Risk of Venous Thromboembolism in Hematological Malignancies: The Scandinavian Thrombosis and Cancer Cohort

Abstract Background: Several studies have shown a high incidence of venous thromboembolism (VTE) in hematological cancers, comparable with solid cancers, although bleeding is also a prominent complication of the hematological patients. Cancer patients, who develop VTE, have a reduced survival and impaired quality of life if compared to those who do not develop VTE. Hematological cancers are rather rare diseases and most studies have described only some of the entities. Here we want to compare the incidence of VTE in seven subtypes in a large cohort. Aim: To investigate the risk of VTE in hematological malignancies compared to matched controls in a prospective population based cohort study, the Scandinavian Thrombosis and Cancer (STAC) Cohort. Methods: TheSTAC Cohort includes 144.952 participants from three population based prospective cohort studies, i.e. The Tromsø Study and the HUNT2 study from Norway, and the Danish Diet, Cancer and Health Study. The participants were enrolled during 1993-1997, and mean follow-up time was 11.7 years. The cohort profile and outcome of first time objectively confirmed VTE events have been described in prior studies. For this study we collected data from the national cancer registries using morphology codes to identify cohort subjects with hematological cancers, divided into 7 groups: multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute leukemia (myeloid and lymphoblastic) (AL), chronic myeloproliferative neoplasms and myelodysplastic syndrome (CMN/MDS), aggressive non-Hodgkin lymphoma (aggr. NHL), Hodgkin lymphoma (HL), and indolent lymphoma (Ind. L). Subjects with a VTE event more than one year before cancer diagnosis were excluded. For each of the cases 5 controls matched on country, sex and age were identified. We used Cox regression models to estimate the relative risk of VTE across the seven different subtypes of hematological malignancies with a time axis starting one year before the diagnosis of cancer (and similar for matched controls) and ending at a VTE event or end of follow-up. Data were adjusted for age by spline regression. Results: During follow-up 891 participants were diagnosed with a hematological malignancy, and in this group 41 VTE events were observed corresponding to an incidence of 12.0 events per 1000 person-years (10-3 p-y). In the control group of 4455 participants 55 VTE events were observed which gave an incidence of events on 2.3* 10-3 p-y. Having a hematological cancer including all seven investigated types was associated with a six-fold increased risk of developing VTE compared to the matched controls. During follow-up 203 participants were diagnosed with MM, and 10 VTE events were observed giving an event rate of 14.6*10-3 p-y; hazard ratio (HR) for VTE was 7.2, 95% confidence interval (CI): 3.6-14.3. CLL was diagnosed in 176 cases, and 11 VTE events were observed in this group (event rate 11.5*10-3 p-y; HR 5.3; 95% CI: 2.7-10.1). Among the 63 participants who were diagnosed with AL during follow-up 2 VTE events were observed corresponding to an event-rate on 12.8*10-3 p-y; (HR 6.9; 95% CI: 1.7-29.0). In the group of CMN/MDS 4 VTE events were observed among 104 patients (event-rate 12.0*10-3 p-y; HR 6.4, 95% CI: 2.3-18.0). In aggressive NHL 10 VTE events were observed among 158 patients resulting in an event-rate of 18.9*10-3 p-y (HR 10.4; 95% CI: 5.2-20.8). Forty-four participants were diagnosed with HL, and 2 VTE events were observed which corresponds to an event-rate of 10.6*10-3 p-y among these patients (HR 5.1; 95% CI: 1.2-21.4). Indolent lymphoma was diagnosed in 143 subjects, and 2 VTE events were observed (event-rate 3.5*10-3 p-y; HR 1.9; 95% CI: 0.47-8.0). The results are summarized in the table: Table. MM CLL AL CMN/MDS Aggr. NHL HL Ind. L N 203 176 63 104 158 44 143 VTE (n) 10 11 2 4 10 2 2 Incidence (*10-3 p-y) 14.6 11.5 12.8 12.0 18.9 10.6 3.5 HR 7.2 5.3 6.9 6.4 10.4 5.1 1.9 95 % CI 3.6-14.3 2.7-10.1 1.7-29.0 2.3-18.0 5.2-20.8 1.2-21.4 0.47-8.0 Conclusion: Indolent lymphoma was the only investigated hematological malignancy that was not associated with a significant increased risk of VTE. The other types of hematological malignancies had an increased risk of VTE ranging from approximately 5-10 times, highest in aggressive non-Hodgkin lymphoma and lowest in Hodgkin lymphoma. However a limitation of the study is the small numbers in some of the groups in spite of the large cohort. Disclosures No relevant conflicts of interest to declare.

