The Impact of Race, Age, and Sex in Chronic Lymphocytic Leukemia (CLL): A Comprehensive SEER Analysis in the Pre and Post Rituximab (R) Eras.

Abstract Abstract 2877 Background: Racial disparity has been well documented in a number of cancers but the impact of race on CLL in the contemporary era is unclear. While preliminary evidence suggests that Black (B) patients (pts) have worse survival than their White (W) counterparts (Shenoy et al, Clin Lymph Myleoma Leuk, 12/2011), the importance of sex, age, socioeconomic status (SES), and whether the wide use of single use or combined therapy with R in CLL over the last decade plus has affected overall survival (OS) have not been fully explored. Further, outcome of Hispanic (H) and Asian/Pacific Islanders (A/PI) CLL pts has not been fully studied. Methods: We examined population based survival data from SEER 13 (1993–2008) for CLL within and across various races. We also investigated the impact of sex, age, and socioeconomic status (SES) on their clinical outcome. Outcomes were examined over two consecutive 8-year (yr) periods: Era-1 (1993–2000) and Era-2 (2001–2008) with the assumption of R therapy in CLL patients being more frequent after 2001 (market research data not shown). Results: We identified 24,964 pts [W =21,363 (85.5%), H =1,197 (4.7%), B =1,709 (6.8%), and A/PI =695 (2.7%)]. Differences were notable for a greater male predominance among A/PI [62% vs. 57% (B), 56% (H), 58% (W); P=0.03]; a higher proportion of pts >80 among W [22% vs. 17% (H), 15% (B), 16% (A/PI); P<0.001], and higher SES among A/PI and W pts compared to B and H (P<0.001). OS for all patients was significantly better in Era-2 vs. Era-1 at 5-yrs (65% vs. 60.4%, P<0.0001). This improvement was statistically significant in all races except A/PI pts (P=0.71) (Table). Improved survival across eras was also noted in all age groups (<50 (P<0.00001), 50–59 (P=0.007), 60–69 (P<0.0001), 70–79 (P<0.0001), >80 yrs (P<0.0001)). Further, improved OS was noted in the two SES classes evaluated (0–15% and 15.1–30% below poverty line respectively). While there were no statistical differences between males and females within either era, improvement in OS was noted in both sexes in Era-2 versus Era-1 (P<0.0001). We subsequently compared OS within and across races (Table). Despite the fact that OS improved in all races, W pts continued to have better OS in Era-2. In Era-1, while W pts had better OS than B and H pts, the OS is similar between W and A/PI. Although OS improved in all SES classes, patients with higher SES continued to have better OS in Era-2 (P<0.0001 for both). Conclusions: The OS of CLL pts has improved in the contemporary era for both sexes, all age groups, and all races except A/PI individuals. The improvement in outcome in Era-2 might be partially explained by increased use of R and other novel agents that became available after 2001. Despite the broad nature of these improvements, racial and SES differences in the survival persist and deserve further validation and pursuit of the causes. Disclosures: Shanafelt: Genentech: Research Funding; GlaxoSmith Klein: Research Funding; Teva/Cephalon: Research Funding; Celgene: Research Funding. Kay:Genentech: Research Funding; Glaxosmith Klein: Research Funding.

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Retrospective Analysis of Clinical Parameters and Survival Data in Patients with Chronic Lymphocytic Leukemia of Younger Versus Older Age Groups.

Blood ◽

10.1182/blood.v106.11.5001.5001 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5001-5001

Author(s):

Abraham Klepfish ◽

M. Sarid ◽

M. Basalov ◽

H. Ghoti ◽

E.A. Rachmilewitz

Keyword(s):

