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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia, accounting for 22 to 30% of cases in the Western world. It is characterized as a mature B-cell malignancy associated with the clonal proliferation of B-cells. The etiology and pathogenesis of CLL involve a multi-step pathway that leads to a clonal expansion and proliferation of abnormal or malignant mature B lymphocytes. This clonal expansion of malignant B cells extends to the bone marrow, blood, and lymph nodes. This activity reviews the role of variable genetic alterations found in chronic lymphocytic leukemia in terms of prognosis. This activity describes the role genetic variants have in the evaluation and treatment of CLL and highlights the role of the interprofessional team in improving care for patients with this condition. Objectives: Describe the pathophysiology of chronic lymphocytic leukemia. Summarize the most common genetic variants associated with chronic lymphocytic leukemia. Explain the screening indications for chronic lymphocytic leukemia. Outline the management strategies for patients with chronic lymphocytic leukemia with genetic variants. Access free multiple choice questions on this topic.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world.[1][2][3] It is characterized as a mature B-cell malignancy associated with B-cell clonal proliferation. The terms CLL and small lymphocytic leukemia (SLL) are used interchangeably. However, the former describes when the patient presents with peripheral blood involvement with greater than 5000 monoclonal B-cells, while the latter describes the lymphoproliferative process, which is limited to the lymph nodes. The technological advances in the last decades have made significant strides in understanding the variant genetics involved in CLL. This article will provide a brief overview of CLL and hone in on the different genetic components of the disease and how they relate clinically to disease management.

The etiology and pathogenesis of chronic lymphocytic leukemia involve a multi-step pathway that leads to a clonal expansion and proliferation of abnormal or malignant mature B lymphocytes. This clonal expansion of malignant B cells extends to the bone marrow, blood, and lymph nodes. Multiple influencing factors can lead to this clonal expansion, including antigenic triggers, cytogenetic abnormalities, and molecular abnormalities such as dysregulated mRNAs and B-cell receptor mutations.[4][5] Inherited genetic abnormalities and environmental factors play a role in the pathogenesis of CLL.[6] The incidence of CLL is higher in the western hemisphere compared to Asia and Africa.[7] The genetic component of CLL is significant, as shown by an 8.5-fold increased risk of CLL for relatives.[8][9] There is a higher frequency in monozygotic than in dizygotic twins.[10][5] Family members of patients with CLL also have a high likelihood of developing monoclonal B cell lymphocytosis. Epigenetics has been shown to play a role in CLL, for example, histone modifications, such as those associated with active enhancer and promoter elements, and regions of the genome that were actively transcribed. Over-expression of transcription factor binding has also been found in single nucleotide polymorphisms (SNP), which carry an increased risk of CLL.[5] SNPs are implicated in 41 loci which shows the familial predisposition. Environmental factors associated with CLL include exposure to Agent Orange and insecticides. The U.S. Department of Veteran Affairs allows veterans access to benefits if they were exposed to Agent Orange while serving in the military.[11] Evidence has also shown that insecticides might be a risk factor for CLL. There is limited evidence that viral infections and ionizing radiation increase CLL risk. Other environmental exposures proposed as risk factors, such as blood transfusions, diet, or other lifestyle factors, have not been supported by current evidence.[9]

Like many diseases, the incidence of chronic lymphocytic leukemia is significantly impacted by geographical region, gender, race, and age. Globally, CLL is estimated to comprise 191,000 cases and 61,000 deaths.[12] Geographically, CLL varies significantly mainly between Western and Eastern countries, with incidence rates among Japan and China occurring at around 10% of Western countries.[13][14] More specifically, the incidence in Asia compared to Europe and the United States is 0.01% and 0.06%, respectively. Further global differences are also seen, with CLL incidence being higher in African countries than in Asian countries but not in their U.S. or European counterparts.[15][16] In the Western world, CLL is considered the most common type of leukemia, with the United States alone accounting for roughly 25 to 35% of all leukemia cases.[1][2][3] U.S data on CLL shows approximately 20,160 newly diagnosed patients annually, with 12,360 and 7,530 of those cases being males and females, respectively. As seen from U.S case distributions in gender, CLL has a significant predilection for males. Specifically, data has shown an approximate male-to-female ratio of 1.2:1 to 1.7:1 with an annual incidence rate of 6.75 and 3.65 cases per 100,000 population in males and females, respectively.[3][7] This male predilection is further supported, with European male-to-female annual incidence rates being 5.87 and 4.01 cases per 100,000 population, respectively.[17] In addition to gender, CLL also has a predilection for older individuals, with the median age at diagnosis being around 70 years old.[18] Lastly, CLL differs by race, with the highest incidence among White individuals. In contrast, the incidence decreases in Hispanic and African Americans and is the least in the Asian population.[7][19]