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Increased Risk of Second Hematological and Non-Hematological Malignancies in CLL Patients Treated with Chemotherapy As Compared to Untreated Patients and Matched Controls - Results from a Danish Population Based Study

Blood ◽

10.1182/blood.v128.22.3219.3219 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3219-3219

Author(s):

Caspar Da Cunha-Bang ◽

Klaus Rostgaard ◽

Jacob Simonsen ◽

Christian H Geisler ◽

Henrik Hjalgrim ◽

...

Keyword(s):

Cancer Registry ◽

Hematological Malignancies ◽

Population Based ◽

Second Cancers ◽

Relative Risks ◽

Increased Risk ◽

Hematological Cancers ◽

National Patient ◽

Danish Cancer Registry

Abstract Background The management of chronic lymphocytic leukemia (CLL) is in rapid transition and tailored individual therapy is a likely future scenario for those needing treatment. Previous studies of CLL have revealed an increased risk of second cancers. The underlying mechanisms are unclear, but may involve shared risk factors, weakened immune surveillance, and chemotherapy exposure. However, little is known about the impact of CLL treatment on second cancer risk. We followed Danish population-based cohorts of treated and untreated CLL patients and compared their risk of second cancers with that of matched controls. Methods All patients registered with a diagnosis of CLL in the Danish Cancer Registry 2002-2013 were included in the analyses. For each CLL patient, we randomly selected 50 CLL-free control persons matched on age and gender from the general population. Patients and controls were followed for new cancers registered in the Danish Cancer Registry 2002-2013 using ICD10 codes. Information about CLL treatment was available from The Danish National Patient Registry allowing us to stratify patients accordingly. Follow up of the patients and controls were done separately for each cancer type without competing risk. Adjusted hazard ratios (HR) and 95% confidence intervals (95%CI) for new cancers by time since CLL diagnosis /matching date for controls were calculated using Cox regression analyses. Results Overall, 4,919 CLL patients with a median person-years of follow-up (PYFU) of 3.9 and 245,877 controls with a median PYFU of 4.6 were included. During follow-up, a total of 694 new malignancies, 54 hematological (excluding CLL) and 640 non-hematological, were registered among the CLL patients (eight patients developed both hematological and non-hematological malignancies). This corresponded to increased relative risks for combined groups of hematological (HR, 1.3; 95% CI, 1.0 to 1.7) and of non-hematological (HR, 1.4; 95% CI, 1.3 to 1.5) cancers, respectively, compared to the controls. Chemotherapy treatment was registered for 1,664 (34%) of the CLL patients during follow-up, and this was accompanied by increased relative risks of both hematological cancers excluding CLL (HR, 2.7; 95% CI, 1.9 to 4.1) and non-hematological cancers (HR, 1.8; 95% CI, 1.6 to 2.1). In contrast, risks of hematological cancer were not increased (HR, 0.9; 95% CI, 0.6 to 1.3) and risk of non-hematological cancers only slightly increased (HR, 1.3; 95% CI, 1.1 to 1.4), among untreated CLL patients. In site-specific analyses the increased risk among treated CLL patients pertained to Hodgkin and non-Hodgkin lymphomas, myelodysplastic syndrome, lung, skin, and thyroid cancer with HR's ranging from 1.8 to 13.3. Conclusions CLL patients treated with chemotherapy are at increased risk of other hematological and non-hematological malignancies. Increased awareness and possibly cancer screening programs are warranted for CLL patients receiving chemotherapy. Detailed analyses of the role of different types of CLL specific treatments on risk of second cancers based on the Danish Cancer Registry, the Danish National Patient Registry and the Danish National CLL Registry are ongoing. Disclosures Geisler: Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy.

