scholarly journals Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3323-3323 ◽  
Author(s):  
Lorenzo Falchi ◽  
Michael Keating ◽  
Susan Lerner ◽  
Xuemei Wang ◽  
Kplola Y Elhor Gbito ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Prognostic Impact ◽  
Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence and Implications of Skin Cancers in Cancercare Manitoba Chronic Lymphocytic Leukemia (CLL) Clinic Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4359-4359
Author(s):  
Sara Beiggi ◽  
Mohammad Pannu ◽  
Versha Banerji ◽  
Dhali H.S. Dhaliwal ◽  
Spencer B. Gibson ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Close Monitoring ◽  
Mutational Status ◽  
Skin Cancers ◽  
Increased Risk

Abstract Background:We previously conducted a population-based study on chronic lymphocytic leukemia (CLL) in Manitoba, which showed that second cancers are twice as common and skin cancers eight times as common in this disease, as compared to an age- and sex-matched control population and patients with follicular lymphoma. It is postulated that this is related to immunosuppression, secondary to the disease and chemo-immunotherapy. Here we set out to investigate rates and types of skin cancers in CLL patients and how these influence the outcome of CLL patients. Methods: Newly diagnosed CLL patients attending the CancerCare Manitoba CLL Clinic from the January 1st, 2002 until December 31st, 2012 were selected for this study. Patients were followed until December 31, 2014. Cox Proportional Hazard models were constructed to predict hazard's ratios (HR) and 95% confidence intervals (95% CI) for survival as well as risk of non-cutaneous malignancies. Association between skin cancer and CLL prognostic markers were investigated by Fisher's Exact test, Student's t-test and logistic regression analysis. P-value <0.05 was considered statistically significant. Statistical analysis was performed using SAS Studio 3.5. Results: There were 582 CLL patients in this study. The median age was 67 years (range 36-99 years) with a M:F ratio of 1.6:1. This compares with a median age of 71.5 years and a M:F ratio of 1.3:1 in the Manitoba CLL population. The median follow-up for the study was 5.8 years (range 0.1-13.0 years). There were 131 (23%) CLL patients with at least one skin cancer; 73 (56%) had their first skin cancer before the diagnosis of CLL and 58 (44%) after. Rates of first skin cancer diagnoses were constant before CLL diagnosis (5.2 per 1000 CLL cases), but began to increase three years prior to the CLL diagnosis (10.2 per 1000 CLL cases) and continued to increase after the CLL diagnosis (22.7 per 1000 CLL cases). There were a total of 368 skin cancers; 208 (57%) were basal cell carcinomas (BCC), 92 (25%) were squamous cell carcinomas (SCC), 47 (13%) were Bowen's disease, 18 (5%) were melanomas, and three (1%) were Merkel cell carcinomas. Interestingly, multiple skin cancers with varying histologies occurred in almost half the patients. When the total number of skin cancers/year was assessed, the number started to increase seven years before the CLL diagnosis and continued to increase yearly after the CLL diagnosis. Within the follow-up period, 154 (27%) patients died, with the major causes of death being CLL and second malignancies. However, the presence of skin cancers did not appear to influence survival. There were a total of three deaths due to skin cancers; two patients died of melanoma and one from BCC. However, the presence of a skin cancer, in CLL cases without a history of a solid tumor, increased the risk of a non-cutaneous malignancy by seven-fold (HR 7.55, 05% CI 3.92 - 14.53, p<0.0001). The presence of a skin cancer prior to the diagnosis of CLL did not predict CLL aggressiveness at diagnosis, as evaluated by Rai stage, Zap-70 or CD38 status, immunoglobulin levels or IGHV mutational status. However, for those patients developing their first skin cancer after the CLL diagnosis, the risk of developing a skin cancer correlated with the unmutated IGHV status (HR 1.54, 95% CI 1.01 - 2.34, p=0.0462) and baseline CD38 positivity (HR 1.58, 95% CI 1.02 - 2.44, p=0.0405). Interestingly, the risk of developing skin cancer was not increased by chemotherapy. Discussion: In summary, with a median follow-up of 5.8 years, 23% of patients had a skin cancer, half before the diagnosis of CLL and half after the CLL diagnosis. The incidence of skin cancers increased prior to the diagnosis of CLL, indicating that immunosuppression possibly preceded the diagnosis of CLL by years. The increased risk of developing skin cancers in patients with unmutated IGHV and CD38 positivity indicates that CLL patients with a more aggressive disease are more likely to develop skin cancer, probably due to a more pronounced immune deficiency. The diagnosis of skin cancer in CLL patients was associated with a seven-fold increased risk of developing a solid tumour. These results underscore the need for close monitoring and active surveillance of CLL patients for skin and other cancers throughout their disease course, by clinicians experienced in skin and other malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence and prognostic impact of other cancers in a population of long-term survivors of chronic lymphocytic leukemia