General Population ◽

Survival Data ◽

Older Patients ◽

Survival Curve ◽

Severe Disease ◽

Age Groups ◽

Lymphocytic Leukemia ◽

Older Age ◽

Younger Patients ◽

The Impact

Abstract Background Chronic lymphocytic leukemia (CLL), a chronic proliferative disorder of mature-looking B-lymphocytes, is the most common leukemia in the western world. CLL is a disease of elderly, with only 10–15% of patients affected at the age of less than 50 years. It is still controversial whether the clinical features and the impact on survival are different between younger and older patients, since the standard statistical methods produce contradicting results. In the present retrospective study of 87 CLL patients, we compared the data between patients above and below 65 years. The analysis of the impact of the disease on survival was carried out using a method described below. Methods Medical records and survival data were obtained from 87 patients with CLL treated in our Institute between 1983 and 2003. Statistical analysis of the clinical and laboratory parameters and survival data was performed using standard methods. The survival loss due to the disease as a percent of the expected survival of gender- and age-matched general population was determined, based on the survival analysis method developed and published recently [Klepfish A et al Am J Med.2005;118:567]. In brief, the age- and gender-matched expected survival in the general population was calculated (data obtained from the Central Government Bureau of Statistics). We used the 7th percentile survival (SPS) for further calculation in order to match the duration of the follow-up period between the patients and the general population. The survival loss was calculated by the formula: [(SPSControl - SPSPatients):SPSControl] x 100%. Results The mean age in the younger and older age groups was 56 and 74 years respectively. The male-to-female ratio was 2:1 in both age groups. The disease was found to be twice more common in patients from Ashkenazi compared with Sephardic descent. The younger group of patients had several features indicative of a more severe disease at presentation: advanced stage (Rai 2–4) – 46% vs. 16%, and diffuse involvement of bone marrow −60% vs. 18%. Younger patients were also more likely to require treatment (30% vs. 8% for fludarabine-containing regimens). Although according to the Kaplan-Meyer curve (see Fig.) a more favorable survival was shown for the younger group, the survival loss showed a reversed pattern. While the older patients lost 10% of the SPS, the survival loss in the younger patients was 44% (p=0.001). Conclusions CLL shows a strong male predominance and is more common in Ashkenazi than in Sephardic Jewish population in all ages. CLL has a more unfavorable presentation and a more severe clinical course in the younger patients (age<66) than in the older age group (age>65). The negative impact of the disease on the survival of CLL patients is higher in the younger patients, since their survival loss in comparison with the matched general population was 4.4 times higher, than that of the older patients. This mode of statistical evaluation confirms the impression that CLL is a more severe disease in younger patients. Fig: Kaplan - Meyer Survival Curve of CLL Patients Fig:. Kaplan - Meyer Survival Curve of CLL Patients

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Variation in Health-Related Quality of Life by Age Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.2085.2085 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2085-2085

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Lymphocytic Leukemia ◽

Age Group ◽

Employment Equity ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Equity Ownership

Abstract Abstract 2085 Introduction. Although advanced patient age is commonly used as a factor in selecting therapy for patients with chronic lymphocytic leukemia (CLL), based on presumed associations with functional status, limited data exist regarding the relationships between age and physical, emotional, social, and functional well being. We examined the relationships between age and these domains of health-related quality of life (HRQOL) for CLL patients treated in US community practices. Methods. Baseline data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by patients in the clinic at enrollment. Patients completed 3 psychometrically validated instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BFI, EQ-5D and FACT-Leu scores were analyzed by age group (<65, 65–74, >74). Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Baseline HRQOL data were reported by 604 patients, enrolled from 161 centers. Patients were predominantly male (62%) and white (90%) with mean age at 69.9 (standard deviation [SD] 11.2) yrs. HRQOL scores by age group are presented: There were no significant differences between the age groups in fatigue as measured by the BFI, or differences in overall HRQOL as measured by the EQ-5D Visual Analogue Scale (VAS) or the FACT-G. Anxiety/depression and self care are EQ-5D domains that also did not vary by age. Although mobility was most impaired in the oldest age group compared to the two younger groups, usual activities and pain/discomfort were worse in both the younger and older cohorts compared to those 65–74 years of age. FACT-Leu results indicated that the social/family domain scores did not vary by age, but that physical, emotional, and functional domains did vary statistically with the oldest typically doing better than the 65–74 year olds, but not necessarily better than those <65. Conclusions. Initial results from the Connect CLL® Registry indicate that HRQOL does not worsen monotonically with older age. In this cohort, both the youngest and oldest age groups had worse HRQOL in certain domains, presenting an inverted v-shaped relationship. Future analyses should be conducted on: (1) how HRQOL may be affected over time with changes in disease; and, (2) how HRQOL may be influenced by alternative therapies. Results reported here should serve as a useful baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Immunophenotypic Profile and Recurrent Somatic Mutations in 131 Chronic Lymphocytic Leukemia Patients: Low Expression of CD25 in NOTCH1-Mutated Cases

Blood ◽

10.1182/blood.v128.22.3201.3201 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3201-3201

Author(s):