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Lymphoproliferative malignancies in patients with neurofibromatosis 1

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01856-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Christina Bergqvist ◽

François Hemery ◽

Arnaud Jannic ◽

Salah Ferkal ◽

Pierre Wolkenstein

Keyword(s):

General Population ◽

Medical History ◽

Hodgkin Lymphoma ◽

Incidence Rate ◽

Population Based ◽

Neurofibromatosis 1 ◽

Population Based Study ◽

Non Hodgkin Lymphoma ◽

History Of

AbstractNeurofibromatosis 1 (NF1) is an inherited, autosomal-dominant, tumor predisposition syndrome with a birth incidence as high as 1:2000. A patient with NF1 is four to five times more likely to develop a malignancy as compared to the general population. The number of epidemiologic studies on lymphoproliferative malignancies in patients with NF1 is limited. The aim of this study was to determine the incidence rate of lymphoproliferative malignancies (lymphoma and leukemia) in NF1 patients followed in our referral center for neurofibromatoses. We used the Informatics for Integrated Biology and the Bedside (i2b2) platform to extract information from the hospital’s electronic health records. We performed a keyword search on clinical notes generated between Jan/01/2014 and May/11/2020 for patients aged 18 years or older. A total of 1507 patients with confirmed NF1 patients aged 18 years and above were identified (mean age 39.2 years; 57% women). The total number of person-years in follow-up was 57,736 (men, 24,327 years; women, 33,409 years). Mean length of follow-up was 38.3 years (median, 36 years). A total of 13 patients had a medical history of either lymphoma or leukemia, yielding an overall incidence rate of 22.5 per 100,000 (0.000225, 95% confidence interval (CI) 0.000223–0.000227). This incidence is similar to that of the general population in France (standardized incidence ratio 1.07, 95% CI 0.60–1.79). Four patients had a medical history leukemia and 9 patients had a medical history of lymphoma of which 7 had non-Hodgkin lymphoma, and 2 had Hodgkin lymphoma. Our results show that adults with NF1 do not have an increased tendency to develop lymphoproliferative malignancies, in contrast to the general increased risk of malignancy. While our results are consistent with the recent population-based study in Finland, they are in contrast with the larger population-based study in England whereby NF1 individuals were found to be 3 times more likely to develop both non-Hodgkin lymphoma and lymphocytic leukemia. Large-scale epidemiological studies based on nationwide data sets are thus needed to confirm our findings.

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Increased risk for stroke in burn patients: A population-based one-year follow-up study

Burns ◽

10.1016/j.burns.2013.05.018 ◽

2014 ◽

Vol 40 (1) ◽

pp. 54-60 ◽

Cited By ~ 4

Author(s):

Shiu-Dong Chung ◽

Chin-Shyan Chen ◽

Herng-Ching Lin ◽

Jiunn-Horng Kang

Keyword(s):

Population Based ◽

Burn Patients ◽

Follow Up Study ◽

Increased Risk ◽

One Year

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Increased risk of tinnitus following a trigeminal neuralgia diagnosis: a one-year follow-up study

The Journal of Headache and Pain ◽

10.1186/s10194-020-01121-6 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Yen-Fu Cheng ◽

Sudha Xirasagar ◽

Tzong-Han Yang ◽

Chuan-Song Wu ◽

Yi-Wei Kao ◽

...