Chronic lymphocytic leukemia is a neoplasm of mature B cells almost always preceded by monoclonal B cell lymphocytosis (MBL) which refers to an absolute increase in peripheral blood lymphocytosis less than 5000/microL without any disease manifestations. Pathogenesis of the disease is complex and consists of multiple factors leading to the clonal expansion of CD5 mature B cells in the peripheral blood, bone marrow, and lymph nodes. As MBL worsens, clinical manifestations relating to the abnormal B cell accumulation and subsequent lack of function become apparent. For instance, decreased functional B cells from MBL hinder the body’s ability to generate immunoglobulins, resulting in hypogammaglobulinemia and ultimately leading to an impaired immune system which is often observed as the disease progresses. The abnormal clonal B cells fail to undergo apoptosis and can continue to proliferate in the lymph nodes resulting in lymphadenopathy, a common manifestation of the disease. Furthermore, in the disease process, neoplastic B cell precursors infiltrate the bone marrow leading to impaired hematopoiesis and peripheral blood cytopenia. Infiltration into the spleen leading to splenomegaly is also observed, resulting in increased sequestration of platelets and red blood cells, which may worsen cytopenia.[20] At the molecular level, the pathogenesis of  CLL is driven by impaired cell apoptosis and increased cell proliferation secondary to genetic abnormalities and aberrant cellular signaling. Over the last decade, significant technological developments in the field of molecular biology have advanced the knowledge of the pathogenesis of CLL. With the advent of FISH (fluorescent in-situ hybridization) technology, it has been found that around 80% of CLL tumors have at least one of four common chromosomal abnormalities. These cytogenetic abnormalities include del(13q14), Trisomy 12, del(11q22-23), and del(17p12), all of which are restricted to B cells.

At the molecular level, the pathogenesis of  CLL is driven by impaired cell apoptosis and increased cell proliferation secondary to genetic abnormalities and aberrant cellular signaling. Over the last decade, significant technological developments in the field of molecular biology have advanced the knowledge of the pathogenesis of CLL. With the advent of FISH (fluorescent in-situ hybridization) technology, it has been found that around 80% of CLL tumors have at least one of four common chromosomal abnormalities. These cytogenetic abnormalities include del(13q14), Trisomy 12, del(11q22-23), and del(17p12), all of which are restricted to B cells. The most common chromosomal abnormality, del(13q14), is observed in approximately 50 to 60% of CLL tumors and pertains to miR15A and miR16A, microRNA deleted regions.[21] These microRNA regions, discussed in more detail later on, regulate the expression of proteins needed for cell apoptosis and, consequently, the normal cell cycle. Therefore, without these microRNA regions, cells cannot appropriately react to stress signals, thereby promoting apoptosis and contributing to the disease process. Additionally, miR16A and miR15A, both found in CLL cells with 13q deletion, upregulates the B cell leukemia/lymphoma (BCL2) gene in CD5+ cells leading to activation of the BCL-2 proto-oncogene aberrant signaling pathway, contributing to the disease process.[22][21] The second most common chromosomal abnormality, Trisomy 12, is found in approximately 10 to 20% of CLL tumors and is involved in the upregulation of the gene RUNX3.[23] Currently, the involvement of the RUNX3 gene and the overall impact of Trisomy 12 on CLL remains unclear and is a topic of further research.[23] Del(11q22-23) has also been found in approximately 10 to 20% of CLL tumors.[24] This deleted region has the ataxia-telangiectasia (ATM) gene, which is responsible for detecting damaged DNA, which plays a crucial function in the normal cell cycle and, ultimately, cell apoptosis.[24]

The second most common chromosomal abnormality, Trisomy 12, is found in approximately 10 to 20% of CLL tumors and is involved in the upregulation of the gene RUNX3.[23] Currently, the involvement of the RUNX3 gene and the overall impact of Trisomy 12 on CLL remains unclear and is a topic of further research.[23] Del(11q22-23) has also been found in approximately 10 to 20% of CLL tumors.[24] This deleted region has the ataxia-telangiectasia (ATM) gene, which is responsible for detecting damaged DNA, which plays a crucial function in the normal cell cycle and, ultimately, cell apoptosis.[24] Understanding this cytogenetic abnormality plays an important role in treatment. CLL cells without or with an abnormal ATM gene function cannot correctly respond to DNA damage induced by chemotherapy and ultimately fail to undergo apoptosis. Del(17p12) is detected in approximately 4-10% of CLL tumors. Del(17p12) leads to the loss of the TP53 gene, which plays a crucial role in cell apoptosis and DNA damage repair. The presence of either Del(17p12) or TP53 mutations has treatment implications; for example, chemotherapeutic agents that work by inducing DNA damage are ineffective in the presence of these mutations.[25][26] In addition to genetic abnormalities, certain gene mutations are vital to CLL pathogenesis, and multiple subpopulations of evolving malignant cells have been identified.[27][28] These alterations affect intracellular or microenvironment-dependent signaling pathways. Genes involving intracellular signaling pathways include those affecting DNA damage (TP53, ATM, POT1), chromatin modifiers (ASXL1, SETD2, HIST1H1B, HIST1HIE, BAZ2A, ZMYM3, SYNE1, CHD2, ARID1, KMT2D), RNA splicing and metabolism (XPO1, MED12, SF3B1, CNOT3, U1, FUBP1, DDX3X, RPS15, ZNF292). Genes involving microenvironment-dependent signaling include the MAPK-ERK pathway (PTPN11, MAP2K1, KRAS, BRAF, NRAS), Notch signaling (FBXW7, NOTCH1), NF-kB signaling (EGR2, TRAF2, TRAFR3, NFKB2, NRKBIE, BIRC3, NKAP), and B cell receptor (BCR) and Toll-like receptor signaling (IRF4, BCOR, TLR2, KLHL6, IRAK1, PAX5, MYD88).[29][30][27][31]