Miriam Castillo ◽

Ana María Hurtado ◽

Tzu Hua Chen-Liang ◽

Julia Muñoz-Ballester ◽

Bartlomiej P Przychodzen ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Somatic Mutations ◽

Lymphoblastic Leukemia ◽

Lymphocytic Leukemia ◽

Limited Information ◽

Male Predominance ◽

Mutational Status ◽

The Impact ◽

Notch1 Mutations ◽

Low Expression

Abstract Background: We and others have reported on the impact of recurrent somatic mutations not only in the multistep pathogenetic process, but also in the clinical heterogeneity of chronic lymphocytic leukemia (CLL) patients. Immunophenotyping, as part of the diagnostic workout, is used for assessing clonality, as a differential diagnosis tool, and to examine the expression of molecules associated with a worse prognosis. Recently, NOTCH1 mutations have been linked to low CD20 levels in CLL and with a relative resistance to anti-CD20 immunotherapy in vitro. But to date, there is limited information on the correlation between cell surface marker expression and the presence of somatic mutations in CLL. The aim of this study was to evaluate potential associations between an extended phenotypic panel and the mutational status of 13 recurrently mutated genes in CLL detected by deep sequencing. Patients and Methods: To this end, we performed targeted NGS sequencing of blood samples, collected at diagnosis, from 131 CLL patients. Every patient underwent, at baseline, a flow cytometry characterization with a panel including (sIg)λ, (sIg)κ, CD19, CD5, CD11b, CD81, CD10, CD79b, CD29, CD38, FMC7, CD22, CD45, CD103, CD11c, CD25, ZAP70, CD11a, and CD24. We designed a TruSeq Custom Amplicon panel (Illumina, Inc. San Diego, CA, USA) containing 13 genes and covering 28.099 bases. The average amplicon size was 238 base pairs and ~ 99.1% of the regions were covered on both strands. Paired-end sequencing (2x250 bp) was performed with MiSeq v2.2 chemistry, and a mean depth of 998 reads/base within the regions of interest was obtained. Raw data were analyzed with IlluminaonJboard Real Time Analysis (RTA v.2.4.60.8) software and MiSeq Reporter. Results: With a median age of 68 y.o. (range, 33-95) and a slight male predominance, the median follow up time of our cohort was 43 months (24-104). We found that 47/131 (35%) patients harbored at least one mutation, with NOTCH1 (n = 13, 10%), ATM (n = 10, %), TP53 (n = 8, %), and SF3B1 (n = 8, 5.5%), as the most frequently mutated genes. Those patients with a NOTCH1 mutation showed a lower CD25 expression (25 mean fluorescence intensity units (MFIu)) than those without a mutation (45 MFIu), p=0.001. In addition, a higher expression of CD5 (265 vs. 219 MFIu, p= 0.02), of the monoclonal light chain (90.5 vs. 58.6 MFIu, p=0.03), and a higher percentage of CD38+ cells in the CD19+CD5+ compartment (37% vs. 19%, p=0.006) were significantly associated with the presence of, at least, one somatic mutation. We could not validate the recently reported association between the presence of NOTCH1 mutations and a low expression of CD20. In our cohort, the MFI expression in NOTCH1 mutated and non-mutated patients was 176 and 135 units, respectively (p=0.2) In the multivariate Cox analysis, the presence of a somatic variant in TP53 and a higher percentage of positive CD38 cells in the tumour population showed both a worse overall survival and shorter time to first treatment. The independence of these two variables was also supported by not finding a significative difference percentage of CD38 positive cells between TP53 mutated and non mutated cases (p=0.5). Conclusions: The associations described herein suggest potential pathogenic pathways in CLL, in particular the CD25-NOTCH1 axis, with a significative inferior expression of CD25 when activating NOTCH1 mutations are present. The relationship found between these two variables, with an inversed direction to that found in physiological conditions, has also been shown in the setting of NOTCH1-mutated acute lymphoblastic leukemia, emerging as a potential targetable pathway in this subset of CLL patients. Disclosures Maciejewski: Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

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Impact of genomic alterations (GAs) on outcomes and their distribution by age groups in metastatic colorectal cancer (mCRC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.560 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 560-560 ◽

Cited By ~ 1

Author(s):

Ibrahim Halil Sahin ◽

Wanqi H Chen ◽

Zhengjia Chen ◽

Mehmet Akce ◽

Olatunji B. Alese ◽

...