Keyword(s):

Trigeminal Neuralgia ◽

Auditory Pathway ◽

Population Based ◽

Geographic Region ◽

Temporomandibular Joint Disorders ◽

Increased Risk ◽

Cohort Study Design ◽

Taiwan National Health Insurance ◽

One Year

Abstract Background Tinnitus due to hyperactivity across neuronal ensembles along the auditory pathway is reported. We hypothesized that trigeminal neuralgia patients may subsequently suffer from tinnitus. Using nationwide, population-based data and a retrospective cohort study design, we investigated the risk of tinnitus within 1 year following trigeminal neuralgia. Methods We used the Taiwan National Health Insurance Research Dataset, a claims database, to identify all patients diagnosed with trigeminal neuralgia from January 2001 to December 2014, 12,587 patients. From the remaining patients, we identified 12,587 comparison patients without trigeminal neuralgia by propensity score matching, using sex, age, monthly income, geographic region, residential urbanization level, and tinnitus-relevant comorbidities (hyperlipidemia, diabetes, coronary heart disease, hypertension, cervical spondylosis, temporomandibular joint disorders and injury to head and neck and index year). All study patients (n = 25,174) were tracked for a one-year period to identify those with a subsequent diagnosis of tinnitus over 1-year follow-up. Results Among total 25,174 sample patients, the incidence of tinnitus was 18.21 per 100 person-years (95% CI = 17.66 ~ 18.77), the rate being 23.57 (95% CI = 22.68 ~ 24.49) among patients with trigeminal neuralgia and 13.17 (95% CI = 12.53 ~ 13.84) among comparison patients. Furthermore, the adjusted Cox proportional hazard ratio for tinnitus in the trigeminal neuralgia group was 1.68 (95% CI = 1.58 ~ 1.80) relative to the comparison cohort. Conclusions We found a significantly increased risk of tinnitus within 1 year of trigeminal neuralgia diagnosis compared to those without the diagnosis. Further studies in other countries and ethnicities are needed to explore the relationship between trigeminal neuralgia and subsequent tinnitus.

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Cardiac Outcomes in a Prospective Cohort of Adult Non-Hodgkin Lymphoma Survivors

Blood ◽

10.1182/blood.v118.21.2656.2656 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2656-2656

Author(s):

Carrie A. Thompson ◽

Hongxiu Luo ◽

Matthew J Maurer ◽

Cristine Allmer ◽

Thomas M. Habermann ◽

...

Keyword(s):

Heart Disease ◽

Hodgkin Lymphoma ◽

Valvular Heart Disease ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Medical Records ◽