In addition to genetic abnormalities, certain gene mutations are vital to CLL pathogenesis, and multiple subpopulations of evolving malignant cells have been identified.[27][28] These alterations affect intracellular or microenvironment-dependent signaling pathways. Genes involving intracellular signaling pathways include those affecting DNA damage (TP53, ATM, POT1), chromatin modifiers (ASXL1, SETD2, HIST1H1B, HIST1HIE, BAZ2A, ZMYM3, SYNE1, CHD2, ARID1, KMT2D), RNA splicing and metabolism (XPO1, MED12, SF3B1, CNOT3, U1, FUBP1, DDX3X, RPS15, ZNF292). Genes involving microenvironment-dependent signaling include the MAPK-ERK pathway (PTPN11, MAP2K1, KRAS, BRAF, NRAS), Notch signaling (FBXW7, NOTCH1), NF-kB signaling (EGR2, TRAF2, TRAFR3, NFKB2, NRKBIE, BIRC3, NKAP), and B cell receptor (BCR) and Toll-like receptor signaling (IRF4, BCOR, TLR2, KLHL6, IRAK1, PAX5, MYD88).[29][30][27][31] Of the many somatic gene mutations described, four alterations, NOTCH1, ATM, SF3B1, and TP53 mutations, are detected in over 5% of patients. Notch proteins control the development of hematopoietic cells by working as transmembrane receptors for the cell. Mutations in the coding and non-coding regions of these NOTCH1 proto-oncogenes can lead to worsening disease through splicing events and an overall increase in their activity.[32] ATM, as mentioned earlier, is a gene responsible for detecting damaged DNA and inducing cell apoptosis.[24] SF3B1 is the gene responsible for nuclear ribonucleoproteins that create spliceosomes needed for messenger RNA splicing, ultimately affecting the cell cycle.[30][33][34] TP53, as mentioned earlier, is crucial for responding to DNA damage and inducing cell apoptosis.[25][26] Another genetic abnormality significant in the pathogenesis of CLL includes aberrant expression of microRNA (miRNA), which are small non-coding RNAs that work at the post-transcriptional level. Studies involving miRNA expression in CLL have found direct associations with disease prognosis. For instance, a study of 56 CLL patients found that miR21 and miR155 were overexpressed in nearly all of the analyzed samples.[35]

Another genetic abnormality significant in the pathogenesis of CLL includes aberrant expression of microRNA (miRNA), which are small non-coding RNAs that work at the post-transcriptional level. Studies involving miRNA expression in CLL have found direct associations with disease prognosis. For instance, a study of 56 CLL patients found that miR21 and miR155 were overexpressed in nearly all of the analyzed samples.[35] Further illustrating this involvement, a more extensive study found significantly elevated plasma miR155 levels in the study subjects with CLL compared to the standard control sample. This same study also found that miR155 was associated with higher mortality and refractory disease burden.[36] MicroRNA expression is controlled through epigenetic modifications involving enzymes and tumor suppressor genes, such as histone deacetylase activity and TP53, respectively.[37][38] Histone deacetylase activity downregulates the expression of miR29b, miR16, and miR15a.[37] While TP53 directly activates miRNA clusters at the 11q location, upregulating miR34b and miR-34c.[38] Another important miRNA is miR150, which in low levels has been associated with high expression levels of FOXP1 and GAB1, both genes involved in BCR signaling in CLL.[39] Outside of the specific gene mutations in CLL, aberrant signaling pathways also play a crucial role in the pathobiology of CLL. The three main pathways implicated include antigen-independent BCR signaling, BCL2 proto-oncogene upregulation, and impaired DNA damage response, with the latter two discussed earlier. The antigen-independent BCR signaling pathway directly affects cell survival, growth, differentiation, and cellular adhesion or migration through antigen-independent or antigen-dependent autonomous signaling of CLL cells. As mentioned above, it is affected by low levels of miR150 and high FOXP1 and GAB1 expression.[39] BCR activation leads to the upregulation of kinases PI3K, SYN, BTK, and LYN, which leads to cytoplasmic domain integrin activation and conformational changes leading to more ligand binding to integrin’s extracellular activity, ultimately affecting cell proliferation, migration, differentiation, and survival.[40]

