BCLL patients may be asymptomatic for prolonged periods of time, and about one-third of all diagnoses are made incidentally [1] [2]. If symptoms manifest, they are non-specific. Constitutional B-symptoms, such as fever, night sweats, and weight loss, are common and may be accompanied by general malaise and weakness. The clinical examination of BCLL patients may reveal generalized lymphadenopathy, hepatomegaly, and splenomegaly.

Additional symptoms may arise from bone marrow failure due to marrow crowding or autoimmune destruction. Hematological studies may confirm anemia, leukocytopenia, and/or thrombocytopenia [1]. Those suffering from anemia will appear pale, and their tolerance to exercise will be reduced. They may claim headaches and palpitations. Leukocytopenia, in turn, is associated with an increased risk of infection. The incidence of cutaneous, respiratory, and urinary infections is particularly high in BCLL patients, and they may give rise to life-threatening pneumonia and sepsis [3]. Low platelet counts may induce a predisposition to bleeding, causing easy bruisability, epistaxis, bleeding gums, and hemorrhages of the gastrointestinal tract. As implied above, autoimmune processes may trigger autoimmune hemolytic anemia and immune-mediated thrombocytopenia, and these conditions may exacerbate the consequences of bone marrow failure.

Moreover, solid tumors may compress adjacent tissues and produce further symptoms related to organ dysfunction. The primary involvement of non-lymphoid organs is rare, but has been described. In this regard, the skin and central nervous system are most frequently affected [4].

• Massive Splenomegaly

  Bulky disease was defined as the presence of lymph-nodes more than 5 cm in longest diameter by CT and/or ultrasound examination or the presence of massive splenomegaly (6 cm below the left costal margin). [mjhid.org]

  Massive splenomegaly (> 6 cm) resolved in 90% of responders and 25% overall. [doi.org]

  Splenomegaly is present in 90% of patients at the time of diagnosis, sometimes becoming massive. [cancernetwork.com]

• Hodgkin Lymphoma

  Granulomatous cutaneous reactions are well described in association with T-cell non-Hodgkin lymphoma and Hodgkin lymphoma, but are rarely seen in association with B-cell non-Hodgkin lymphoma or leukemia. [ncbi.nlm.nih.gov]

  To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδ isoform expression and constitutive PI3K pathway activation. [bloodjournal.hematologylibrary.org]

  SLL: In contrast to CLL, SLL is much less common, making up only about 4% of non-Hodgkin lymphomas. The distribution of the neoplastic cells in SLL is mainly extramedullary with very few leukemic cells in blood. [webpathology.com]

• Swelling

  Acute leukemias affect immature cells; the disease develops rapidly, with symptoms including anemia, fever, bleeding, and swelling of the lymph nodes. [britannica.com]

  If you have symptoms, they may include painless swelling of the lymph nodes in the neck, underarm, stomach, or groin fatigue pain or a feeling of fullness below the ribs fever and infection weight loss tests that examine the blood, bone marrow, and lymph [icd9data.com]

  If you have symptoms, they may include Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin Fatigue Pain or a feeling of fullness below the ribs Fever and infection Weight loss Tests that examine the blood, bone marrow, and lymph [medlineplus.gov]

  A doctor should be consulted if any of the following problems occur: Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin. Tiredness that does not go away. Pain or fullness below the ribs. Fever and infection. [web.archive.org]

  […] symptoms develop, they may include: getting infections often anaemia – persistent tiredness, shortness of breath and pale skin bleeding and bruising more easily than normal a high temperature night sweats swollen glands in your neck, armpits or groin swelling [nhs.uk]

• Sepsis

  Grade 3-4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related. [ncbi.nlm.nih.gov]

  The incidence of cutaneous, respiratory, and urinary infections is particularly high in BCLL patients, and they may give rise to life-threatening pneumonia and sepsis. [symptoma.com]

  Three deaths were due to PD, 3 were due to pneumonia, and pulmonary embolism, sepsis, and rhinocerebral mucormycosis caused the remaining 3 deaths. [doi.org]

  Five patients in PR-i died during ongoing remission: 2 patients from complications of treatment-related myelodysplasia, 1 patient from neutropenic sepsis, 1 patient from carcinoma of the lung, and 1 patient from undetermined cause. [dx.doi.org]

  […] infection rates appeared favorable relative to the 26% incidence reported with the FCR regimen. 15 Moreover, despite the 87% incidence of grade 3 or 4 neutropenia based on laboratory assessments, infections were manageable, with only 2 patients experiencing sepsis [bloodjournal.hematologylibrary.org]