P Value ◽

Non Hodgkin Lymphoma ◽

Increased Risk

Abstract Abstract 2656 Background Treatment of non-Hodgkin lymphoma (NHL) can lead to development of cardiovascular disease (CVD). We sought to describe the cumulative incidence of CVD in adult NHL survivors diagnosed in the recent treatment era (since 2002) and identify clinical and treatment predictors for its development. Methods All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). The MER offers enrollment to all consecutive patients with newly diagnosed NHL who are US residents and age >18 years. Clinical data from the time of diagnosis and treatment data are abstracted from medical records using a standard protocol. Patients are prospectively contacted via telephone or in person per protocol every 6 months for the first 3 years from diagnosis and yearly afterwards to assess disease status and development of comorbid conditions. CVD events, including heart failure (HF), myocardial infarction (MI), arrhythmia, pericarditis, and valvular heart disease, occurring after diagnosis were identified during follow-up and validated against medical records. HF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. MI was validated using case definition standards of coronary heart disease, while arrhythmia, pericarditis, and valvular heart disease were validated using clinical definitions. The prevalence of CVD and associations between CVD and clinical characteristics (sex, age) and treatment (radiation, anthracyclines) were performed using Cox models with a competing risk approach. Results 1164 patients with NHL were enrolled into the MER at Mayo Clinic between 9/1/2002–2/28/2008. 646 were male (56%) and median age at diagnosis was 62 years (range 20–93). Median follow-up of all cases was 59 months (range 1–105). 131 patients reported CVD prior to the diagnosis of NHL and were excluded from analyses. An additional 76 patients did not have follow-up and were excluded. Of the 957 remaining patients, 75 (7.8%) self-reported a new diagnosis of CVD. Of these, 71 cases had available medical records. 57 of the 71 reviewed cases (80%) were validated (18 HF, 9 MI, 21 arrhythmia, 2 pericarditis, and 10 valvular heart disease). Cumulative incidence of CVD at 1, 3, 5, and 7 years was 1.3%, 3.7%, 5.2%, and 7.4%, respectively. Median time from NHL diagnosis to CVD was 26.5 months (range 1–84). Older age was associated with increased risk of overall CVD (p-value<0.001). Gender (p=0.59), radiation therapy (p=0.61), and anthracycline treatment (p=0.25) were not associated with the incidence of overall CVD. Among types of CVD, anthracycline use was associated with development of HF (HR=5.30; p-value=0.008) and arrhythmia (HR=2.68; p-value=0.04). Radiation was associated with development of arrhythmia (HR=2.73; p-value=0.03), while older age was associated with development of HF (HR=1.36 per 5 year increment; p-value=0.003) and arrhythmia (HR=1.25 per 5 year increment; p-value=0.02). Conclusions The risk of CVD in patients with NHL is approximately 1% per year after the initial diagnosis of lymphoma. The most commonly occurring CVDs in this cohort of NHL survivors were arrhythmia and HF. Treatment with anthracyclines and radiation are associated with increased risk of developing some types of CVD. 80% of self-reported CVD events in NHL survivors were validated using epidemiologic criteria. Future studies will include building models incorporating comorbid health conditions and lifestyle factors to determine risk of CVD as well as the impact of CVD on quality of life. Disclosures: No relevant conflicts of interest to declare.

