ALBERT

Description: Vitamin D insufficiency is common globally and low levels are linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT (hazard ratio[HR] = 1.66; P = .005) and OS (HR = 2.39; P = .01) were shorter for 25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 25(OH)D insufficient. After a median follow-up of 9.9 years, TTT (HR = 1.59; P = .05) and OS (HR 1.63; P = .06) were again shorter for 25(OH)D-insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization testing, 25(OH)D insufficiency remained an independent predictor of TTT (HR = 1.47; P = .008), although the association with OS was not significant (HR = 1.47; P = .07). Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.

Description: Background: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Everolimus (RAD001, Novartis Pharmaceuticals) is an oral investigational antineoplastic agent that targets mTOR. Objectives: To learn the anti-tumor activity and toxicity of single-agent RAD001 in pts with relapsed/refractory aggressive NHL. Patients and Methods: Patients were eligible if they had measurable disease, a platelet count 〉75,000, an absolute neutrophil count 〉1,000, and a creatinine and bilirubin

Description: Abstract 1268 Poster Board I-290 Purpose There are reports of an increased risk of skin cancers in patients with B-Chronic Lymphocytic Leukemia (CLL). These skin cancers include basal cell and squamous cell carcinoma. This analysis was performed to more completely define the prevalence of skin cancers in patients in the Mayo Clinic Rochester CLL database and to look for contributing factors. Methods The Mayo Clinic Rochester CLL Database includes all patients with a diagnosis of CLL since January 1995 seen in the Division of Hematology and who have signed institutional review board approved consents for research. For this study, 2240 patients were analyzed to compare differences in characteristics between CLL patients with and without skin cancer. Chi-square statistics were used to compare qualitative variables (age categories, gender, referral status, ALC categories, CD38, ZAP-70, IgVH gene mutation status, FISH categories, Rai stage), and t-tests were used for quantitative variables (age at diagnosis, ALC values). Overall survival (OS) and time to first treatment (TFT) analyses were performed with results being displayed using Kaplan-Meier curves and p-values calculated using a log-rank test. Prevalence of melanoma among CLL patients was compared to the age-adjusted prevalence of melanoma in individuals in the Iowa SEER registry. Results Median follow-up for the 2240 patients diagnosed between 1/1/1995 and 8/11/2009 was 4.6 years. In aggregate, 293 (13.1%) patients were found to have non-melanoma skin cancer (squamous cell carcinoma or basal cell carcinoma) cancer. The diagnosis of non-melanoma skin cancer occurred before the CLL diagnosis in 39% and at or after the diagnosis of CLL in 61%. There were 57 (2.5%) cases of melanoma in association with CLL. The diagnosis of melanoma occurred before the CLL diagnosis in 38% and at or after the diagnosis of CLL in 62%.The prevalence of non-melanoma skin cancer and melanoma skin cancer were both higher in non-referred (geographically regional) CLL patients than referred CLL patients (16.6% vs. 11.4%, p

Description: Abstract 1245 Poster Board I-267 Introduction Chronic lymphocytic leukemia (CLL) patients with del(11q) by fluorescence in situ hybridization (FISH) have a poor prognosis. These patients often have younger age of onset, bulky lymphadenopathy, and short clinical response to treatment with purine analogues. Deletion of 11q in CLL is thought to involve loss-of-function of ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses. As part of a larger study of early-intermediate stage, high risk CLL patients, we applied whole genome copy number variation (CNV) analysis to characterize the genomic alterations in CLL patients with and without del(11q) by FISH. Patients and Methods We studied 17 patients aged 29-67 with early-intermediate stage, untreated CLL who had high risk for disease progression based on evaluation of molecular and immunophenotypic markers. Of these patients, six had del(11q) by FISH analysis. No patients in this study had del(11q) as a sole FISH abnormality. CLL cells and normal cells were separated by magnetic bead selection from patient peripheral blood samples with absolute lymphocyte counts that ranged from 7.4 to 106 × 109/L. CNV analysis was performed on purified genomic DNA from the CLL cells and from normal cells for each patient in order to distinguish acquired CNVs in malignant cells from polymorphic CNVs in the human