Impact of type 2 diabetes on mortality, cause of death, and treatment in chronic lymphocytic leukemia.

Age-related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine-Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first-line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co-occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research.

Impact of concurrent indolent lymphoma on the clinical outcome of newly diagnosed diffuse large B-cell lymphoma.

Some patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell-like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio [HR] = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.

Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era.

The development of cardiovascular disease (CVD) in long-term survivors of lymphoma is of increasing importance. Here, we characterize the cumulative incidence and risk factors for CVD in lymphoma patients diagnosed in the current treatment era. From 2002-2015, newly diagnosed lymphoma patients (>18 years) were enrollment into a prospective cohort study that captured incident CVD, consisting of congestive heart failure (CHF), acute coronary syndrome (ACS), valvular heart disease (VHD), and arrhythmia. The cumulative incidence of CVD was calculated with death modeled as a competing risk. We estimated the association of treatment with anthracyclines or radiotherapy and traditional CVD risk factors with incidence of CVD using hazard ratios (HR) and 95% confidence intervals (CI) estimated from Cox regression. After excluding prevalent CVD at lymphoma diagnosis, the study consisted of 3063 patients with a median age of 59 years (range 18-95). The cumulative incidence of CVD at 10-years was 10.7% (95% CI, 9.5%-12.1%). In multivariable analysis, increasing age (HR = 1.05 per year, p < 0.001), male sex (HR = 1.36, p = 0.02), current smoker (HR = 2.10, p < 0.001), BMI > 30 kg/m2 (HR = 1.45, p = 0.01), and any anthracycline treatment (HR = 1.57, p < 0.001) were all significantly associated with risk of CVD. Anthracyclines were associated with increased risk of CHF (HR = 2.71, p < 0.001) and arrhythmia (HR = 1.61, p < 0.01), but not VHD (HR = 0.84, p = 0.58) or ACS (HR = 1.32, p = 0.24) after adjustment for CVD risk factors. Even in the modern treatment era, CVD remains common in lymphoma survivors and preventive efforts are required that address both treatment and CVD risk factors.

Impact of metformin use on the outcomes of newly diagnosed diffuse large B-cell lymphoma and follicular lymphoma.

The diabetes mellitus (DM) drug metformin targets mechanistic/mammalian target of rapamycin and inhibits lymphoma growth in vitro. We investigated whether metformin affected outcomes of newly diagnosed diffuse large B-cell (DLBCL, n = 869) and follicular lymphoma (FL, n = 895) patients enrolled in the Mayo component of the Molecular Epidemiology Resource cohort study between 2002 and 2015. Hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age, sex, body mass index, prognostic index and treatment were used to estimate the association of metformin exposure (No DM/No metformin; DM/No metformin; DM/Metformin) with event-free (EFS), lymphoma-specific (LSS) and overall (OS) survival. Compared to No DM/No metformin DLBCL patients, there was no association of DM/Metformin (n = 48; HR = 1·05, 95% CI 0·59-1·89) or DM/No metformin(n = 54; HR = 1·41, 95% CI 0·88-2·26) with EFS; results were similar for LSS and OS. Compared to No DM/No metformin FL patients, there was no association of DM/Metformin (n = 37; HR = 1·16, 95% CI 0·71-1·89) or DM/No metformin (n = 19; HR = 1·16, 95% CI 0·66-2·04) with EFS; results were similar for LSS. However, DM/Metformin was associated with inferior OS (HR = 2·17; 95% CI 1·19-3·95) compared to No DM/No metformin. In conclusion, we found no evidence that metformin use was associated with improved outcomes in newly diagnosed DLBCL and FL.

The utility of prognostic indices, early events, and histological subtypes on predicting outcomes in non-follicular indolent B-cell lymphomas.

Indolent B-cell lymphomas other than follicular lymphoma account for up to 10% of all B-cell neoplasms. While they typically follow a slowly progressive course, some patients experience rapid progression and early mortality. Prognostic scoring systems have not been adopted, hindering the ability of clinicians or researchers to predict outcomes, or risk-stratify patients during clinical trials. To address this, we evaluated the utility of existing prognostic indices and novel, early disease-related outcomes, to predict subsequent long term survival. Baseline characteristics and outcomes data were generated from a longitudinal cohort study that prospectively enrolled 632 patients newly diagnosed with marginal zone lymphoma, lymphoplasmacytic lymphomas, or B-cell lymphomas not otherwise specified, beginning in 2002. The International Prognostic Index (IPI), Follicular Lymphoma International Prognostic Index (FLIPI), and MALT International prognostic index (MALT-IPI) demonstrated c-statistics that ranged from 0.593-0.612 for event-free survival (EFS), and 0.683-0.714 for overall survival (OS). Patients who attained event-free survival at 12 months (EFS12) experienced similar mortality to the US general population (standardized mortality ratio [SMR] 1.19; 95% CI 0.95-1.46). Patients who did not attain EFS12 had subsequent worse morality (SMR 3.14 (95% CI 2.05-4.59). The MALT-IPI demonstrated utility in predicting subsequent long-term outcomes among patients with non-follicular indolent B-cell lymphomas. This index should be used by clinicians giving guidance to patients at the time of initial diagnosis, and risk stratification during clinical studies. The divergent long-term outcomes experienced by patients who do or do not attain EFS12 suggest there exists a subset of patients who harbor high-risk disease. Future research efforts should focus on methods to identify these patients at the time of diagnosis, in order to enable risk-tailored therapy.