Outside of the specific gene mutations in CLL, aberrant signaling pathways also play a crucial role in the pathobiology of CLL. The three main pathways implicated include antigen-independent BCR signaling, BCL2 proto-oncogene upregulation, and impaired DNA damage response, with the latter two discussed earlier. The antigen-independent BCR signaling pathway directly affects cell survival, growth, differentiation, and cellular adhesion or migration through antigen-independent or antigen-dependent autonomous signaling of CLL cells. As mentioned above, it is affected by low levels of miR150 and high FOXP1 and GAB1 expression.[39] BCR activation leads to the upregulation of kinases PI3K, SYN, BTK, and LYN, which leads to cytoplasmic domain integrin activation and conformational changes leading to more ligand binding to integrin’s extracellular activity, ultimately affecting cell proliferation, migration, differentiation, and survival.[40] Lastly, the antigen-independent BCR signaling pathway is also affected by somatic mutations of immunoglobulin heavy chain variable region (IGHV) genes. Mutated IGHV has weaker BCR signaling through narrower antigen specificity, resulting in higher mutation burden and lower driver mutation frequency. Because of this, mutated IGHV CLL cells have a slower proliferation making the disease process more benign and less clinically aggressive. Contrarily, unmutated IGHV CLL cells have sustained BCR signaling by binding to multiple epitopes resulting in lower mutation burden and higher driver mutation frequency. Ultimately this process leads to quicker clonal expansion and more clinically aggressive disease.[29][30][41]

The lymph node architecture is effaced by small mature lymphocytes with condensed nuclear chromatin. Pseudofollicles have a pale nodular appearance due to the proliferation of large lymphocytes having open nuclear chromatin and more abundant cytoplasm. Chronic lymphocytic leukemia is a low-grade B-cell malignancy and is often characterized by a low proliferation index except for pseudofollicles, which may show increased Ki-67 expression. The expression of CD20, CD5, and CD23 by the neoplastic cells either by flow cytometry or immunohistochemistry is diagnostic of CLL. Additional findings include smudge cells found as cellular debris and commonly associated with the disease.[42]

Chronic lymphocytic leukemia is often an incidental diagnosis in an asymptomatic patient found to have peripheral blood lymphocytosis on complete blood picture evaluation. However, approximately 5 to 10% of patients present with one or more “B” symptoms, including Fevers of >100.5 F (38 C) for two or more weeks without evidence of infection, night sweats without evidence of injections, extreme fatigue, or unintentional weight loss of ≥10 percent of body weight in the last six months.[42] The physical examination can reveal lymphadenopathy in 50 to 90% of patients.[43][44] Lymphadenopathy commonly affects cervical, supraclavicular, and axillary lymph node regions with enlarged lymph nodes that are round, non-tender, firm, and mobile. Organomegaly can occur with splenomegaly and hepatomegaly identified in 25 to 55% and 15 to 25% of patients, respectively.[43][44] Cutaneous involvement, which is the most common extra lymphoid presentation of the disease manifesting as presenting as papules, blisters, ulcers, macules, and nodules, is rare, occurring in only 5% of the cases.[45][46] Skin biopsy can differentiate it from Richter transformation. Uncommonly, hyperleukocytosis can lead to cerebrovascular accidents such as strokes and transient ischemic attacks secondary to increased blood hyperviscosity.[47]

Chronic lymphocytic leukemia should be suspected in the presence of the above-described clinical findings or laboratory findings such as lymphocytosis, cytopenias, or immunoglobulin abnormalities. The necessary tests for initial assessment and diagnosis of CLL consist of a complete blood count with differentials (CBC w/Diff), peripheral smear, and flow cytometry.[42] CLL is diagnosed using the updated 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) national cancer institute guidelines. As per the criteria, CLL is diagnosed with a peripheral blood monoclonal B-cell lymphocytosis more than or equal to 5,000 /microL [≥ 5 × 109 /L] sustained for at least three months. Peripheral blood smear findings include smudge cells, leukemic cells with a narrow border of cytoplasm, and a dense nucleus with indiscernible nucleoli. Clonality of the B lymphocytes is confirmed through flow cytometry on the peripheral blood or bone marrow aspirate, revealing immunoglobulin light chain restriction. Other findings include coexpression of B-cell-associated antigens (CD23, CD20, and CD19) and mature B and T-cell antigens (CD5). Sometimes, a biclonal population is identified, one with kappa and the other with lambda light chain restriction. A recent study estimated biclonality in 1.4% of CLL cases.[48] Peripheral blood fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) or Sanger sequencing analysis are useful prognostication tools and may affect treatment options. For instance, loss of ATM gene or identification of Del(11q22-23) and loss of TP53 or identification of Del(17p12), which leads to the loss of TP53, is associated with poor response to drugs whose mechanism of action involves DNA damage.[25][26] Del(17p) and TP53 mutations are estimated to affect approximately 7 to 10% of treatment-naive CLL patients and 10-47% of all CLL patients, respectively.[49][50][51] NGS can also detect immunoglobulin heavy chain variable region (IGHV) gene mutation as a 2% or more difference in nucleotide sequence compared to germline DNA. CLL with mutated IGHV are clinically less aggressive and have a low frequency of driver mutations.[29][41][52]