genome. We used the Illumina human660w-quad beadchip, a single nucleotide polymorphism (SNP)-based microarray for whole-genome genotyping and CNV analysis that contains more than 550,000 tag SNPs and approximately 100,000 additional markers that target regions of common CNV. CNV data was analyzed using CNV partition (Illumina Genome Studio software) and PennCNV. Results CNV analysis reveals hemizygous deletions of 11q in all 6 patients positive for del(11q) by FISH. The size of the deletion varies from ∼980 Kb to ∼44 Mb. All deletions include the region of the ATM gene at 11q22.3. No large homozygous deletions of 11q were detected. The three largest interstitial deletions (∼39 Mb, ∼41 Mb, ∼44 Mb) span 11q14.1-q23.3. A slightly smaller deletion of ∼33 Mb spans 11q14.2-q23.3. One deletion of ∼8.6 Mb covers 11q22.1-q22.3. The smallest deletion of ∼980 Kb is found within 11q22.3, centered on the ATM gene. Three out of 6 patients show complex interstitial deletions of 11q that consist of two or more discontinuous segments of loss of heterozygosity (LOH) separated by short undeleted regions. Five out of 6 patients with 11q deletions also show 13q hemizygous deletion by CNV analysis and by FISH. In 4 of these patients, the 11q and 13q interstitial deletions are the only acquired CNV events detected in the CLL genome. In one patient with 11q and 13q interstitial deletions, CNV analysis also shows chromosome 12 copy number (CN)=3 (also detected by FISH), CN=3 at 3q24-telomere (tel), and LOH events consistent with hemizygous deletion at 11p13 and 7p15.2-tel. Most noteworthy are 2 patients negative for any FISH abnormality who show copy-neutral LOH of most of 11q. The region of copy-neutral LOH includes 11q12-tel in one patient and 11q13.1-tel in the other patient. The copy-neutral LOH event involves close to 100% of the CLL cells in one patient, but only about 50% of the CLL cells in the other patient. Conclusions Whole genome CNV analysis by SNP-based microarrays greatly expands our ability to detect acquired genomic events in CLL cells and provides a powerful tool for CLL clinical research. Applying this new genomic technology to CLL patients with 11q deletions reveals marked complexity in the size and structure of hemizygous deletion events, which include the region of the ATM gene at 11q22.3 and can be discontinuous, indicative of complex genomic events. We identified copy-neutral LOH of 11q in 2 patients, a finding not previously described in CLL cells. Copy-neutral LOH of 11q is a genetic mechanism by which biallelic mutations of ATM, in cooperation with the loss of other tumor suppressor genes on 11q, may contribute to poor outcomes in some CLL patients without detectable FISH abnormalities. Additional studies, including sequencing of the ATM gene in 11q copy-neutral LOH patients, are required to confirm this hypothesis. Disclosures Shanafelt: Genentech, Hospira, Polyphenon E International, Celgene, Cephalon, Bayer Health Care Pharmaceuticals: Research Funding. Kay:Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding; Biogenc-Idec, Celgene, Genetech, Genmab: Membership on an entity's Board of Directors or advisory committees. Zent:Genentech: Research Funding; Bayer: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

Description: The standard of care for CLL is to treat only patients with obvious clinical progression because earlier intervention is not of proven benefit. The discovery of more accurate prognostic markers for CLL could change that paradigm. The predictors of more aggressive disease include 17p13 deletion (17p13−), 11q22-3 deletion (11q22−), unmutated (UM) immunoglobulin heavy-chain variable region (IgVH), and expression of ZAP-70 and CD38. In addition, monoclonal antibody (MoAb) therapies provide effective treatment with less toxicity than chemotherapy and are likely to be most efficacious in early stage CLL. The combination of alemtuzumab (ALEM) and rituximab (RIT) is of interest because of non-overlapping mechanisms of action. ALEM is also effective therapy for patients with defects in the p53 apoptotic pathway that are more resistance to purine analogue therapy. We tested the hypothesis that MoAb therapy with ALEM and RIT will eliminate/greatly decrease the high risk clone characterized by 17p13−, 11q22−, or UM IgVH plus either ZAP70+ or CD38+, in early stage CLL. Methods This trial will enroll a maximum of 30 patients and be considered promising if ≥ 19 patients respond. All patients with previously untreated CLL (Rai stage 0 −II) not meeting NCI-WG 1996 treatment criteria and with a high risk CLL clone were evaluated for enrollment. Treatment duration was 30 days (subcutaneous