Human Pegivirus infection and lymphoma risk and prognosis: a North American study.

We evaluated the association of Human Pegivirus (HPgV) viraemia with risk of developing lymphoma, overall and by major subtypes. Because this virus has also been associated with better prognosis in the setting of co-infection with human immunodeficiency virus, we further assessed the association of HPgV with prognosis. We used risk factor data and banked plasma samples from 2094 lymphoma cases newly diagnosed between 2002 and 2009 and 1572 frequency-matched controls. Plasma samples were tested for HPgV RNA by reverse transcription polymerase chain reaction (RT-PCR), and those with RNA concentrations <5000 genome equivalents/ml were confirmed using nested RT-PCR methods. To assess the role of HPgV in lymphoma prognosis, we used 2948 cases from a cohort study of newly diagnosed lymphoma patients (included all cases from the case-control study). There was a positive association of HPgV viraemia with risk of lymphoma overall (Odds ratio = 2·14; 95% confidence interval [CI] 1·63-2·80; P < 0·0001), and for all major subtypes except Hodgkin lymphoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma, and this was not confounded by other lymphoma risk factors. In contrast, there was no association of HPgV viraemia with event-free survival (Hazard ratio [HR] = 1·00; 95% CI 0·85-1·18) or overall survival (HR = 0·97; 95% CI 0·79-1·20) for lymphoma overall, or any of the subtypes. These data support the hypothesis for a role of HPgV in the aetiology of multiple lymphoma subtypes.

Outcomes among North American patients with diffuse large B-cell lymphoma are independent of tumor Epstein-Barr virus positivity or immunosuppression.

The prevalence, presenting clinical and pathological characteristics, and outcomes for patients with diffuse large B-cell lymphoma that is Epstein-Barr virus positive remain uncertain as does the impact of congenital or iatrogenic immunosuppression. Patients with newly diagnosed diffuse large B-cell lymphoma with available tissue arrays were identified from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource. Patients infected with human immunodeficiency virus or who had undergone a prior organ transplant were excluded. Epstein-Barr virus-associated ribonucleic acid testing was performed on all tissue arrays. A history of significant congenital or iatrogenic immunosuppression was determined for all patients. At enrollment, 16 of the 362 (4.4%) biopsies were positive for Epstein-Barr virus. Thirty-nine (10.8%) patients had a significant history of immunosuppression. Patients with Epstein-Barr-positive diffuse large B-cell lymphoma had no unique clinical characteristics but on pathology exhibited a higher frequency of CD30 positivity (25.0% versus 8.1%, respectively; P<0.01), and non-germinal-center subtype (62.5% versus 34.1%, respectively; P<0.01). No baseline clinical characteristics were associated with a history of immunosuppression. With a median follow up of 59 months, and after adjustment for International Prognostic Index, there was no association of Epstein-Barr virus positivity or immunosuppression with event-free survival at 24 months (odds ratio=0.49; 95% confidence interval: 0.13-1.84 and odds ratio=0.81; 95% confidence interval: 0.37-1.77) or overall survival (hazard ratio=0.86; 95% confidence interval: 0.38-1.97 and hazard ratio=1.00; 95% confidence interval: 0.57-1.74). In contrast to non-Western populations, our North American population had a low prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma that did not convey an adverse prognosis. A history of immunosuppression, while known to be a risk factor for the development of diffuse large B-cell lymphoma, did not affect subsequent prognosis.

Quality of life at diagnosis predicts overall survival in patients with aggressive lymphoma.

Our aim was to evaluate whether quality of life (QOL) scores at diagnosis predict survival among patients with aggressive lymphoma. Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE and systematically followed for event-free and overall survival (OS). QOL was measured with the Functional Assessment of Cancer Treatment-General (FACT-G), which measures 4 domains: physical, social/family, emotional, and functional well-being (WB); a single item Linear Analogue Self-Assessment (LASA) measuring overall QOL; and a spiritual WB LASA. From 9/2002 to 12/2009, 701 patients with aggressive lymphoma who completed baseline QOL questionnaires were enrolled. At a median follow-up of 71 months (range 6-128), 316 patients (45%) had an event and 228 patients (33%) died. All baseline QOL measures but emotional WB were significantly associated with OS (all P < 0.04); of which all but LASA spiritual remained significant after adjusting for IPI and NHL subtype. The strongest associations were with total FACT-G (adjusted HR = 0.86, 95% CI: 0.79-0.94, P = 0.00062) and functional WB (adjusted HR = 0.88, 95% CI: 0.83-0.93, P < .0001). QOL LASA was associated with OS (adjusted HR = 0.92, 95% CI: 0.87-0.97, P = 0.0041). Patients with clinically deficient QOL (overall QOL ≤50) had a median OS of 92 months compared with 121 months for patients with QOL >50 (P = 0.0004). In this large sample of patients with aggressive lymphoma, we found that baseline QOL is independently predictive of OS. QOL should be assessed as a prognostic factor in patients with aggressive lymphoma.