Asymptomatic Patients Patients without significant symptoms or laboratory abnormalities such as severe cytopenia or significant hypogammaglobulinemia are observed without treatment for signs of progression since there is no evidence to support clinical benefit. Rather treatment initiation in asymptomatic patients is associated with a risk of toxicity without clinical benefit.[53][54][55] International prognostic score (IPS-E) risk stratification, based on three risk factors: absolute lymphocyte count greater than 15,000/microL, presence of palpable lymph nodes, and unmutated IGHV, is a valuable tool in predicting the likelihood of treatment initiation in asymptomatic patients. Patients with no risk factors are considered low risk and have less than one percent likelihood of requiring treatment at one year and eight percent at five years. Those with one out of three risk factors are considered to be an intermediate risk, with three percent expected to require treatment by one year and twenty-eight percent at five years. Finally, those with two or three risk factors are considered high risk. It is expected that fourteen percent will need treatment at one year and sixty-one percent at five years.[56] Symptomatic Disease Treatment for CLL is indicated in patients with significant clinical symptoms from CLL or in the presence of laboratory abnormalities such as significant cytopenia and symptomatic hypogammaglobulinemia. The International Workshop on Chronic Lymphocytic Leukemia (iWCLL) requires the presence of at least one criterion to diagnose the active disease: signs of worsening marrow failure, such as progressive or new thrombocytopenia, anemia, splenomegaly, or lymphadenopathy that is symptomatic or progressive, autoimmune anemia or thrombocytopenia not responsive to steroids, extranodal involvement, and constitutional symptoms such as weight loss, severe fatigue, fevers or night sweats.[42]

Treatment for CLL is indicated in patients with significant clinical symptoms from CLL or in the presence of laboratory abnormalities such as significant cytopenia and symptomatic hypogammaglobulinemia. The International Workshop on Chronic Lymphocytic Leukemia (iWCLL) requires the presence of at least one criterion to diagnose the active disease: signs of worsening marrow failure, such as progressive or new thrombocytopenia, anemia, splenomegaly, or lymphadenopathy that is symptomatic or progressive, autoimmune anemia or thrombocytopenia not responsive to steroids, extranodal involvement, and constitutional symptoms such as weight loss, severe fatigue, fevers or night sweats.[42] Multiple treatment combinations are available, but with limited evidence directly comparing the treatment options. Following are the important classes of drugs commonly used in the treatment of CLL: BTK inhibitors (Bruton tyrosine kinase), including ibrutinib and acalabrutinib, BCL2 inhibitor venetoclax, anti-CD-20 monoclonal antibodies rituximab, ofatumumab, obinutuzumab, alkylating agents such as chlorambucil, cyclophosphamide, bendamustine and purine analogs such as fludarabine and pentostatin Factors affecting the treatment selection include stage, molecular and cytogenetic characteristics of the disease, patient fitness, and goals of care for treatment. Some important molecular and cytogenetic considerations impacting treatment selection are discussed below. The presence of del 17p or TP53 mutations is associated with poor response to cytotoxic chemotherapeutic regimens, including purine analog-based regimens. However, there is clinical evidence supporting the efficacy of BTK inhibitors such as Ibrutinib and acalabrutinib and BCL-2 inhibitor venetoclax as monotherapy or in combination with anti-CD 20 monoclonal antibodies.[57][58][59] Another molecular factor predictive of treatment response is the IGHV mutation status. Unmutated IGHV is a marker of aggressive disease, and similar to TP53 or del 17p mutations, BCL-2 inhibitors and BTK inhibitors are effective in the presence of unmutated IGHV compared to purine analog-based regimens.[60]

Differential diagnoses caused by clonal lymphocytosis include: Prolymphocytic Leukemia The condition presents with lymphadenopathy and organomegaly. However, this condition differs from CLL as prolymphocytes in the smear differ from CLL cells.[61][62] Hairy Cell Leukemia (HCL) HCL can present with lymphocytosis, organomegaly, and cytopenias. However, HCL rarely presents with lymphadenopathy as opposed to CLL. Additionally, HCL immunophenotyping and smear will show distinct differences from CLL.[63] Follicular Lymphoma (FL) FL presents similarly to CLL, with both tumor cells being similar in size and having similar clinical findings such as waxing and waning diffuse painless lymphadenopathy. However, it differs from CLL as biopsy will show a nodular growth pattern usually not seen in CLL. In cases where CLL does have a similar growth pattern to FL, further examination of FL cells will reveal irregular nuclear centrocytes and larger centroblasts as opposed to CLL cells which have round to oval nuclei.[64] Lymphoplasmacytic Lymphoma (LPL) LPL is a lymphoproliferative disorder that can present clinically similar to CLL.[42][65] Laboratory findings will show that patients with LPL have a monoclonal paraprotein spike which can also be seen in CLL. Additionally, a minority of LPL can also be positive for CD5, as seen with CLL. However, both conditions can be differentiated as CLL’s M-spike will be below 0.5g/dL as opposed to LPL, where M-spike is always over 0.5 g/dL.[66] Mantle Cell Lymphoma (MCL) MCL can share clinical and morphological features with CLL as both conditions present a leukemic phase, cells with nuclear irregularities, and positive CD5 and CD20 markers. However, both conditions differ, with CLL cells having negative cyclin D1 and a large portion positive for CD23, as opposed to MCL, which has the complete opposite.[67] Furthermore, in cases where CLL and MCL share both cyclin D1 and CD23 findings, biopsies showing clear center lymphoid proliferation centers will exclude MCL.[68] Lastly, MCL will differ from CLL by having FISH studies positive for t(11:14). Splenic Marginal Zone Lymphoma (SMZL)