Keyword(s):

Survival Data ◽

Cox Model ◽

Prognostic Significance ◽

Age Groups ◽

Survival Outcomes ◽

Age Group ◽

Term Survival ◽

Exact Test ◽

Initial Stage ◽

The Impact

560 Background: Although clinical outcomes has substantially improved over the last decade, long term survival in mCRC remains rare. Molecular profiling (MP) of CRC is routinely conducted to identify potential therapeutic targets. The aim of this project is to evaluate the impact of uncommon GAs on outcomes and characterize their distribution by age. Methods: Pts were eligible if they had mCRC (synchronous or metachronous) and underwent MP between 01/2013 and 05/2018. GAs were obtained from Foundation Medicine reports. Clinical data were collected by trained personnel by detailed chart review. Multivariable survival analyses (MA) with Cox model were conducted for survival outcomes and Fisher’s exact test was used to assess the differences among age groups (< 45, 45-60, > 60). The study was reviewed by Institutional IRB ( IRB00097021 ). Results: 161 patients with mCRC had MP, and 159 of those patients had survival data. The most commonly detected GAs were APC (133/161, 82.6%) TP53 (128/161, 79.5%). In univariate analyses mutations in BRCA 1/2, RB1, SOX9, CDK8, FLT3, and IRS2 amplification were associated with worse survival outcomes. In MA, including initial stage of disease, GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 remained statistically significant (Table). When we performed MA by age groups, mutations SOX9 in age group < 45 and BRCA1/2 in age group 45-60 were significant predictors of worse outcomes. We also compared the frequency of mutations among age groups and FAM123B was significantly more common in age group 45-60 (P = 0.038). Conclusions: Our data suggests that GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 may predict worse outcomes in mCRC. Therapeutic approaches targeting these pathways should be investigated. Differences in distribution and prognostic significance of mutations were observed based on age. [Table: see text]

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CD49d Is The Strongest Flow Cytometry-Based Predictor Of Overall Survival In Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.672.672 ◽

2013 ◽

Vol 122 (21) ◽

pp. 672-672 ◽

Cited By ~ 1

Author(s):

Pietro Bulian ◽

Tait D Shanafelt ◽

Chris Fegan ◽

Antonella Zucchetto ◽

Lilla Cro ◽

...

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Early Stage ◽

Cox Model ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Bivariate Analysis ◽

The Impact

Abstract Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multi-center analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as overall survival (OS) and treatment free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cut-off. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLL, and Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥30% of neoplastic cells expressing CD49d were considered CD49d+. The decrease in OS at 5 and 10-years among CD49d+ cases was 7% and 23% (decrease in TFS 26% and 25% respectively). The pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR=2.0) in a Cox model adjusted for clinical and biological prognosticators. Hierarchical trees including all cases, or restricted to early stage or patients ≤65 years, always selected CD49d as the most important flow-cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patients' subsets with poorer outcome independent of CD38 and ZAP-70. Conclusions In this analysis of ∼3000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Burger:Pharmacyclics: Research Funding.

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Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment

Blood ◽

10.1182/blood-2018-99-118916 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3132-3132

Author(s):

Bryce Manso ◽

Kimberly Gwin ◽

Charla R Secreto ◽

Henan Zhang ◽

Wei Ding ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Healthy Controls ◽

Advisory Committees ◽

The Impact

Abstract Peripheral immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) is well-studied and likely relates to the incidence of serious recurrent infections and second malignancies that plague CLL patients. However, the current paradigms of known immune abnormalities are not able to consistently explain these complications and it is not easy to correct CLL patient immune status. Here, we expand on our preliminary reports that demonstrate bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced short-term functional capacity of hematopoietic progenitors in BM using colony forming unit assays (Figure 1A-C) and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations (exemplified by Lin-CD34+ HSPCs, Figure 1D). We further report that protein levels of the transcriptional regulators HIF-1α, GATA-1, PU.1, and GATA-2 are overexpressed in distinct HSPC subsets from CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Interestingly, sustained myelopoiesis, evaluated by limiting dilution analysis in long-term culture-initiating cell (LTC-IC) assays maintained for five weeks, revealed no difference between healthy controls and CLL patients. These new data indicate that when HSPCs are removed from the leukemic microenvironment for ample in vitro culture time, they recover the ability to sustain myelopoiesis. To further assess the impact of the CLL microenvironment on HSPC biology, isolated HSPCs (CD34+ BM cells) from healthy controls were exposed in vitro to known leukemic microenvironment constituents. Exposure to TNFα, a cytokine constitutively produced by CLL B cells, resulted in rapid increases in PU.1 and GATA-2 proteins (Figure 2A-D). Similarly, addition of TNFα to the LTC-IC assay resulted in a striking ablation of myelopoiesis, even at the highest input cell concentration. Further, overexpression of PU.1 and GATA-2 were observed in HSPCs following co-culture with CLL B cells, a result that was not recapitulated when cells were exposed to IL-10, another cytokine constitutively produced by CLL B cells. These findings indicate specific components of the leukemic microenvironment are involved in HSPC modulation. Together, these findings expand on our previous observations of BM hematopoietic dysfunction in untreated CLL patients and offer new molecular insights into the contribution of the leukemic microenvironment on immunodeficiency in CLL. Disclosures Ding: Merck: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Chemoimmunotherapy for Patients with Chronic Lymphocytic Leukemia: MD Anderson Experience Beyond FCR300