• Constitutional Symptom

  […] with CLL include Constitutional symptoms (fever, night sweats, extreme fatigue, weight loss) Significant hepatomegaly, splenomegaly, or lymphadenopathy Recurrent infections Symptomatic anemia and/or thrombocytopenia Disease-directed treatment options [msdmanuals.com]

  Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs: Unintentional weight loss of 10% or more within the previous 6 months; significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual [bloodjournal.hematologylibrary.org]

  Grade 1 and 2 constitutional symptoms consisted of fevers, chills, diaphoresis, myalgias, headache, and fatigue. Grade 2 hypogammaglobulinemia was corrected with infusions of intravenous immune globulin. [doi.org]

• Pathologist

  An international collaboration in which tissue from similar cases is referred to a central pathologist for immunophenotyping and cytogenetical study, and clinical data are centrally compiled, may assist in defining this rare malady as a discrete clinico-pathologic [doi.org]

  A pathologist views the sample under a microscope to look for abnormal cells. Certain factors affect treatment options and prognosis (chance of recovery). Treatment options depend on: The stage of the disease. [web.archive.org]

  A pathologist would call a lymph node in 2015 from an SLL patient, CLL/SLL. [lymphomation.org]

  R. and M.G. were the pathologists who reviewed and confirmed the diagnoses; P.N., C.M.R. [nature.com]

• Palpitations

  They may claim headaches and palpitations. Leukocytopenia, in turn, is associated with an increased risk of infection. [symptoma.com]

• Night Sweats

  Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. [lymphoma.org]

  sweats as well as cervical lymphadenopathy, splenomegaly and frequent infections. [orpha.net]

  Symptoms of CLL may include: Abnormal bruising (if platelets are low) Enlarged lymph nodes, liver, or spleen Excessive sweating, night sweats Fatigue Fever Infections that keep coming back (recur) despite treatment Loss of appetite or becoming full too [nlm.nih.gov]

  Symptoms and signs may be absent or may include lymphadenopathy, splenomegaly, hepatomegaly, fatigue, fevers, night sweats, unintentional weight loss, and early satiety. Diagnosis is by flow cytometry and immunophenotyping of peripheral blood. [msdmanuals.com]

  Patients may be asymptomatic or the disease may manifest in generalized lymphadenopathy, malaise and weakness, fever, night sweats, and weight loss. [symptoma.com]

• Flushing

  As we have seen before, CAL-101 has the ability to flush CLL cells out of their comfortable and safe niches in the lymph nodes, where they are hard to reach and even harder to kill. [web.archive.org]

• Guillain-Barré Syndrome

  We report a case of Guillain-Barré Syndrome (GBS) which appeared after mobilization therapy in a patient with B-cell chronic lymphocytic leukemia (B-CLL). [ncbi.nlm.nih.gov]

Hematological studies revealing lymphocytosis and variable cytopenias are usually the first indication of a lymphoproliferative disorder like BCLL. The final diagnosis of BCLL requires the presence of at least 5,000 B cells per µl in the peripheral blood and proof of a clonal B-cell population. Flow cytometric analyses of lymph node biopsy samples are generally carried out to this end and show B cells positive for light chain restriction, CD5, CD23, CD79b, and surface immunoglobulins. CD20 expression is low. Microscopically, tumor cells have a typical appearance of smudge cells, which are artifacts produced during the slide preparation. The share of phenotypically or immunophenotypically atypical cells is generally <15% [2]. A bone marrow biopsy is not required to diagnose BCLL but may become necessary to confirm the histological transformation of tumor cells [5].

With regards to the molecular characteristics of tumor cells, the following features should be determined [6] [7]:

• Cytogenetic abnormalities, e.g., del(17p), del(13q), del(11q), trisomy 12, and complex karyotype (poor response to chemoimmunotherapy; increased risk for histological transformation)
• Inactivation of TP53 or CDKN2A/B tumor suppressor genes; activation of C-MYC oncogene (unsatisfactory response to chemoimmunotherapy)
• Mutation of immunoglobulin heavy-chain variable (IGHV; unmutated IGHV as a predictive biomarker for lack of benefit from chemoimmunotherapy but not from ibrutinib)
• Impairment of NOTCH signaling (predicting resistance to rituximab and ofatumumab, but not obinutuzumab; augments the risk of Richter transformation)

During follow-ups, the patient's response to treatment is assessed by clinical, radiological, and laboratory criteria. A complete response to therapy comprises the total reduction of lymphadenopathy and organomegaly, the decrease of bone marrow lymphocytes <4,000 per µl and the stabilization of peripheral blood lymphocytes at values <30%. Furthermore, hemoglobin, neutrophil and platelet counts should rise to near-physiological ranges. Patients should also be tested for minimal residual disease, whereby the threshold is set at 1 tumor cell detectable per 10,000 leukocytes. Patients with <0.01% of tumor cells are considered negative for minimal residual disease [8].