MCL can share clinical and morphological features with CLL as both conditions present a leukemic phase, cells with nuclear irregularities, and positive CD5 and CD20 markers. However, both conditions differ, with CLL cells having negative cyclin D1 and a large portion positive for CD23, as opposed to MCL, which has the complete opposite.[67] Furthermore, in cases where CLL and MCL share both cyclin D1 and CD23 findings, biopsies showing clear center lymphoid proliferation centers will exclude MCL.[68] Lastly, MCL will differ from CLL by having FISH studies positive for t(11:14). Splenic Marginal Zone Lymphoma (SMZL) CLL and SMZL will both have peripheral smear lymphocytosis and share expression for CD5, CD43, CD23, and IgD. Additionally, both can also present with splenomegaly. However, SMZL can express CD20 and bright SmIg, both findings not seen in CLL.[69][70][71] Furthermore, CLL differs from SMZL in center lymphoid proliferation centers not seen in the latter.[72] Differential diagnoses caused by reactive lymphocytosis include infections. Infections in which lymphocytosis significantly occurs include pertussis, infectious mononucleosis, and toxoplasmosis. In viral infections, peripheral smear will show activated T cells as atypical lymphocytes, in which the cells have large cytoplasms containing azurophilic granules. However, lymphocytosis is non-clonal and transient for all these infections, with white blood cell (WBC) counts normalizing within weeks, unlike in CLL, where lymphocytosis is clonal and persists for over three months. Furthermore, due to the non-clonal causes of lymphocytosis, immunophenotyping through flow cytometry will fail to show the diagnostic findings required for CLL.

Research is still ongoing concerning optimal treatment selection and sequencing of various options in the course of treatment. For example, one recent study evaluated patients in the early stage of chronic lymphocytic leukemia who were not in an active disease state.[73] The study focused on chemotherapy compared to no intervention but rather an observation. When used in this population, ibrutinib leads to a delayed onset of progression to the active stage of the disease. It also leads to a decreased necessity for patients requiring more targeted therapies in the future for CLL. However, findings on ibrutinib have also shown increased toxicity. Unfortunately, the available research is still limited, and in this case, the long-term outcomes are unclear, including survival rates and widespread clinical application of these interventions early on. Therefore, guidelines remain that patients in early-stage who are not showing any signs of active disease should remain in observation.

Chronic lymphocytic leukemia staging uses two stratification systems: Binet staging, primarily used in Europe, and the modified Rai-Sawitsky staging, primarily used in the United States. Both systems, as illustrated below, use a complete blood count and physical exam findings to stratify the patients into low, intermediate, and high-risk groups.[44][43] Modified Rai Clinical Staging System for CLL Low Risk: Stage 0: Lymphocytosis in peripheral blood or bone marrow. Intermediate Risk: Stage I: Lymphocytosis plus lymphadenopathy (enlarged lymph nodes). Stage II: Lymphocytosis plus hepatomegaly or splenomegaly with or without lymphadenopathy. High Risk: Stage III: Lymphadenopathy plus anemia (hemoglobin < 11 g/dL) plus organomegaly (spleen or liver) with or without lymphadenopathy. Stage IV: Lymphadenopathy plus thrombocytopenia (platelet <100,000/MCL) with or without organomegaly (spleen or liver) or lymphadenopathy.[43] Binet Staging System for CLL Low Risk Stage A: ≤ 2 involved sites of lymphoid enlargement* with no anemia or thrombocytopenia. Intermediate Risk Stage B: ≥ 3 lymphoid enlargement involved sites* with no anemia or thrombocytopenia. High Risk Stage C: Same lymphoid enlargement as stage A or B, but with the presence of anemia (hemoglobin < 10 g/dL) or thrombocytopenia (platelet < 100,000/mcL).[44] * Lymphoid-bearing sites: Cervical lymph nodes, axillary lymph nodes, inguinal-femoral lymph nodes, liver, and spleen[44]

CLL prognosis is largely determined by the Rai and Binet staging systems and other etiologies causing cytopenia, including marrow failure, autoimmune cytopenias, or prior therapy. A large retrospective study found that CLL patients with autoimmune cytopenias have an overall better prognosis when compared to bone marrow-induced cytopenias.[74] As detailed earlier under the staging section, the Rai and Binet systems relate directly to prognosis. A published series from 1975 showed that Rai low-risk stage 0 comprised 18% of cases and had a historical median overall survival (OS) of over 150 months.[43] The intermediate risk, Rai stage I and stage II, comprised 23% and 31% of cases and an estimated median OS of 101 months and 71 months, respectively. At high risk, Rai stage III and IV comprised 17% and 11% of cases, respectively, and both had a median OS of 19 months.[43] As previously illustrated, the Binet staging system also risk stratifies patients into low, intermediate, and high-risk categories. Published data from 1981 showed that Binet stage A had a comparable median OS to age-matched controls, while stage B and stage C had a median OS of 84 and 24 months, respectively.[75][44] Following the established Rai and Binet staging systems, other prognostic scores/indexes on further CLL variant genetics include the CLL international prognostic index (CLL-IPI), CLL1 prognostic model (CLL1-PM), International Prognostic Score for Early-stage CLL (IPS-E), and Four Factor Prognostic Model for Ibrutinib. CLL-IPI CLL-IPI's system parameter consists of 4 points for TP53 mutations or Del(17p), 2 points for >3.5 mg/L of serum beta-2 immunoglobulin, 2 points for unmutated IGHV, 1 point for intermediate or high-risk Binet or Rai staging, and 1 point for age greater than 65 years. The point score system divides into four different groups, with 0 to 1 point being low risk, 2 to 3 points being intermediate risk, 4 to 6 points being high risk, and 7 to 10 points being very high risk. The scoring system was established and validated from extensive studies, which showed the 5 to 10-year OS of low risk at 91 to 87%, intermediate risk at 80 to 40%, high risk at 53 to 16%, and very high risk at 19 to 0%.[76] CLL1-PM