Blood ◽

10.1182/blood.v128.22.2047.2047 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2047-2047 ◽

Cited By ~ 1

Author(s):

Dai Chihara ◽

Philip A Thompson ◽

Hagop M. Kantarjian ◽

Susan M. O'Brien ◽

Alessandra Ferrajoli ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Risk Model ◽

Lymphocytic Leukemia ◽

Cox Proportional Hazards Model ◽

High Dose ◽

First Line ◽

Ighv Gene ◽

The Impact

Abstract Background: Novel, targeted therapies, such as ibrutinib, have transformed outcomes for patients with relapsed CLL and for older and unfit patients in the first-line setting. However, chemoimmunotherapy (CIT) remains the standard-of-care in fit patients. We reported that a subgroup of patients with IGHV mutated CLL experience prolonged PFS and potential cure after first-line CIT withfludarabine, cyclophosphamide and rituximab (FCR). However, FISH data was not available for this cohort of patients. Accurate knowledge of which patients are likely to experience prolonged PFS after FCR is essential to better select patients who may benefit from CIT in the era of novel therapies. Patients and Methods: We analyzed 492 patients who were treated on six clinical trials of first-line CIT between 2004 and 2015. Treatments were FCR, (n=277) FCR with high dose rituximab (n=65), FCR plusmitoxantrone (n=30), FCR plusalemtuzumab (n=60) and FCR with GM-CSF (n=60). Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes using a Cox Proportional Hazards model. Cumulative incidence was calculated by competing risk (death without event) regression analysis. Results: The median age of patients was 59 (range 28-84). Sixty-seven percent of the patients were male, 33% of the patients had mutated IGHV gene. Thirty percent of patients had del(13q), 19% had Trisomy12, 21% had del(11q), 8% had del(17p) and 21% were negative by FISH. Fifty-nine percent of patients received six cycles of CIT. With a median follow up duration of 6.2 years, the median PFS and OS were 6.3 years and not reached, respectively. Recently reported risk model by Rossi and colleagues using IGHV mutation status and FISH results (Blood 2015) discriminated PFS very well; 5-year PFS for low risk {mutated without del(11q)}, intermediate risk {unmutated or del(11q)} and high risk group {del(17p)} were 81%, 45% and 22%, respectively. Of note, there was a plateau in PFS after 8 years in patients with mutated IGHV gene, with 10-year PFS of 63% (Figure A). There was a significantly improved OS after relapse by the time. Three-year OS in patients who started salvage chemotherapy in 2004 to 2012 and 2012 to 2016 were 59% and 83%, respectively, suggesting the impact of improved salvage treatment options, particularly B cell signaling pathway inhibitors (Figure B). Five-year cumulative incidence of Richter transformation (RT) and AML/MDS was 4.8% and 4.2%, respectively (Figure C, D). There was a difference in onset for these two complications; 52% of RT occurred within 2 years, while 62% of AML/MDS occurred in 2-4 years after CIT. Overall, 110 patients (22.4%) died during the follow-up; the three major causes of death were CLL progression (4.9%), Richter transformation (3.7%) and AML/MDS (3.3%). Conclusion: Patients with mutated IGHV gene and who do not have del(11q) or del(17p) have favorable outcomes and demonstrate a plateau on the PFS curve, consistent with prior studies. Effective salvage therapy has improved outcomes at relapse, but the development of RT and AML/MDS remain major causes of mortality in CLL patients. Given favorable outcomes for patients with mutated IGHV gene treated with FCR, further studies are warranted to identify predictors of non-response among the mutated patients, risk factors for development of AML/MDS and RT and whether choice of first-line therapy can modulate this risk. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jain:Servier: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Infinity: Research Funding. Wierda:Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