• Cytopenia

  Five patients had refractory cytopenia with multilineage dysplasia, and 3 patients had refractory anemia with excess blasts-2 (RAEB-2). [dx.doi.org]

  Richter Transformation (RT) must be considered if CLL patient had fever, weight loss, cytopenia and resistance to standard therapy. [semanticscholar.org]

  A possible explanation for the incidence of laboratory-assessed cytopenia with O-FC was the presence of pretreatment baseline cytopenia in 29% of patients in the 500-mg cohort and in 33% of patients in the 1000-mg cohort (data not shown). [bloodjournal.hematologylibrary.org]

About one-third of BCLL patients is not expected ever to develop sequelae that require treatment or affect survival [1]. These patients may, however, suffer from side effects by drugs used in the management of BCLL. Accordingly, the current consensus is to not start treatment until required to reduce or delay the imminent onset of symptoms due to BCLL. In the face of comorbidities, however, it may not be easy to attribute signs and symptoms to leukemia.

Front-line treatments of BCLL include cytotoxic chemoimmunotherapy and small molecule inhibitors, although corticosteroids may suffice to control autoimmune hemolytic anemia and immune-mediated thrombocytopenia. In any case, treatment decisions are based on the patient's general condition, on clinical and molecular factors [7].

• Chemotherapy generally uses purine analogs and alkylators. The efficacy of chemotherapy can be significantly enhanced by the addition of anti-CD20 monoclonal antibodies, such as rituximab, ofatumumab, and obinutuzumab. It should be considered, though, that the likelihood of adverse events is greater with the application of anti-CD20 monoclonal antibodies [1]. For patients aged <65 years, the standard treatment regimen comprises fludarabine, cyclophosphamide, and rituximab, while the elderly bendamustine and rituximab are usually preferred in the elderly [9].
• Ibrutinib is an inhibitor of Bruton's tyrosine kinase and may be administered to diminish B-cell signaling and maturation. Similarly, idelalisib, a reversible kinase inhibitor which targets the phosphatidylinositol 3 kinases, has been shown to suppress the proliferation, migration, activation, and survival of B cells [9].
• Venetoclax is one of the small molecule inhibitors used in BCLL therapy. Venetoclax promotes B-cell apoptosis by antagonizing BCL-2, an inhibitor of programmed cell death.

Several mechanisms of resistance have been described for small molecule inhibitors [6]. If the molecular characterization of tumor cells implies resistance to certain compounds, they are not to be used in the respective patient - to reduce the overall toxicity of therapy and to minimize costs. Indeed, the introduction of small molecule inhibitors has been accompanied by an exponential increase in medical expenses.

For a long time, BCLL has been deemed incurable, and any therapy merely aimed at the maintenance of life quality and the prolongation of survival times. Considerable advances in BCLL therapy, however, made this condition manageable and often even curable: In the absence of minimal residual disease, 10-year progression-free survival rates amount to 65% and overall survival is about 70%. Positivity for minimal residual disease is associated with a reduction of 10-year progression-free and overall survival to 10 and 30%, respectively [8].

The patient's prognosis considerably worsens upon the histological transformation of BCLL into more aggressive lymphomas. In this context, Richter transformation into diffuse large B-cell lymphoma or classical Hodgkin lymphoma is observed in 2-10% of all cases. These patients hardly respond to therapy, and median survival times are estimated at 5 to 8 months [5].

First-degree family members of BCLL patients are at higher risks of developing CLL than the general population [1]. This argues in favor of a genetic component in the etiology of BCLL, but the contribution of hereditary factors to the development of the disease remains incompletely understood. In this context, a series of single nucleotide polymorphisms have been shown to confer a modest but significant increase in BCLL risk [10]. In general, the successive acquisition and progressive accumulation of mutations of oncogenes and tumor suppressor genes are assumed to result in leukemia. Mutations and chromosomal aberrations affecting more than 40 driver genes have been identified in BCLL:

• The majority of BCLL patients harbors at least one of the four most common chromosomal abnormalities, namely del(13q14), del(11q22-23), del(17p12), and trisomy 12 [6].
• Notch 1 (NOTCH1, 9q34.3), ATM serine/threonine kinase (ATM, 11q22.3), splicing factor 3b subunit 1 (SF3B1, 2q33.1), baculoviral IAP repeat-containing protein 3 (BIRC3, 11q22.2), chromodomain-helicase-DNA-binding protein 1 (CHD2, 15q26.1), tumor protein p53 (TP53, 17p13.1), and myeloid differentiation primary response protein 88 (MYD88) are among the most frequently mutated genes [11].