ALEM dose escalation, 3 mg - 10 mg - 30 mg on days 1–3) then 30 mg Monday, Wednesday and Friday for 4 weeks. RIT (375 mg/m2/dose IV x 4) was administered weekly staring on day 8. All patients received PCP and herpes virus prophylaxis and had CMV viral DNA testing for 7 months. Response was evaluated using NCI-WG 1996 criteria and minimal residual disease (MRD) was measured in peripheral blood using sensitive flow cytometry (1:104) for CD19+/CD5+/CD79b− lymphocytes. Results Since January 2005, 17 patients have been enrolled and the interim analyses are for the first 11 patients accrued. Median age was 62 years (29 – 75) with 6 males and 5 females. The qualifying high risk features were 17p13− (n = 4), 11q22− (n = 3), and UM IgVH + CD38+ +/− ZAP-70+ (n = 4). Median time from diagnosis to treatment was 11 months (2–72). Clinical stage (Rai) was 0 in 3 patients, I in 5 patients and II in 3 patients. Median absolute lymphocyte count was 25.6 x 109/L (15.9 – 81.8), Hgb 14.4 g/dL (12 – 15.8), and platelet count 171 x 109/L (125 – 312). Two patients had serious adverse reactions requiring intervention (CMV reactivation responsive to treatment; febrile drug reaction to sulfamethoxazole/trimethoprim). Grade 3–4 adverse reactions not requiring interventions were leukopenia (n = 4), neutropenia (n = 2), anemia (n = 1), elevated ALT (n = 1), and skin reaction to ALEM (n =1). There were no “first dose” reactions. All patients responded to therapy with 5 CR (4 of these MRD negative), 3 nodular PR, and 3 PR. Median duration of response has not yet been reached at median follow up of 11.7 months (6.5 – 14.9). Patients with a MRD negative CR had recurrence of detectable MRD at 120 – 210 days after completing therapy but all remain in CR. One patient died off study of complications of a myeloablative allogeneic transplant for progressive CLL. Discussion ALEM and RIT is effective and tolerable therapy for early stage high risk CLL. All patients responded with 36% achieving a MRD negative CR but serial MRD assays showed that the CLL clone was not deleted. This promising, treatment requires further improvement.

Description: Mutation status of the immunoglobulin heavy chain variable region (IgVH) in B cell chronic lymphocytic leukemia (B-CLL) is a critical prognostic tool. Although patients with unmutated (UM) IgVH genes exhibit an overall shorter survival than those with mutated (M) IgVH genes, considerable heterogeneity in clinical progression exists among UM B-CLL patients. The goal of this study was to evaluate UM CLL patients (n=215) in a large B-CLL cohort for Ig V, D, and J gene usage and relevant clinical parameters to identify Ig molecular features in addition to UM vs. M status that have prognostic value. Consistent with the literature, the most commonly expressed IgVH gene in our UM B-CLL cohort was VH 1–69 (69/215). We first evaluated D and J usage in VH 1-69 vs. non-VH 1–69 UM patients. The factors that were significantly different between VH1–69 vs. non-VH 1–69 cohorts were JH6 usage (p=0.0014), D3–3 usage (p=0.0025), and the combination of JH6 and D3–3 usage (p=0.0002). We then examined potential associations between patient time to treatment (TTT) and specific IgVH molecular features. Although there was a trend that VH 1–69 patients exhibited a shorter TTT than non-VH 1–69 patients, the association did not reach statistical significance (p=0.06). When all UM patients were instead grouped on the basis of D and J usage, JH6 usage was not significantly associated with TTT, but D3–3 usage, irrespective of VH or JH usage, significantly correlated with shorter TTT (p=0.005). Of interest, when JH6 patients were excluded from the analysis, differences in TTT between those with and without D3–3 usage were particularly pronounced (p=0.011). We next explored whether a specific D3–3 reading frame (RF) is associated with TTT. Within the group of D3–3 patients, we evaluated differences in TTT between those with RF 2 (n=38) vs. RF 3 (n=19) but did not study RF1 patients due to small numbers (n=6). Comparison of D3–3/RF 3 patients (n=19) with all other UM patients (n=190), did not reveal a significant difference in TTT, however, there was a significant difference (p=0.012) in TTT between D3–3/RF 2 patients (n=38) and all other UM patients (n=171). Rai risk was still the best overall prognostic factor, and was the only significant factor (p