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Phase I/II Trial of Ofatumumab/Lenalidamide for Patients with Relasped/Refractory B-Cell Non-Hodgkin Lymphoma: High Response Rate in Indolent Lymphoma

Blood ◽

10.1182/blood.v120.21.3692.3692 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3692-3692

Author(s):

Julie M Vose ◽

Fausto R. Loberiza ◽

R. Gregory Bociek ◽

Philip Bierman ◽

James O. Armitage

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

High Response Rate ◽

Indolent Lymphoma ◽

Non Hodgkin Lymphoma

Abstract Abstract 3692 Introduction: Lenalidomide and ofatumumab have demonstrated clinical activity as single agents in a variety of types of non-Hodgkin lymphoma (NHL). This trial is a phase I/II trial combining these two agents for treatment of patients with relapsed and refractory B-cell NHL. Methods: Patients with relapsed and refractory B-cell NHL of any histology were enrolled on a phase I/II trial combining lenalidomide and ofatumumab. Nine patients were on the phase I part of the trial and received a fixed dose of ofatumumab 1000 mg weekly × 8 doses along with lenalidomide 15 mg (N=3), or10 mg (N=6) for 21/28 days until the time of progression. The phase II portion of the study has 28 patients on the study with adequate follow-up at the time of analysis. The phase II doses were ofatumumab 1000 mg weekly × 8 along with lenalidomide 10 mg on 21/28 days. The lenalidomide was dose adjusted according to standard dose reduction criteria. All patients were on either a daily aspirin or other anticoagulation for thrombosis (DVT) prophylaxis. Results: Thirty seven evaluable patients had adequate follow-up at the time of the analysis. The patients had a median age of 65 years (range 36–81), 76% were male, and 89% have an ECOG performance status of 0–1. The majority of patients had a relapsed indolent lymphoma with 12/37 (32%) follicular lymphoma (FL), 6/37 (16%) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 7/37 (19%) mantle cell lymphoma (MCL), one unclassifiable indolent lymphoma (3%), and 11/37 (30%) diffuse large B-cell lymphoma (DLBLC). The median duration of follow-up of surviving patients was 13 months (range 4–24). The complete response (CR) rate was 2/37 (5%) (one each FL and DLBCL) and the partial response (PR) rate was 13/37 (35%) for an overall response rate (ORR) of 15/37 (40%). The 1 year progression-free survival (PFS) was 41% (95% CI; 23–58) and the 1-year overall survival (OS) was 68% (95% CI; 49–82). In an analysis of response by patient variables, those significant included the patients with an FL histology (ORR 83%) vs. DLBCL (ORR 18%) or other(SLL, MCL, unclassifiable) (ORR 21%) (p= 0.001) and lactic dehydrogenase (LDH) normal (ORR 56%) vs. elevated (ORR 14%) (p= 0.01). In an analysis of variables for PFS, the variables with significance include diagnosis of FL (1-year PFS 67%) vs. DLBCL (9%) and SLL, MCL, unclassifiable (45%) (p=0.002), LDH normal (1-year PFS 55%) vs. elevated LDH (1-year PFS 19%), and number of prior chemotherapies 1–2 (1-year PFS 58%) vs. > 3 (1-year PFS 19%). Higher grade toxicities included grade 4 neutropenia in 9/37 (24%), one each of grade 4 bacteremia, one grade 4 DVT, stroke, and acute renal failure. Conclusions: The combination of lenalidomide and ofatumumab was well tolerated by most patients. The patients with indolent NHL had a high response rate of 83% and a 1-year PFS of 67%. Disclosures: Vose: Glaxo Smith Kline: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidamide and Ofatumumab will be discussed for use in indolent and aggressive non-Hodgkin lymphoma.