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The Impact of Race, Age, and Sex in Follicular Lymphoma (FL): A Comprehensive SEER Analysis in the Pre- and Post-Rituximab Eras

Blood ◽

10.1182/blood.v120.21.1576.1576 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1576-1576

Author(s):

Chadi Nabhan ◽

Briseis Aschebrook-Kilfoy ◽

Brian C-H Chiu ◽

Kimberly Kruczek ◽

Anand Patel ◽

...

Keyword(s):

Socioeconomic Status ◽

Racial Disparity ◽

Conflicts Of Interest ◽

Age Groups ◽

Population Based ◽

Low Ses ◽

Asian Pacific Islander ◽

Asian Pacific ◽

The Impact ◽

Persistent Inequality

Abstract Abstract 1576 Background: While racial disparity has been documented in a number of cancers, the impact of race, sex, and socioeconomic status (SES) on FL outcomes is not well defined. Furthermore, the impact of modern therapeutics on these disparities has not been fully explored. Methods: We examined population-based FL overall survival (OS) data from SEER 13 (1993–2008) for race, sex, age, and socioeconomic status (SES) over two consecutive 8-year periods: Era 1 (1993–2000, n=7,409) and Era 2 (2001–2008, n=9,083). Results: We identified a total 16,492 FL patients (pts) (white (W): n=13,441 (81.5%); Hispanic (H): n=1,417 (8.5%); Asian/Pacific Islander (A/PI): n=887 (5.3%); and Black (B): n=747 (4.5%)). Median age at diagnosis differed significantly according to race: (in years, yrs) W: 62.1, H: 57.3, A/PI: 60.5, B: 56.6; P<0.01 for each race vs. W. For all pts, OS was superior in Era 2 vs. Era 1 (5-yr OS: 77% vs. 68%, respectively, P<0.0001). Further, OS was significantly improved for all age groups (<50, 50–59, 60–69, and 70–79 yrs) as well as for males (P=0.0019) and females (P<0.0001) across eras. Interestingly, females had superior OS compared with males in Era 1 (P=0.004), but not in Era 2 (P=0.83). We subsequently compared OS within and across races (see Table). All races, except A/PI, had improved 5-yr OS rates (age adjusted) from Era 1 to Era 2 (W: <0.001, H: 0.049, A/PI: 0.15, B: 0.003). Notably, A/PIs had the highest OS in Era 1, while H had the poorest OS in Era 2. These differences were more evident in males compared with females within each race. Finally, pts with higher SES had improved OS compared with low SES in both eras (P=0.02 in era 1 and <0.0001 in era 2), although OS was improved across eras within low and high SES populations (P<0.0001). Conclusions: Collectively, we identified improved OS in FL across eras, which was apparent for all ages, both sexes, and all races. However, racial disparities persist, including inferior OS for H and superior OS for A/PIs in the contemporary era. The disproportionate improvement in OS over eras and persistent inequality in outcomes based on race warrants continued examination. Disclosures: No relevant conflicts of interest to declare.

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Age Differences in Disease Characteristics, Patterns of Care, and Outcomes of Follicular Lymphoma (FL) in the United States (US): Report From the National Lymphocare Study (NLCS)

Blood ◽

10.1182/blood.v120.21.3708.3708 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3708-3708

Author(s):

Chadi Nabhan ◽

Michelle Byrtek ◽

Shadi Latta ◽

Keith L Dawson ◽

Xiaolei Zhou ◽

...

Keyword(s):

Research Funding ◽

Age Groups ◽

Age Group ◽

Employment Equity ◽

Disease Characteristics ◽

Baseline Factors ◽

Equity Ownership ◽

Grade 3 ◽

The Impact ◽

To Receive

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

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Ibrutinib for Bridging to Allogeneic Hematopoietic Stem Cell Transplantation (alloHCT) in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) Is Safe and Effective: First Results of a Survey By the Chronic Malignancy and the Lymphoma Working Parties of the EBMT

Blood ◽

10.1182/blood.v128.22.4657.4657 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4657-4657 ◽

Cited By ~ 5

Author(s):