CLL-IPI's system parameter consists of 4 points for TP53 mutations or Del(17p), 2 points for >3.5 mg/L of serum beta-2 immunoglobulin, 2 points for unmutated IGHV, 1 point for intermediate or high-risk Binet or Rai staging, and 1 point for age greater than 65 years. The point score system divides into four different groups, with 0 to 1 point being low risk, 2 to 3 points being intermediate risk, 4 to 6 points being high risk, and 7 to 10 points being very high risk. The scoring system was established and validated from extensive studies, which showed the 5 to 10-year OS of low risk at 91 to 87%, intermediate risk at 80 to 40%, high risk at 53 to 16%, and very high risk at 19 to 0%.[76] CLL1-PM CLL1-PM and IPS-E are scores used for prognosis evaluation of early-stage CLL. CLL1-PM is a scoring system consisting of 14 points comprised of Del(17p) at 3.5 points, unmutated IGHV at 2.5 points, Del(11q) at 2.5 points, >3.5 mg/L of serum beta-2 microglobulin at 2.5 points, less than 12 months of lymphocyte doubling time at 1.5 points, and age greater than 60 years at 1.5 points. They are divided into very low risk at 0 to 1.5 points, low risk at 2 to 4 points, high risk at 4.5 to 6.5 points, and very high risk at 7 to 14 points, with their 5 to 10 year OS being 86 to 67%, 52 to 26%, 28 to 3%, and 11 to 0%, respectively.[77][53] IPS-E The IPS-E stratifies CLL patients by three risk factors: palpable lymph nodes, lymphocytosis (>15,000/microL), and unmutated IGHV. Those with no risk factors are low risk, those with one risk factor are intermediate risk, and those with 2-3 risk factors are high risk. The three risk groups have shown that the 1-year likelihood percent of requiring treatment is less than 1%, 3%, and 14% for low risk, intermediate-risk, and high risk, respectively. For the 5-year likelihood percent of requiring treatment, data shows 8%, 28%, and 61% for low risk, intermediate-risk, and high risk, respectively.[56] Four Factor Prognostic Model

The IPS-E stratifies CLL patients by three risk factors: palpable lymph nodes, lymphocytosis (>15,000/microL), and unmutated IGHV. Those with no risk factors are low risk, those with one risk factor are intermediate risk, and those with 2-3 risk factors are high risk. The three risk groups have shown that the 1-year likelihood percent of requiring treatment is less than 1%, 3%, and 14% for low risk, intermediate-risk, and high risk, respectively. For the 5-year likelihood percent of requiring treatment, data shows 8%, 28%, and 61% for low risk, intermediate-risk, and high risk, respectively.[56] Four Factor Prognostic Model The Four Factor Prognostic Model for Ibrutinib is a 4-point system consisting of 1-point variables of>250 units/L of lactate dehydrogenase, Del(17p) or TP53 mutations, ≥5 mg/L serum beta-2 microglobulin, and refractory or relapsed disease. Those with 0-1 points are low-risk, 2 points are intermediate-risk, and 3-4 points are high-risk. Data shows the 3-year OS is 93%, 83%, and 63% for low-risk, intermediate-risk, and high-risk groups, respectively.[78] Relating to CLL variant genetics, recent advancements in technology and science have provided markers that aid in predicting disease course and assessing disease prognosis, some aiding in both.[79] TP53 mutations and Del(17p), which lead to loss of Tp53 function, are two significant predictive markers, given that they predict worse outcomes with chemoimmunotherapy compared to targeted therapies such as BLC2 and BTK inhibitors. Additionally, TP53 mutations and Del(17p) are currently both prognostic markers used in all therapies available, as individuals with these markers have been found to have poorer outcomes when compared to those without them.[80] IGHV mutations are also important predictive markers, occurring in close to 50% of CLL tumors.[81][82][83] Complex karyotype with greater than five abnormalities predicts poor prognosis independent of TP53 or IgVH status. From a predictive aspect, studies have shown that CLL patients with IGHV mutations have a prolonged-lasting disease remission status post chemoimmunotherapy compared to those with unmutated IGHV.