Description: Background: Over the last decade, increasing numbers of families with at least 2 cases of CLL or other B-cell lymphoproliferative disorders have been described. Methods: Families seen at Mayo Clinic with at least one individual diagnosed with CLL and one or more first or second degree relative diagnosed with CLL or a B-cell lymphoproliferative disorder(LPD) were identified. Clinical characteristics and risk stratification test results (cytogenetic abnormalities by FISH, level of CD38 expression, and IgVH gene mutation status) were extracted and reviewed. Serum, intracellular and CLL B cell secreted levels of pro- and anti-angiogenic cytokines (VEGF, BFGF, and TSP) were also compared between cases of familial and sporadic CLL. Results: Seventy-one families seen at Mayo Clinic were identified meeting criteria for familial CLL. Of the 71 index CLL families, 78.9% (n=56) had at least one other first or second-degree relative with CLL or a B cell LPD, 15.5% (n=11) had 2 other affected members, and 5.6% (n=4) had 3 or more affected members. Of affected family members with B-cell LPDs other than CLL, 64% (n=25) had non-Hodgkin lymphoma, 21% (n=8) had Hodgkin disease, 10% (n=4) had multiple myeloma or Waldenstrom macroglobulinemia, and 5% (n=2) had another lymphoid leukemia (1 ALL, 1 hairy cell leukemia). The median age was 62, with 63% males and 37% females. The majority of individuals had an early Rai stage at diagnosis (stage 0–66%, stage I-19%). Results of cytogenetic testing by FISH, CD38 status, IgVH gene mutation status appear similar in familial and sporadic CLL cases seen at Mayo clinic during the same time interval. No clear pattern of IgVH gene mutation status, IgVH gene family usage, level of CD38 expression, or cytogenetic abnormalities by FISH was seen among multiple affected members from the same family. There were also no significant differences noted in serum, intracellular, and CLL B cell secreted levels of VEGF, BFGF or TSP in the familial samples when compared to a cohort of non-familial samples. Conclusions: Expression of cytogenetics by FISH, immunophenotype, IgVH mutation status and levels of serum, intracellular and cytoplasmic pro- and anti-angiogenic factors(VEGF, BFGF, and TSP) were similar in individuals with familial and sporadic CLL.

Description: Abstract 4252 Background: Multiple recent studies have demonstrated the survival benefits of reduced intensity allogeneic stem cell transplant for high risk CLL patients. These transplant series, however, represent highly selected cases where age, co-morbidities and performance status preclude transplant in many patients with CLL. The portion of newly diagnosed CLL patients that are eventually considered for transplant is unknown, as well as the proportion that are referred for transplant evaluation; the proportion that actually receive stem cell transplant, and the reasons for not pursuing transplant in referred patients. We conducted a cohort study of newly diagnosed CLL patients to address this gap in knowledge. Methods: We used the Mayo Clinic database to identify all patients with newly diagnosed CLL seen at Mayo Clinic within 1 year of diagnosis between July of 2003 and May of 2011 (time interval during which reduced intensity allogeneic stem cell transplantation was part of routine care at Mayo Clinic). Electronic medical record and laboratory studies were reviewed to identify all patients referred for stem cell transplant evaluation (either allogeneic transplant for progressive CLL or autologous stem cell transplant for Richter's transformation). Patients referred for transplant were analyzed to determine what proportion completed transplant and, for those who were not transplanted, the reason they were not transplanted (e.g. lack of insurance approval, co-morbidity, lack of a donor, inadequate disease control, death prior to transplant or patient preference). Results: A total of 1250 patients with newly diagnosed CLL between July 2003 and May 2011 who were seen at Mayo Clinic within 1 year of diagnosis were identified. The mean age at diagnosis was 63.6 yrs and 34.2% were women. With respect to disease stage, 48.7% were Rai stage 0, 45.5% Rai stage I/II, and 5.8% Rai stage III/IV. CLL FISH analysis revealed 126 (13.6%) patients who had either del (17p) or del (11q) and 801 (86.4%) patients who had other FISH abnormalities or normal FISH results. After a median follow-up of 41 months, 425 (34%) of patients have received treatment. A total of 54 patients (4.3%) were referred for a transplant evaluation during follow-up. Of these 54 patients, 48 (3.8% overall cohort) were referred for consideration of allogenic transplant for treatment of progressive CLL and 6 (0.5%) were referred for autologous transplant for treatment of Richter's transformation. Baseline characteristics associated with subsequent transplant referral included age at diagnosis (median: 56 yrs) (p 〈 0.0001, Odds