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Spectrum of Second Primary Malignancies in Pediatric and Adult Langerhans Cell Histiocytosis Cases

Blood ◽

10.1182/blood-2020-143279 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 51-52 ◽

Cited By ~ 1

Author(s):

Richa Parikh ◽

Ronald S. Go ◽

Gaurav Goyal

Keyword(s):

General Population ◽

Hodgkin Lymphoma ◽

Solid Tumors ◽

Adult Population ◽

Hematologic Malignancies ◽

Population Based ◽

Second Primary ◽

Non Hodgkin Lymphoma ◽

Increased Risk ◽

Second Primary Malignancies

Introduction: Langerhans cell histiocytosis (LCH) is a rare MAPK-ERK pathway driven histiocytic neoplasm that occurs in pediatric as well as adult population. Despite improvement in clinical outcomes, there is some data to suggest an increased propensity to develop second primary malignancies (SPMs) in LCH patients. However, population-based studies analyzing the incidence and spectrum of SPMs in pediatric and adult LCH patients are lacking. In this study, we utilized the Surveillance, Epidemiology and End Results (SEER) database to examine the various SPMs occurring among pediatric and adult LCH cases. Methods: We used the November 2018 submission of the SEER 18 registry, which covers ~27.8% of the US population based on the 2010 census, as our database. We used the SEER*Stat version 8.3.6 statistical software to analyze data. We identified cases diagnosed with LCH as their first primary malignancy between 2000 and 2016 using International Classification of Diseases for Oncology edition 3 (ICD-O-3) codes, including LCH NOS (not otherwise specified) (9751/1), LCH (9751/3), LCH, unifocal (9752/1), LCH, multifocal (9753/3), LCH, disseminated, borderline (9754/1) and Disseminated LCH (9754/3). These cases were followed for 180+months, and the standardized incidence ratio (SIR) or relative risk and absolute excess risk (AER) were calculated. We examined the differences in occurrence of SPMs among the pediatric (Age <18 years) and adult population (Age ≥18 years). Additionally, we evaluated the concurrent and prior cancers in LCH patients as an exploratory objective. Results: The study included 1392 cases with LCH (Table 1), with median age at diagnosis 8 years (range newborn - 86 years). Out of these cases, 1205 (87%) were diagnosed as LCH and 186 (13%) as disseminated LCH. 936 cases (67%) were diagnosed at age <18 years (pediatric LCH), while 456 cases (33%) were diagnosed at age ≥18 years (adult LCH). The overall age-adjusted incidence rate for LCH was found to be 1 per 1,000,000. The incidence rate was 2.6 per 1,000,000 in pediatric LCH group and 0.4 per 1,000,000 in the adult LCH group. Out of the entire cohort, 20 (1.4%) cases developed a total of 21 SPMs [SIR 2.07; 95% Confidence Interval (CI): 1.28-3.16]. Median latency period to development of SPMs was 28 months. The pediatric LCH group had an overall higher risk of developing SPMs [SIR 6.42, 95%CI 2.08-14.97] than the general population, especially for hematologic malignancies [SIR 18.76, 95%CI 6.09-43.78], mainly, nodal Hodgkin lymphoma [SIR 60.93, 95%CI 7.38-220.12] and extranodal non-Hodgkin lymphoma [SIR 60.88, 95%CI 1.54-339.2]. No solid tumors were seen in this group. The adult LCH group did not have an overall increased risk of developing SPMs than the general population [SIR 1.71, 95%CI 0.98-2.77], except for Acute Lymphocytic Leukemia (ALL) [SIR 66.29, 95%CI 1.68-369.36] especially 60-119 months from diagnosis of LCH and miscellaneous cancers [SIR 11.43, 95%CI 2.36-33.39] especially 12-59 months after diagnosis of LCH. 62.5% of SPMs that developed in the adult LCH group were solid tumors, however, the overall risk for developing solid tumors was not higher than the general population [SIR 1.2, 95%CI 0.58-2.2], except for carcinoma in-situ of vulva [SIR 62.72, 95%CI 1.59-349.45] 2-11 months from diagnosis of LCH. Overall, tumors of the respiratory system (21%), female breast (13%) and prostate (9%) were the most common malignancies occurring prior to development of LCH whereas tumors of the respiratory system (28%), non-Hodgkin lymphoma (20%) and endocrine system (13%) occurred concurrent to LCH. Conclusion: To our knowledge, this is the first comprehensive population-based study assessing the incidence of SPMs in pediatric and adult LCH. Our study shows that the incidence of LCH is higher in the pediatric age group compared to adults. We found an increased risk for hematologic malignancies, specifically for Hodgkin and non-Hodgkin lymphoma in pediatric LCH compared to the general population. Among adult LCH, however, the risk was higher for development of ALL and carcinoma in-situ of vulva when compared to the general population. Our results may help guide survivorship and surveillance strategies among LCH patients. More studies are needed to understand the molecular underpinning leading to increased SPM formation in LCH patients. Disclosures No relevant conflicts of interest to declare.

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Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2004-02-0557 ◽

2004 ◽

Vol 104 (7) ◽

pp. 2155-2162 ◽

Cited By ~ 100

Author(s):

Christine F. Skibola ◽

Matthew S. Forrest ◽

Fabio Coppedé ◽

Luz Agana ◽

Alan Hubbard ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Genetic Polymorphisms ◽

San Francisco ◽

Methylenetetrahydrofolate Reductase ◽

Large Cell ◽

Population Based ◽

Folate Metabolism ◽

Non Hodgkin Lymphoma ◽

Genotype Frequencies ◽

Increased Risk

Abstract Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R] → double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)-6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL. (Blood. 2004;104: 2155-2162)

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Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden

Blood ◽

10.1182/blood-2008-12-191676 ◽

2009 ◽

Vol 114 (4) ◽

pp. 791-795 ◽

Cited By ~ 95

Author(s):

Ola Landgren ◽

Sigurdur Y. Kristinsson ◽

Lynn R. Goldin ◽

Neil E. Caporaso ◽

Cecilie Blimark ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Monoclonal Gammopathy ◽

Case Reports ◽

Population Based ◽

Lymphocytic Leukemia ◽

Degree Relative ◽

First Degree Relatives ◽

Non Hodgkin Lymphoma ◽

Increased Risk ◽

Undetermined Significance

Abstract Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

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Second Malignancy After Treatment for Non-Hodgkin Lymphoma: a Systematic Review and a Meta-Analysis of Population-Based and Cohort Studies.