To date, there is no evidence of occupational or environmental risk factors contributing to the risk of developing CLL. Still, multiple factors have been discussed as possible promoters of the disease, e.g., live in rural areas, hepatitis C, exposure to Agent Orange, lack of exposure to sunlight [2].

In the western world, BCLL is the most common type of adult leukemia, accounting for up to 30% of newly diagnosed cases of leukemia [9]. In the United States, the overall incidence of BCLL has been estimated at 5 per 100,000 people. Men are affected about twice as often as women, and patients of Caucasian origin and Ashkenazi Jews are predisposed to the disease. The median age at the time of diagnosis is 72 years, with two-thirds of patients being over the age of 65 when BCLL is recognized [2]. Notwithstanding, BCLL has been described in young adults and pediatric patients.

BCLL is characterized by the uncontrolled proliferation and accumulation of degenerated CD5+ B cells in the bone marrow, blood, lymph nodes, liver, and spleen. Tumor cells don't mature appropriately and are unable to fulfill their function in the immune system. They do, however, displace functional cells and form solid tumors that interfere with organ function. These cells' reduced ability to undergo apoptosis accelerates this process. Accordingly, BCLL patients may develop bone marrow failure with cytopenias, lymphadenopathy and immunodeficiency, as well as hepatomegaly and splenomegaly.

Mutations and chromosomal aberrations inducing the degeneration of B cells generally affect key regulators of cell cycle and apoptosis, and these gene defects facilitate the persistence of additional mutations. The typical genome of BCLL has been estimated to include about 2,000 molecular lesions, with only a few mutations occurring at a relatively high frequency [6].

Considerable knowledge gaps regarding the etiology of BCLL hamper the development of prevention guidelines. Metaprophylaxis, however, does play a major role in the management of BCLL. Most patients suffer from immune dysregulation and propensity to infections, and complications of infections account for as much as 60% of disease-related deaths [12]. In this context, the following recommendations can be given:

• Evaluation of status of relevant viral infections (e.g., hepatitis B and C, HIV, CMV) before starting BCLL therapy
• Provision of pneumococcal and influenza vaccination for all patients
• Avoidance of vaccines containing live pathogens
• Neutropenic fever should prompt the administration of G-CSF
• Antibiotic prophylaxis in symptomatic patients with recurrent infections or serum immunoglobulin G levels <500 mg/dl, possibly complementation with immunoglobulin therapy

Treatment-specific recommendations have been elaborated, too. The interested reader is referred to the respective review published by Tadmor et al. [3].

According to the classification of the World Health Organization, BCLL is a type of non-Hodgkin lymphoma and mature B-cell neoplasm [13] [14]. It tends to follow an indolent course, and diagnoses are often made incidentally. Nevertheless, life-threatening complications may arise from disease-related bone marrow failure and transformation into an aggressive lymphoma. Although the clinical outcome has been associated with a series of parameters, the search for useful prognostic markers with high predictive power has not yet been concluded [2]. At the same time, intense research is focused on the development of drugs that allow for long-term disease control and even cure while minimizing the impact of side effects [6] [11].

As of today, treatment is generally delayed until the onset of symptoms, but essential time may be lost in cases of high-risk BCLL: Here, patients might benefit from an early initiation of therapy. One major challenge is to identify these patients; another one consists in the provision of effective and well-tolerated treatment to the majority of those affected by BCLL.

B-cell chronic lymphocytic leukemia (BCLL) is one of the most common types of leukemia and thus a form of blood cancer. It is mostly diagnosed in the elderly and tends to follow an indolent course. Accordingly, BCLL patients may remain asymptomatic for prolonged periods of time. Incidental diagnoses are common and are usually based on hematological studies yielding abnormal results.

Therapy may not be required before the onset of symptoms. In this context, it is important to thoroughly characterize tumor cells, to carry out a detailed risk assessment in order to prepare a personalized treatment plan. Most patients respond well to therapy and experience partial or even complete relief from symptoms.

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