Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk

Disease overview: Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma. Diagnosis:The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10 and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein.The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes.Risk stratification: The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age > 60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0-1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis.Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis.Risk-adapted therapy: Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival advantage for early treatment with either chemotherapy or single agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved response rates, duration of response and overall survival (OS).Randomized studies have shown additional benefit for maintenance rituximab.Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, other immunotherapies, and stem cell transplantation (SCT) are also considered for recurrent disease.

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“…The median age at diagnosis is 65 years . The incidence is slightly increased among relatives of persons with FL …”

Section: Disease Overview and Clinical Presentationmentioning

confidence: 99%

Follicular lymphoma: 2020 update on diagnosis and management

2019

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“… 6 The risk of developing CLL is significantly higher in the patients with a family history of CLL (the relative risk is 8.5 times higher in the offspring of patients with CLL). 7 A national registry records all family cases. The risk of secondary cancers is increased in patients with CLL.…”

Section: Epidemiologymentioning

confidence: 99%

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO)

et al. 2020

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As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

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“…2,3 Germline contribution to hematological malignancy (HM) is incompletely defined, with multitumor cohorts suggesting $15% germline contribution 4 and recent phenotype-driven studies from large cohorts identifying significant familial clustering across all HM subtypes. 5 More than 14 genes are known to predispose to autosomal-dominant FHM. 6 In the most recent World Health Organization classification of myeloid neoplasms and acute leukemia, familial HMs were recognized as an entity, "Myeloid neoplasms with germline predisposition," with annotation of several predisposition syndromes, including those described in this review.…”

Section: Introductionmentioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

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Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

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Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk

Abstract: Sud and colleagues interrogated the familial risk of hematological malignancy in association with over 150 000 patients. The majority of hematological malignancies showed increased familial relative risk, most prominently in association with B-cell malignancies.

Cited by 53 publications

References 117 publications

Follicular lymphoma: 2020 update on diagnosis and management

Follicular lymphoma: 2020 update on diagnosis and management

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO)

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

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