Ratio (OR) for each year older = 0.91, 95% Confidence Interval (CI)=(0.88, 0.95)), Rai stage (III/IV vs. 0) (p = 0.0002, OR = 22.7, 95% CI=(5.1, 102.4)) and FISH (del(11q), del(17p) vs Normal, del(13q) or Trisomy 12) (p 〈 0.0001, OR = 7.3, 95% CI=(3.3, 16.1)). Gender, Rai stage (I/II vs. 0), and patient residence (local vs. not local) were not significant. Among the 54 patients referred for transplant, 28 (51.9%) completed a transplant. This included 22 (45.8%) patients referred for allogenic transplant and 6 (100%) patients referred for autologous transplant. Among the 26 patients referred who did not undergo transplant, the principal reasons were patient preference (n = 6, 23.1%), patient still being evaluated for transplant as of the study end date (n = 6, 23.1%), alternative therapy chosen (n = 5, 19.2%), inadequate disease control (n = 3, 11.5%), death prior to transplant (n = 3, 11.5%), lack of insurance approval (n = 2, 7.7%), and lack of a donor (n = 1, 3.8%). Conclusion: 4.3% of the newly diagnosed CLL patients in this series were considered for stem cell transplant at some point during follow-up. Young age, high Rai stage and high risk FISH abnormalities are principal reasons for transplant referral. Only 51.9% of those considered for transplant completed transplant. The principal reasons for referral patients not completing transplant who had adequate time to follow were patient preference, alternative therapy, inadequate disease control and death prior to transplant. The remaining 6 patients (23%) are in process of transplant evaluation with longer follow required. These analyses provide first incidence data for CLL transplant referral in a cohort of newly diagnosed patients. Disclosures: Zent: Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKlime: Research Funding. Shanafelt:Celgene: Research Funding; Teva/Cephalon: Research Funding; GlaxoSmith Klein: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Polyphenon E International: Research Funding.

Description: Abstract 1790 CLL is incurable with conventional therapies and prognosis is poor in patients with relapsed or treatment refractory disease. Patients with purine analogue refractory disease and defective TP53 function have limited therapeutic options. Based on: 1) The ability of purine analogues to decrease tumor burden; 2) Higher response rates in patients treated with alemtuzumab and rituximab vs. alemtuzumab alone; and 3) Data showing that more frequent lower doses of rituximab could be more effective than standard therapy, we hypothesized that combination therapy with pentostatin, alemtuzumab and low dose rituximab (PAR) would be effective and tolerable therapy for patients with relapsed/refractory CLL and those with previously untreated progressive CLL who had 17p13-. This two stage phase II University of Iowa/Mayo Clinic Lymphoma SPORE clinical trial (NCT00669318) was approved by Mayo Clinic and the University of Iowa IRBs according to the principles of the Declaration of Helsinki. The aims are to assess: 1) Complete (CR) and overall responses; and 2) Progression-free survival (PFS), duration of response, and time to next treatment (TTT). Patients with progressive CLL (including the SLL variant) defined by standard criteria are eligible for this study if they had either previously treated CLL or previously untreated CLL with 17p13-. Cycle 1 of therapy is 5 weeks with rituximab 20 mg/m2/d IV Mon-Wed-Fri starting day 1, subQ alemtuzumab beginning days 3–5 with a dose escalation (3 mg–10 mg– 30 mg/d) and then 30 mg/d Mon-Wed-Fri, and pentostatin 2mg/m2/dose/IV days 8 & 22. Cycles 2–3 are each of 4 weeks duration and are the same as weeks 2–5 of cycle 1. Patients who achieve CR after cycle 2 with a negative CT scan and bone marrow study with no evidence of residual CLL cells after immunohistochemical staining, do not receive cycle 3 of therapy. All patients receive granulocyte growth factor support after pentostatin therapy as well as PCP and herpes virus prophylaxis. Patients are tested for CMV reactivation by PCR weekly during therapy and treated with valganciclovir if reactivation is detected. We report the results of the planned interim analysis performed after completion of therapy for the first 19 patients (July 2008 - October 2010). The median patient age was 63 years (range 47–78) with 74% males. Two patients with 17p13- were previously untreated. Of the 17 previously treated patients (median 2 prior regimens, range 1–6), 8 (47%) had purine analogue refractory CLL (disease progression 〈 6 months of treatment). Nine (47%) patients had advanced clinical stage (Rai III-IV). Adverse molecular prognostic factors