2016 ◽  
Vol 27 (6) ◽  
pp. 1100-1106 ◽  
Author(s):  
L. Falchi ◽  
C. Vitale ◽  
M.J. Keating ◽  
S. Lerner ◽  
X. Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Long Term Survivors

Survival trends in chronic lymphocytic leukemia in the era of oral targeted therapies in the United States: SEER database analyses (1985 to 2017).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7524-7524
Author(s):  
Neda Alrawashdh ◽  
Ali McBride ◽  
Daniel O. Persky ◽  
Joann Sweasy ◽  
Brian Erstad ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Rates ◽  
Relative Survival ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Seer Database ◽  
Cure Model ◽  
Gender And Age ◽  
Long Term Survivors

7524 Background: The survival of chronic lymphocytic leukemia (CLL) patients has progressively improved after the approval of new targeted therapy for first-line treatment and relapsed disease. We performed a corresponding analysis from the U.S. population-based SEER database (1973–2017) to explore the trend of survival and the effect of advanced CLL treatment on overall survival in CLL patients. Methods: Data were extracted from SEER*Stat for all patients 15 years or older with a primary diagnosis of CLL with or without subsequent cancers. A period analysis was performed to estimate the 5- and 10-year relative survival rates for patients diagnosed (dx) during different calendar periods from 1985 to 2017, based on gender and age at time of diagnosis (15–44, 45–54, 55–64, 65–74, 75–84, 85 years or older). A mixture cure model was used to examine the proportion of long-term survivors per gender and age category among CLL patients diagnosed between 1985 and 2015. Cox proportional hazard modeling was used to calculate the hazard ratios (HRs) of death adjusted for gender and age at diagnosis for two cohorts: (a) diagnosed in 2000–2003 and followed to 2012; (b) 2004–2007 and followed to 2015. Results: For males, the 5-year age-adjusted relative survival rate improved progressively from 72.0% (dx 1985-1989) to 88.2% (dx 2010-2014); for females, from 76.8% (dx 1985-1989) to 90.8% (dx 2010-2014). The corresponding 10-year age-adjusted relative survival rates were 47.3% (dx 1985-1989) and 72.5% (dx 2005-2009) for males; and 58.2% (dx 1985-1989) and 78.7% (dx 2005-2009) for females. The table below shows the proportions of long-term survivors for the 1985–2017 cohort as estimated in the mixed cure model. The HRs (95%CI) of death for cohort (b) in comparison to cohort (a) were 0.58 (0.43–0.78), 0.58 (0.48–0.70), 0.57 (0.49–0.67), 0.68 (0.54–0.85); and 0.83 (0.68–1.02) for age categories of 45–54, 55–64, 65–74, 75–84, and 85 years or old. Conclusions: Survival is significantly improved by calendar period among patients diagnosed after 2004 and treated in the era of advanced therapies. Females and younger patients had a higher probability of long term survival. Future studies should consider such covariates as treatment type, disease stage and genetics.[Table: see text]

scholarly journals Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort

Haematologica ◽  
2018 ◽  
Vol 104 (5) ◽  
pp. e208-e210 ◽  
Author(s):  
Maria Winqvist ◽  
Per-Ola Andersson ◽  
Anna Asklid ◽  
Karin Karlsson ◽  
Claes Karlsson ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Real World ◽  
Lymphocytic Leukemia ◽  
Compassionate Use

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia

2019 ◽  
Vol 9 (10) ◽  
Author(s):  
Vivek Kumar ◽  
Sikander Ailawadhi ◽  
Leyla Bojanini ◽  
Aditya Mehta ◽  
Suman Biswas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematological Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Primary ◽  
Standardized Incidence Ratio ◽  
Improved Outcomes ◽  
History Of ◽  
Second Primary Malignancies

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

scholarly journals V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1410-1416 ◽  
Author(s):  
Alexander Kröber ◽  
Till Seiler ◽  
Axel Benner ◽  
Lars Bullinger ◽  
Elsbeth Brückle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Chain Gene ◽  
P Value ◽  
Prognostic Impact ◽  
Survival Times ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor &lt;.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

Sign in / Sign up

Export Citation Format

Share Document