Blood ◽

10.1182/blood.v114.22.1918.1918 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1918-1918

Author(s):

Stefano Sacchi ◽

Monica Pirani ◽

Luigi Marcheselli ◽

Raffaella Marcheselli ◽

Alessia Bari ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Myeloid Leukemia ◽

Observational Studies ◽

Meta Analysis ◽

Population Based ◽

Second Malignancy ◽

Second Cancer ◽

Haematological Malignancies ◽

Non Hodgkin Lymphoma

Abstract Abstract 1918 Poster Board I-941 Background: The risk of second malignancy in non-Hodgkin lymphoma (NHL) survivors have been described in several studies, but the available evidence have yielded conflicting results. Thus, we performed a systematic review and a meta-analysis on population-based and cohort studies to provide a quantitative assessment of the available evidence on the risk of secondary occurrence of cancer after treatment for NHL. Primary aims of our research were to evaluate the pooled Relative Risk (RR) of second cancer for overall malignancies and for every cancer. Methods: A Medline search from 1985 to 2008 was conducted for identification of relevant observational studies that provide estimates of RR, as measured by standardized incidence ratios (SIR) that is the observed-expected ratio of second malignancy appearing during follow up of NHL. The reference lists of identified articles were inspected to identify additional papers. Criteria for including studies in the meta-analysis were: a) studies on naïve patients with any stage of NHL, b) studies reporting measure of SIR or data allowing such outcome to be derived and c) English language. The article included, had to have been published in peer-reviewed literature. We did not exclude papers on the base of therapeutic regimens. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Pooled RR and 95% confidence interval (CI) were calculated using random effect models. Tests on heterogeneity and sensitivity analysis was conducted. Also, the publication bias was evaluated. Results: Eleven papers meet the inclusion criteria reporting RRs for all malignancies. These studies included 223,593 patients affected by NHL of which 14,952 presented a second cancer. RRs ranged from 0.93-1.90 and the meta-RR for second malignancy was 1.24 (95%CI: 1.11-1.39). The analysis on solid tumours, excluding haematological malignancies, based on seven studies did not show a significantly higher risk for secondary cancer: the meta-RR was 1.06 (95%CI: 0.84-1.34). However, some kind of cancer showed a statistically significant excess of risk, as lung cancer (meta-RR on nine studies: 1.46 95%CI: 1.33-1.59) and bladder cancer (meta-RR on eight studies: 1.42 95%CI: 1.33-1.51). Prostate (meta-RR on ten studies: 1.08 95%CI: 0.93-1.24) and breast cancer (meta-RR on eleven studies: 0.99 95%CI: 0.83-1.19) has demonstrated no evidence of association with NHL therapy. Moreover, we found a higher risk of developing Hodgkin lymphoma and myeloid leukemia (respectively meta-RR on seven studies: 6.44 95%CI: 5.59-11.55 and meta-RR on five studies: 7.81 95%CI: 2.59-24.46). Regarding leukemia, however we have to consider that they include either acute or chronic leukemia and sometime could also include higher risk myelodisplastic syndrome . No evidence of publication bias was observed. Conclusion: Although there exist a number of paper on this topic, until now there are not been attempts to perform a meta-analysis on RR of second malignancies after treatment for NHL. Indeed comparative analysis on the incidence of second cancer presents several issues, including the heterogeneity of NHL, the source of data, the time during which the study was performed, the different schedule of chemotherapy, the dosage of radiotherapy used in the different period of time and the length of follow-up. Although these problems could reduce the accuracy of the meta-analysis, our results indicate that NHL treatment is associated with a significantly higher risk of second malignancy, in particular for some specific cancer like lung and bladder and same haematological malignancies as Hodgkin lymphoma and myeloid leukemia. Finally, we think that it is important to determine by meta-analysis the incidence of each second cancer in survivor of NHL as for some malignancies screening test could be performed and early diagnosis could be made. Disclosures: No relevant conflicts of interest to declare.

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