were 17p13- (n=8, 42%, 2 also had 11q22-), 11q22- (n=1), unmutated IGHV (12/17, 71%), ZAP70+ (≥20%, 12/17, 71%) and CD38+ (≥30%, 6/18, 33%). The median beta-2-microglobulin level was 4.3 (range 2.4 – 12.6). Grade 3–4 treatment related toxicities were 9 non-hematological and 20 hematological events. Grade 3–4 infections occurred in 3 patients including one patient requiring hospitalization for CMV re-activation. Fourteen (74%) patients responded to treatment with 6 (32%) CR (includes 2 CRi) and 8 (42%) partial responses (PR). Five (26%) patients had stable disease (SD). Eleven (58%) patients completed 3 cycles of therapy. One patient achieved a CR with no residual disease after 2 cycles of therapy and received no further treatment per protocol. Median duration of response is 7 months (95% CI: 4–not reached (NR)). Among the 8 patients with 17p13- there were 3 CR/CRi, 4 PR, and 1 SD. Four patients proceeded to allogeneic transplant with reduced intensity conditioning (RIC) and were censored for TTT at the initiation of transplant related therapy. With a median of 16 (range 6 – 35) months of follow up, median PFS is 7 months (95% CI: 5–NR), median TTT is 27 months (95% CI: 5-NR) and the calculated median overall survival is 23 months (95% CI: 14–NR). We report that PAR is effective and tolerable therapy in this population of relapsed refractory patients with high to very-high risk CLL. In addition, the responses in patients with 17p13- were similar to that of the patients who did not have 17p13-. The treatment regimen was useful for disease control in 3 patients who proceeded to reduced intensity conditioning allogeneic transplantation. This study shows that PAR could play an important role in the treatment of recurrent and high risk CLL. Supported by the University of Iowa/Mayo Clinic Lymphoma SPORE CA097274 Disclosures: Zent: GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.

Description: Abstract 2835 Background: Extrinsic growth and survival signals provided by nonneoplastic cells present within the tumor microenvironment promote the growth and survival of CLL cells. For example, bone marrow stromal cells, blood-derived “nurse-like” cells and follicular dendritic cells have been shown to promote the survival of CLL cells via the provision of both soluble and cell-contact dependent factors. More recently, monocytes were convincingly shown to support the survival of CLL cells during in vitro culture, and many of the factors (e.g. BLyS/BAFF, SDF-1, CD14) previously implicated in supporting the growth and survival of CLL cells are produced by monocytes. To explore the potential clinical implications of these in vitro findings, we evaluated the relationship between the absolute monocyte count (AMC) at diagnosis and disease progression in a well defined cohort of CLL patients. We hypothesized that the presence of a relative monocytosis at presentation in patients newly diagnosed with CLL may create a nurturing environment for CLL cells and be associated with more rapid disease progression. Methods: Previously untreated patients diagnosed with CLL/SLL within 12 months of presentation to the Mayo Clinic (from 1/1/2000-8/31/2010) were identified (n=1396). The AMC was obtained from routine complete blood counts (CBC) with automated or manual differentials that were performed within 3 months of diagnosis (n=947). The primary study objective was to determine whether the AMC is associated with time to first treatment (TTFT) in CLL. The secondary objective was to determine whether the AMC had independent prognostic value after adjusting for CD38/CD49d/Zap-70 expression, IGHV gene mutation status, and cytogenetic (11q-, 17p-) findings by FISH analysis. Results: The median age was 66 years and the median AMC was 550/μL (380–812/ μL, 1st-3rd quartile) at diagnosis (normal range: 300–900/μL). No significant difference in the median AMC was observed by age, gender; CD38, CD49d, or Zap-70 expression; IGHV gene mutation status or cytogenetic findings. Patients were followed for a median of 3.2 years (range: 0–10.3), with disease progression requiring the initiation of treatment observed in 268 (28%) patients. On multivariate analysis using a Cox proportional hazards model which incorporated age, gender and Rai stage, the AMC (as a continuous variable) was associated with TTFT with a hazard ratio (HR) of 1.099 (per unit change; 95% CI, 1.003–1.205; p=0.04). The optimal cutpoint for the association between AMC and TTFT was determined to be ≥1, 170/μL, a threshold that remained an independently significant predictor of TTFT after adjusting for age, gender and Rai stage with a HR of 5.1 (95% CI, 2.56–10.10, p