Zent, Clive S.

Radioimmunotherapy (RIT) for relapsed indolent non‐Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B‐cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial, we tested systemic administration of both CpG and RIT. Eligible patients had biopsy‐proven previously treated CD20+ B‐cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m2 days 1,8, and 15; 111In‐ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of 90Y‐ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hr without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18‐NR); and median duration of response (DR) of 35 months (4.6–76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation. Am. J. Hematol. 88:589–593, 2013. © 2013 Wiley Periodicals, Inc.

Key Points Lenalidomide consolidation repairs T-cell immune synapses in CLL patients. Lenalidomide consolidation improved the quality of response in CLL patients treated with chemoimmunotherapy.

To clarify the presentation and course of patients with chronic lymphocytic leukemia (CLL) and amyloidosis. Mayo databases were interrogated for patients who carried a diagnosis of amyloidosis and CLL evaluated at Mayo Clinic, Rochester from January 1974 to October 2012. Charts were abstracted and data analyzed. Of the 33 patients identified, 20 (61%) were diagnosed with AL and 13 (39%) with non‐AL. Only four patients had immunoglobulin light chain amyloidosis (AL) that could be solely attributed to the CLL clone; another six had both a plasma cell clone and a CLL clone that shared the same light chain. Median overall survival was 15.6 months for patients with AL and 58.1 months for patients with non‐AL. For patients with AL management involved chemotherapy targeted toward monoclonal plasma cells, lymphocytes or both, and for patients with non‐AL no specific amyloid treatment was administered. AL is a rare complication of CLL, but in this elderly population of patients non‐AL is nearly as common. Distinguishing between these two groups is essential since patients with non‐AL amyloidosis have better outcomes and they do not require cytotoxic chemotherapy to treat their amyloidosis. Am. J. Hematol. 88:375–378, 2013. © 2013 Wiley Periodicals, Inc.

AbstractFree light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Monoclonal FLC and polyclonal FLC were associated with poor overall survival compared with patients with normal FLC. Results remained significant after adjusting for Rai stage. The FLC assay is a simple, widely available clinical test with similar prognostic utility as routinely used prognostic biomarkers for CLL. Among persons with FLC abnormalities, the type of abnormality affects prognostic significance.

Abstract Background. Vitamin K1 (phylloquinone) is a fat soluble vitamin found mainly in green leafy vegetables, with smaller amounts found in other vegetables, vegetable oils, and some fruits. Vitamin K-dependent gamma-carboxylation of specific glumatic acid residues is critical to the functioning of several key proteins in the coagulation cascade. Vitamin K compounds also inhibit IL-6 and other inflammatory cytokines and serve as transcription factors that foster cell-cycle arrest and apoptosis, pathways relevant to lymphomagenesis. We tested the hypothesis that dietary and supplemental intake of Vitamin K was inversely associated with risk of NHL and the common subtypes of diffuse large B cell, follicular, and chronic lymphocytic leukemia/small lymphocytic lymphomas. Methods. We evaluated dietary and supplemental intake of vitamin K and NHL risk in a clinic-based study of 603 newly diagnosed NHL cases and 1007 frequency-matched controls enrolled at the Mayo Clinic from 2002-2008. Usual diet two years before case diagnosis or control enrollment was assessed using a self-administered, 128-item food frequency questionnaire. Dietary intake of vitamin K was estimated using the Food Processor SQL system. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, and total energy. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results. The mean age at diagnosis was 60.8 years for cases and 57% were male; for controls, the mean age at enrollment was 60.1 years and 53% were male. Median intake of vitamin K from diet among controls was 63.5 ug/day; 16% used a multivitamin supplement that included vitamin K. NHL risk was inversely associated with intake of dietary vitamin K (p-trend=0.001); compared to intake <39.3 ug/d, risk was decreased for intakes of 39.3-63.4 ug/d (OR=0.76; 95% CI 0.57-1.02), 63.5-107.7 ug/d (OR=0.74; 95% CI 0.55-1.00), and >107.7 (OR=0.56; 95% CI 0.40-0.77). There was an U-shaped association for supplemental intake of Vitamin K and NHL risk; compared to no use, supplemental intake of <5.9 ug/d (OR=0.63; 95% CI 0.37-1.08) and 5.9-17.6 ug/d (OR=0.53; 95% CI 0.30-0.93) were inversely associated with NHL risk, while intake of >17.6 ug/d (OR=1.13; 95% CI 0.73-1.74) showed no association. There was no evidence of heterogeneity by NHL subtype (p=0.4). Further adjustment for education, family history of NHL, pack-years of smoking, body mass index, and alcohol consumption did not alter these results, nor did adjustment for a food-frequency questionnaire-based estimate of total antioxidant intake. Conclusion: Higher intake of vitamin K from the diet was inversely associated with risk of NHL overall and for the major subtypes. These first results, which require replication, suggest that the coagulation pathway or other biologic effects of vitamin K may play a role in lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2811.

Abstract 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.

Chronic lymphocytic leukemia (CLL) patients with p53 pathway dysfunction have poor responses to conventional chemoimmunotherapy and short survival. This small but important cohort of CLL patients would benefit from early identification and appropriate management. The challenge is to develop clinically useful tests of p53 pathway function.

Purpose The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients with a circulating population of clonal B cells, a total B-cell count of less than 5 × 109/L, and no other features of a B-cell lymphoproliferative disorder including lymphadenopathy/organomegaly. The natural history of clinically identified MBL is unclear. The goal of this study was to explore the outcome of patients with MBL relative to that of individuals with Rai stage 0 chronic lymphocytic leukemia (CLL). Patients and Methods We used hematopathology records to identify a cohort of 631 patients with newly diagnosed MBL or Rai stage 0 CLL. Within this cohort, 302 patients had MBL (B-cell counts of 0.02 to 4.99 × 109/L); 94 patients had Rai stage 0 CLL with an absolute lymphocyte count (ALC) ≤ 10 × 109/L; and 219 patients had Rai stage 0 CLL with an ALC more than 10 × 109/L. Data on clinical outcome were abstracted from medical records. Results The percentage of MBL patients free of treatment at 1, 2, and 5 years was 99%, 98%, and 93%, respectively. B-cell count as a continuous variable (hazard ratio [HR] = 2.9, P = .04) and CD38 status (HR = 10.8, P = .006) predicted time to treatment (TTT) among MBL patients. The likelihood of treatment for MBL patients was lower (HR = 0.32, P = .04) than that of both Rai stage 0 CLL patients with an ALC less than 10 × 109/L (n = 94) and Rai stage 0 CLL patients with an ALC more than 10 × 109/L (n = 219; P = .0003). Conclusion Individuals with MBL identified in clinical practice have a low risk for progression at 5 years. Because B-cell count seems to relate to TTT as a continuous variable, additional studies are needed to determine what B-cell count should be used to distinguish between MBL and CLL.