IGHV mutations are also important predictive markers, occurring in close to 50% of CLL tumors.[81][82][83] Complex karyotype with greater than five abnormalities predicts poor prognosis independent of TP53 or IgVH status. From a predictive aspect, studies have shown that CLL patients with IGHV mutations have a prolonged-lasting disease remission status post chemoimmunotherapy compared to those with unmutated IGHV. Additionally, the CLL14 trial in 2020 showed that unmutated IGHV was a predictive marker for treatment benefits when comparing venetoclax with obinutuzumab to obinutuzumab with chlorambucil.[80] Also associated with unmutated IGHV are NOTCH1 mutations. However, this marker's current data is unclear and is still under investigation for confirmatory findings.[76] The last predictive markers discussed include BLC2, BTK, and PLCg2 mutations, which can predict treatment efficacy and are often tested after initiating treatment. Specifically, studies have shown worse predicted clinical outcomes in those with BTK and PLCg2 mutations and status post-treatment with BCR inhibitors. Regarding BCL2 mutations, studies have shown that those with the mutation and treated with venetoclax have worse predicted clinical outcomes when treated with venetoclax therapy again.[84][85][86] Lastly, two other factors associated with worsening prognosis include lymphocyte doubling time, particularly in less than 12 months, and Beta-2 microglobulin.[87][88]

Infections are one of the most common complications of chronic lymphocytic leukemia, both before and post-treatment, due to an abnormal functioning humoral and cell-mediated immune system. Mainly due to the immunocompromised state from both disease and treatments, patients are primarily susceptible to opportunistic infections such as herpes simplex virus, cytomegalovirus, pneumocystis jirovecii, Aspergillus, and mycobacterial pathogens.[89][90][91][92] Hematologic complications are often seen, given the nature of the disease. Anemia is one of CLL's most common complications, mainly due to marrow infiltration from disease progression, marrow suppression from chemotherapy, autoimmune hemolytic anemia, hypersplenism, red cell aplasia, and gastrointestinal blood loss due to treatments and disease complications. Autoimmune hemolytic anemia is estimated to occur in approximately 4 to 10% of CLL cases throughout the disease course.[93][94] Red cell aplasia is somewhat of a rare complication, with incidence not fully understood at this time; however, it is estimated to occur in 0.5% of CLL cases.[95] Thrombocytopenia can present as a complication at any time throughout the disease course from many etiologies, including disease burden on platelet suppression, treatments, infections, and autoimmune disease. Immune thrombocytopenia (ITP) is a significant complication, occurring in 2 to 5% of CLL cases.[96] Leukostasis is a complication that is a medical emergency and typically becomes symptomatic when WBC counts exceed 400,000/microL. Gastrointestinal-related complications from CLL treatments include severe colitis and life-threatening diarrhea due to idelalisib and phosphoinositide 3-kinase (PI3K) delta inhibitor. Furthermore, Idelalisib can also cause hepatotoxicity. In addition to gastrointestinal involvement, pneumonitis is another potentially fatal treatment complication of idelalisib and ibrutinib.[97] Secondary cancers related to CLL are largely hematologic and solid malignancies, including colon, lung, prostate, and breast.[98] Furthermore, aggressive lymphoma, commonly known as Richter syndrome or Richter transformation, occurs in approximately 1 to 10% of CLL cases.[99][100]

Education plays a significant role in caring for patients with chronic lymphocytic leukemia. It begins from the diagnosis and continues throughout the patient's disease course. It must be carried out as a multidisciplinary approach, including all the healthcare workers the patient encounters. The importance of proper education is especially highlighted in patients diagnosed at an early stage and without active disease. In these patients, evidence-based research supports observation and no intervention.[42] Providing the appropriate and necessary education to the patient, family members, or caregivers as to why observation is the ideal course at that moment can create a very frustrating situation for those seeking immediate intervention. Additionally, it is also vital to discuss opportunities such as clinical trials. In some circumstances, even though observation is the recommendation, some patients can still be eligible for clinical trials. Lastly, it is essential for physicians caring for patients with CLL to keep up-to-date on available clinical trials, research, and updates in management recommendations. Although this is, in general, a necessary medical concept, it is particularly significant for CLL given ongoing investigations, evolving guidelines, and medication availability.

Optimizing patient care for chronic lymphocytic leukemia requires interprofessional communication between clinicians (MDs, DOs, NPS, and PAs) of different specialties, including primary care clinicians, hematology, and oncology. Care coordination among nursing staff, home health care support teams, pharmacists, case management, and social workers is crucial. Oncology specialized pharmacists can make critical contributions, coordinating their input with the clinicians ordering drugs, verifying appropriate dosing, performing medication reconciliation, and providing counsel to patients and nurses. Other considerations that could enhance patient-centered care include support from hospice care teams, psychiatry, therapists, or mental health professionals. All interprofessional team members must maintain accurate and up-to-date records of every interaction or intervention with the patient, including any status changes. This will permit every team member to have the latest accurate patient case data. Any concerns must be immediately communicated to other team members to implement coordinated interventions if necessary. This interprofessional approach will yield the best possible outcomes for CLL patients. [Level 5] Participation in clinical trials should be encouraged whenever available and feasible. Continued medical education on the latest developments, clinical trial options, and ongoing research are encouraged, given the rapidly changing nature of the field of the disease.