Peter Dreger ◽

Mauricette Michallet ◽

Jennifer Hoek ◽

Ariane Boumendil ◽

Mohamad Sobh ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Gvhd ◽

Disease Status ◽

Observation Time ◽

Lymphocytic Leukemia ◽

Hematopoietic Stem ◽

The Impact

Abstract BACKGROUND: The advent of the Bruton's tyrosine kinase inhibitor ibrutinib has improved the outlook of patients with CLL and MCL failing chemoimmunotherapy (CIT). However, the impact of ibrutinib on the feasibility and safety of a subsequent alloHCT is unknown. Here we present results of the ibrutinib cohort of an ongoing EBMT survey on the outcome of alloHCT following prior exposure to pathway inhibitors (PI) in patients with CLL or lymphoma (EBMT study code LWP 2013-N-03/CMWP 44204425). DESIGN: Eligible were patients aged >18 years registered with the EBMT data office for a planned alloHCT for CLL or lymphoma after pre-exposure to ibrutinib at any time before transplant. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers were requested to provide additional treatment and follow-up information. Statistical analysis used Gray's test to assess the impact of baseline characteristics on the cumulative incidence of relapse (REL) in a competing risk framework. RESULTS: As of July 4, 2016, 38 patients (84% male) were evaluable in the ibrutinib cohort. Diagnosis was CLL in 28 patients, MCL in 9 patients, and follicular lymphoma (FL) in 1 patient. The median age was 51 (33-68) years and the median number of treatment lines prior to ibrutinib 2 (1-9). Eight of the 9 patients with MCL but none of the other patients had a prior autoHCT. Patients had been on ibrutinib for a median of 190 (39-432) days. In 2 patients, ibrutinib had been stopped because of disease progression >100d before transplant, whereas the interval between ibrutinib withdrawal and alloHCT was 15-100d in 30%, 4-14d in 51%, and 0-1d in 14% of the patients. Of the CLL patients, 43% had a TP53 lesion, and 87% and 79% met at least one of the 2007 and 2014 EBMT criteria for high-risk CLL, respectively, including PI failure in 29%. Disease status at alloHCT was sensitive in 78% of the CLL patients, and in 60% of the patients with lymphoma. Conditioning was reduced-intensity in 60% of the transplants and included in-vivo T cell depletion with ATG (71%) or alemtuzumab (11%) in the majority of cases. Donors were identical siblings in 26%, matched unrelated in 66%, and partially matched unrelated in 8%, with PBSC (89%) being the predominant stem cell source (bone marrow 8%, cord blood 3%). The median time to reach neutrophils of >0.5/nl and platelets of >20/nl was 17 (10-26) and 15 (10-46) d post transplant, respectively. Acute GVHD grade 2-4 (3-4) was observed in 37% (10%) of 30 evaluable patients, and limited and extensive chronic GVHD occurred in 24% and 16% of 25 patients at risk. With a median observation time of survivors of 8 (1-24) months, there were only 2 non-relapse deaths, translating into a 1-year non-relapse mortality (NRM) of 6% (95%CI 0-15%). 1-year REL, progression-free survival, and overall survival was 36%, 61%, and 73% for CLL, and 14%, 75%, and 75% for lymphoma. In the 25 evaluable patients with CLL, PI-sensitive compared to refractory disease status at alloHCT tended to be associated with a lower 1-y REL (29% vs 60%; p 0.071), whereas prior PI failure, TP53 status, duration of ibrutinib exposure, interval between ibrutinib withdrawal and alloHCT, and conditioning intensity had no significant impact on REL. CONCLUSIONS: Ibrutinib for bridging to alloHCT for CLL and MCL does not appear to adversely affect engraftment, GVHD risk, and NRM. Patients with CLL still responding to ibrutinib at the time of alloHCT might benefit from ibrutinib bridging as our preliminary results indicate that also after PI exposure sensitive disease translates into a lower risk of relapse. Therefore, ibrutinib may improve the perspective of CIT-refractory patients scheduled for alloHCT. The optimum timing of ibrutinib administration in the interrelation to alloHCT in CLL and MCL needs to be defined by additional studies. Disclosures Dreger: Gilead: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Berg:Celgene: Other: Travel Funding; Astellas: Other: Travel Funding; Alexion: Other: Travel Funding. Niederwieser:Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Montoto:Gilead: Research Funding; Roche: Honoraria. Schetelig:Sanofi: Honoraria.

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