at baseline and at time of response assessment. Results. Between 01/2009 and 01/2013, 62 patients were accrued in the study, 32 in the arm A (PCR-B) and 30 in arm B (PCR alone). A higher rate of grade 3-4 cardiovascular toxicity was observed with the use of PCR-B (34% vs 0%, p<0.001): this included 7 cases of hypertension, 2 cases of congestive heart failure, 1 myocarditis, and 1 case of torsade de point. A higher CR rate (50% vs 33%, p = 0.21) and a significantly longer median progression-free (p = 0.04) and treatment-free (p = 0.05) survival were achieved with the use of PCR-B. No difference in chemokine kinetics was observed between the 2 arms, except for VEGF, which significantly increased after PCR-B. In the PCR-B arm, chemokine kinetics for CCL-3 (median drop 5.0 vs. median drop 31.8, respectively; p = 0.02) and CCL-4 (median drop 23.8 vs. median drop 120.9, respectively; p = 0.01) were significantly associated with achievement of CR. No significant correlations were found between cytokine plasma levels and responses for patients treated in the PCR only arm. Conclusions. The addition of bevacizumab to CIT is safe and effective, although associated with higher cardiovascular toxicity, in particular hypertension. The addition of bevacizumab produces higher CR rates, translating into improved progression-free survival, and is associated with decreased plasma levels of CCL-3 and CCL-4. Citation Format: PAOLO STRATI, TAIT D. SHANAFELT, BETSY LAPLANT, ADAM PETTINGER, CONNIE LESNICK, DANIEL NIKCEVICH, TIMOTHY CALL, WEI DING, CURTIS HANSON, NEIL KAY. The addition of bevacizumab to chemoimmunotherapy prolongs progression-free survival in patients with chronic lymphocytic leukemia (CLL) through modulation of the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1423.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti‐CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8‐12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m2 weekly)(n = 16) or low dose (20 mg/m2 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression‐free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti‐CD20 mAb therapy as a potentially more effective use of anti‐CD20 mAb in the treatment of CLL. Am. J. Hematol. 91:308–312, 2016. © 2015 Wiley Periodicals, Inc.

Abstract Background: PI3K/Akt activation is downstream of the B cell receptor (BCR) signaling cascade and is critical to mediate the interactions between CLL B-cell and bone marrow stroma which support leukemic survival. MK-2206 is a potent oral allosteric Akt inhibitor and we have demonstrated in vitro synergism with bendamustine (B) to induce CLL apoptosis. MK-2206 selectively abolishes BCR-stimulated cytokines CCL3, CCL4, CCL2, and IL-2Ra and significantly inhibits the BCR signaling pathway (Ding, BJH, 2013). We sought to assess the safety, maximal tolerated dose (MTD) and efficacy of MK-2206 in combination with B-rituximab (BR) in relapsed and refractory CLL/SLL patients in a phase I/II trial (NCCTG N1087 Alliance). Methods: Previously treated symptomatic CLL/SLL patients with up to 3 prior lines of therapy and ECOG performance status of 0-2 were eligible. Patients with 17p deletion or prior treatment with B were excluded. A standard phase I design was used to determine the MTD of MK-2206 in combination with BR (B 70mg/m2 for 2 days per cycle; R cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2). Phase II employed the MTD to evaluate safety and efficacy of the combination. Response was evaluated 2 months after the last cycle of therapy per IWCLL 2008 criteria. Results: 13 patients with a median age of 68 years (range 44-75) and 1.2 prior lines of therapy were treated. CLL FISH showed: del(11q) in 4 (31%), trisomy 12 in 2 (15%), del(13q) in 3 (23%), del(6q) (8%), del(17cen) (8%) and normal results in 2 (15%). IGHV was unmutated in 10 (91%) and mutated in 1 patient (9%) and was missing in 2 cases. ZAP-70 was positive in 8 (73%) and negative in 3 patients (27%). CD38 was positive in 8 (62%) and negative in 5 patients (38%). 70% of patients had received prior chemoimmunotherapy. At 90 mg of MK-2206, 1/6 patients experienced a DLT of grade 3 febrile neutropenia and hemolysis. 2/6 patients on the 135 mg dose experienced a DLT. One patient had grade 3 febrile neutropenia and one patient had a grade 3 acneiform rash. MTD was determined to be MK-2206 90 mg. The most common grade 3/4 adverse events were neutropenia (46%) including febrile neutropenia (23%), diarrhea (15%) and thrombocytopenia (15%). The most common all-grade toxicities were neutropenia (69%), thrombocytopenia (62%), anemia (54%), nausea (54%), diarrhea (39%), rash (38%), and hyperglycemia (31%). 10 patients were treated at 90 mg and 3 patients were treated at the 135 mg dose. The ORR was 92% (n=12). Responses were: 3 CR (23%), 2 CR with incomplete marrow recovery (CRi) (15%), 1 clinical CR (CCR) (8%) without marrow confirmation, 1 nodular partial remission (nPR) (8%), 5 PR (38%), and 1 progressive disease (8%). Median follow-up was 20 months (6-31 months). Median PFS in the CR/CRi group was not reached (NR) with 100% of patients progression free versus 12 months (95% CI 2 months-NR) if CR/CRi was not achieved (p=0.027). Median overall survival was NR in either the CR/CRi or non-CR/CRi groups but 2 deaths occurred in the latter group (p=0.44). One patient developed Richter transformation and died at 15 months and a second patient who had achieved PR died from autoimmune hemolytic anemia and fungal infection at 27 months. Two out of five patients who achieved CR or CRi had bone marrow MRD negative status at the final response evaluation. Conclusions: The Akt inhibitor MK-2206 administered at 90 mg once weekly in combination with BR is tolerated in patients with relapsed or refractory CLL and compares favorably to BR alone (59% ORR and 9% CR, Fischer, JCO, 2011). An ORR of 92% was observed with a 38% of patients achieving CR or CRi. The trial was terminated prematurely due to withdrawal of sponsor support, however further testing of Akt inhibition is needed given the promising results. Citation Format: Jeremy T. Larsen, Tait D. Shanafelt, Jose F. Leis, Betsy R. LaPlant, Timothy G. Call, Clive S. Zent, Curtis A. Hanson, Charles Erlichman, Thomas M. Habermann, Craig B. Reeder, Deborah A. Bowen, Michael Conte, Justin C. Boysen, Charla R. Secreto, Connie E. Lesnick, Renee C. Tschumper, Diane F. Jelinek, Neil E. Kay, Wei Ding. The Akt inhibitor MK-2206 in combination with rituximab and bendamustine demonstrates efficacy in relapsed/refractory chronic lymphocytic leukemia: Updated results from the NCCTG N1087 Alliance study. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B02.