The association of physical activity before and after lymphoma diagnosis with survival outcomes.

The impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma-specific (LSS) and event-free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002-2012). We calculated Leisure Score Indexes (mLSI) from the self-reported usual adult PA (baseline) and at 3-years post-diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72-0.94); LSS 0.74 (0.61-0.90); EFS 0.92 (0.82-1.02)] and FU3 [HR (CI): OS 0.64 (0.46-0.88); LSS 0.32 (0.18-0.59); EFS 0.82 (0.61-1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49-1.00) and LSS (HR = 0.49, CI 0.26-0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.

ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.

Early event status informs subsequent outcome in newly diagnosed follicular lymphoma.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc.

Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma.

We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12-88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps.

Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein-10 predicts inferior prognosis in untreated diffuse large B-cell lymphoma.

The detection of serum free light (FLC) is useful in the diagnosis of several hematological diseases. The role and biological relevance of monoclonal or polyclonal FLC elevations in predicting long-term outcome in diffuse large B-cell lymphoma (DLBCL) is unknown. We determined the relationship of the type of FLC elevations to outcome, tumor genotype, and pattern of serum cytokine elevations in 276 patients with untreated DLBCL. Elevated FLC was an adverse prognostic factor through 6 years of follow-up (monoclonal, Event free survival (EFS) HR = 3.56, 95% CI: 1.88-6.76, P <0.0001; polyclonal, EFS HR = 2.56, 95% CI: 1.50-4.38, P = 0.0006). About 73% of DLBCL tumors with monoclonal FLC elevations were activated B-cell type (ABC) versus 33% from patients with normal FLC. Only ABC-DLBCL lines secreted kappa FLC in vitro and this secretion could be inhibited by the NF-κB inhibitor bortezomib. Patients with monoclonal FLC had significantly (all P <0.001) increased serum levels of IL-12, sIL-2Rα, IL-1R, and IP-10. Patients with polyclonal elevations of FLC had higher levels of IL-6 (P = 0.033), IL-8 (P =0.025), sIL2Rα (P = 0.011), and IL-1R1 (P = 0.041). The combination of elevated FLC and a CXC superfamily chemokine IP-10 predicted a particularly inferior outcome characterized by late relapse. These increased abnormal FLC and cytokines are potentially useful biomarkers for prognosis and selecting agents for untreated DLBCL.

Elevated soluble IL-2Rα, IL-8, and MIP-1ß levels are associated with inferior outcome and are independent of MIPI score in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a unique type of lymphoma with a prognosis intermediate between indolent and aggressive types. The purpose of this study was to study blood cytokine levels in newly diagnosed and relapsed MCL patients with respect to patterns of abnormalities and relationship to the MCL International Prognostic Index (MIPI) score. We analyzed blood levels of 30 cytokines using a multiplex ELISA in 88 patients with newly diagnosed MCL (pre-treatment levels) and 20 with relapsed MCL and compared them with controls without known lymphoma. Elevated cytokine levels were compared with clinical outcome and the MIPI score. In the 88 newly diagnosed MCL patients, we found significantly elevated levels compared with controls of IL-12, IP-10, sIL-2Rα, MIG, IL-1RA, IL-8, MIP-1α, and MIP-1ß (all P < 0.05). Of these elevated cytokines, sIL-2Rα, IL-8, MIG, MIP-1α, and MIP-1ß were predictive of inferior event-free survival, and sIL-2Rα (HR = 1.94; P = 0.038), IL-8 (HR = 2.17; P = 0.015), and MIP-1ß (HR = 2.10; P = 0.016) were independent of MIPI score; only sIL-2Rα (HR = 2.35; P = 0.041) was associated with overall survival after adjustment for MIPI. In the relapsed MCL patient group, the only significantly elevated plasma cytokines that predicted EFS were sIL-2Rα (HR = 2.90; P = 0.04) and IL-8 (HR = 3.75; P = 0.02). Elevated blood levels of sIL-2Rα and the pro-inflammatory cytokines IL-8 and MIP-1ß are poor prognostic factors in MCL patients and independent of MIPI score. These factors, if validated, will provide important additions to the MIPI and guide the development of new therapies for patients with elevated levels of these cytokines.

Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

ABSTRACT: High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia.

Free 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.

Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia.

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.

Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas.

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.