Abstract Background. Non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs have been suggested as protective agents against the development of non-Hodgkin lymphoma (NHL), but data are limited, particularly for NHL subtypes. Further, some in vitro, animal and epidemiologic data suggest there may be a synergistic effect of these two agents in cancer prevention, but there has been no test of this hypothesis in NHL. Methods. We evaluated the use of NSAIDs and statins in a clinic-based study of 1683 newly diagnosed cases and 2168 frequency matched controls enrolled from 2002-2012. Regular use (at least once/week for at least one year) of low dose (baby) aspirin, standard or extra strength aspirin, ibuprofen, other NSAIDs (e.g., naproxen, etc), COX-2 inhibitors, as well as statins or other cholesterol lowering drugs, was ascertained using a self-administered questionnaire. Frequency, amount and duration of use were also collected. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, education, body mass index, smoking history, alcohol use, and history of rheumatoid arthritis and osteoarthritis. Pathologic classification of NHL subtypes was centrally reviewed, and subtype-specific NHL risks were estimated using polychotomous logistic regression for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, N = 495), diffuse large B-cell (DLBCL, N = 326), follicular (FL, N = 410) and marginal zone (MZL, N = 134) lymphomas. Results. The mean age of cases was 61.8 years and 59% were men, while the mean age of controls was 61.6 years and 53% were men. We observed an inverse association of low dose aspirin use with risk of NHL (OR = 0.82; 95% CI 0.70-0.96), with stronger associations for more pills per day, longer duration of use and greater number of pill-years. In contrast, we observed no evidence of an association with NHL risk with use of regular or extra-strength aspirin, ibuprofen, other NSAIDs, or COX-2 inhibitors, nor use of statins or other cholesterol-lowering drugs. When we modeled the joint use of low dose aspirin and statins, the strongest inverse association was observed for low dose aspirin use only, followed by use of both aspirin and statins; there was no association with statin use only and no evidence for any interaction of low dose aspirin and statins on NHL risk. For low dose aspirin, the strongest inverse trends were observed for DLBCL, followed by FL and MZL, while there were no consistent associations for CLL/SLL. Conclusions. We found a strong inverse association of low dose aspirin use with risk of NHL and the subtypes of DLBCL, FL, and MZL, but no association for regular/extra strength aspirin, other NSAIDs or statin use. While confirmation is needed, our findings for low dose aspirin but not use of other NSAIDs suggest that anti-platelet or other effects of low dose aspirin may be of etiologic significance in lymphomagenesis. Citation Format: James R. Cerhan, Megan M. O'Bryne, Grzegorz S. Nowakowski, Timothy G. Call, Carrie A. Thompson, Tait D. Shanafelt, William R. Macon, Neil E. Kay, Thomas M. Habermann, Susan L. Slager, Mark Liebow. Aspirin and other nonsteroidal anti-inflammatory drugs, statins, and risk of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2015-877

Abstract Introduction. CLL has a highly heterogeneous clinical course. In fact, while some patients experience a very aggressive disease, others may present with an indolent form, and eventually die of “other” causes. Here we report the findings of a prospective cohort study evaluating the comorbidities and causes of death in newly diagnosed patients with CLL. Methods. Clinical information was collected from 1174 patients with newly diagnosed CLL (within 9 months of diagnosis), who consented to participate in a prospectively observational trial with standardized longitudinal follow-up between 01/2002 and 11/2014. All comorbidities were diagnosed before presentation. Results. Baseline characteristics are shown in the Table. Co-existent health conditions included: cardiac (28% of patients), respiratory (18%), endocrinological (14%), rheumatologic (42%), gastrointestinal (33%), genitourinary (35%), and psychiatric diseases (17%), diabetes (10%), hyperlipidemia (41%), other cancers (20%), stroke (3%), hypertension (40%), venous thromboembolism (3%), substance abuse (5%), sexually-transmitted infections (3%), and obesity (32%). After a median follow up of 4 years, 197 patients died and the cause of death could be accurately determined in 135 patients. Among these, death was due to CLL progression in 69 (51%) patients, infections in absence of CLL progression in 7 (5%), other cancers in 29 (21%), and other comorbid health conditions in 30 (22%). CLL patients (N = 1174)Number (%), median [range]Age (years)63 [23-89]Males791 (67)Females383 (33)Rai stage 0604 (51)I-II512 (44)III-IV54 (4)missing4 (1)B2M < 4 mg/dL717 (61)> 4 mg/dL97 (8)missing360 (31)CD49d negative638 (54)positive277 (24)missing259 (22)CD38 < 30%780 (66)> 30%332 (28)missing62 (6)ZAP70 negative650 (55)positive380 (32)missing135 (13)IGHV mutated506 (43)unmutated394 (34)missing274 (24)FISH del13q395 (34)negative173 (14)+12276 (23)del11q90 (8)del17p50 (4)other2 (1)missing188 (16) Conclusions. Despite the advanced age at CLL diagnosis, the frequent presence of comorbidities, and the indolent nature of the disease, CLL progression is the ultimate cause of death in 51% of newly diagnosed CLL patients, with an additional 26% dying of causes potentially related to CLL, such as infections and second cancers. The influence of comorbidities and other clinical factors at diagnosis (e.g. smoking, Charlson Comorbidity Index) on survival and ultimate cause of death are being abstracted, and will be presented at the meeting. Citation Format: Paolo Strati, Kari Chaffe, Sara Achenbach, Timothy Call, Neil Kay, James Cerhan, Susan Slager, Tait Shanafelt. Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5267. doi:10.1158/1538-7445.AM2015-5267

Abstract Introduction Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that is known to have a familial component to disease risk. Although 31 loci have been found to be associated with CLL risk, the functional variant(s) driving these associations is mostly unknown. Here we set out to identify rare, highly-penetrant, cosegregating, susceptibility variants within the known GWAS discovered loci using whole exome sequencing (WES) data in CLL families from the Mayo Clinic family study of B-cell malignancies. Methods We performed WES on germ line DNA of 93 CLL families with two or more members with CLL, using Agilent capture kits and Illumina HiSeq2000. Bioinformatics analyses leveraged the following software packages: Novoalign, Picard, The Genome Analysis Toolkit (GATK), and the Biological Reference Repository (bioR). Quality control filters were implemented; subjects with mis-specified relationships were removed, as were variants with <75% call rate, <8X coverage, and those identified as sequencing artifacts. Each GWAS locus was defined by +/- 1Mb of the top GWAS hit within the locus. Linkage disequilibrium (LD) was calculated among the single nucleotide variants (SNVs) located within each locus. Potentially functional SNVs were identified based on: a) uncommon in public databases (< 5%), b) cosegregating in at least two CLL families, c) being highly conserved and in coding regions, and d) functional prediction status of deleterious (SIFT Score), damaging (PolyPhen Score), and a moderate, or high variant impact (SNP Effect). Results In our 93 CLL families, we sequenced 443 individuals: 160 with CLL, 73 with monoclonal B cell lymphocytosis (MBL), and 210 relatives that were not diagnosed with CLL or MBL at the time of sequencing. Median age of CLL diagnosis was 59 years (range 34-87), and 56% were male. Among the MBL individuals and relatives, the median age at recruitment was 55 years (range 18-93), and 40% were male. A total of 317,666 SNVs passed our sequencing quality control filters of which 10,731 were within +/- 1 Mb of known GWAS hits from 31 loci. Of these SNVs, 91% were in coding regions, 18% were reported to have high or moderate impact, 6% were estimated to be damaging and 6% were predicted to be deleterious. From these SNVs, we identified 76 putatively functional variants distributed across 25 GWAS loci that were cosegregating in the individuals with CLL or MBL in multiple CLL pedigrees. These SNVs were all located in coding regions with high or moderate impact and were predicted to be damaging and deleterious. Of these 76 variants, 56 had a frequency of <0.005 in 1000 Genomes’ European population while the remaining 20 had a frequency of 1%. Conclusions Through WES, we identified a number of rare, penetrant and potentially predisposing SNVs located within 25 of the 31 CLL GWAS-discovered loci. These segregating variants provide a list for future validation and functional studies. Citation Format: Sara Beiggi, Daniel R. O'Brien, Sara J. Achenbach, Kari G. Chaffee, Timothy G. Call, Neil E. Kay, Tait D. Shanafelt, Julie Cunningham, James R. Cerhan, Celine M. Vachon, Susan L. Slager. Cosegregating variants in chronic lymphocytic leukemia (CLL) families that are located in loci discovered by genome wide association studies (GWAS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2764. doi:10.1158/1538-7445.AM2015-2764

Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL.