Chronic lymphocytic leukemia

Source: Wikipedia, the free encyclopedia.
(Redirected from
B-cell chronic lymphocytic leukemia
)
"B-cell CLL" redirects here. For the gene family, see B-cell CLL/lymphoma.
Chronic lymphocytic leukemia
Other namesB-cell chronic lymphocytic leukemia (B-CLL)
Five-year survival ~88% (US)[3]
Frequency904,000 (2015)[6]
Deaths60,700 (2015)[7]

Chronic lymphocytic leukemia (CLL) is a type of

lymphocytes (a type of white blood cell).[2][8] Early on, there are typically no symptoms.[2] Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur.[2][9] Enlargement of the spleen and low red blood cells (anemia) may also occur.[2][4] It typically worsens gradually over years.[2]

Risk factors include having a family history of the disease, with 10% of those who develop CLL having such ancestry.

blood cells.[2]
CLL is divided into two main types:

Diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells.[5]

Early-stage CLL in

BTK inhibitors such as ibrutinib and acalabrutinib are often recommended for first line treatment of CLL.[12] The medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy.[13]

CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths.

Five-year survival following diagnosis is approximately 83% in the United States.[3] It represents less than 1% of deaths from cancer.[7]

Signs and symptoms

A diagram showing the cells affected by CLL

Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high

lymph nodes.[9] If enlarged lymph nodes are caused by infiltrating CLL-type cells, a diagnosis of small lymphocytic lymphoma (SLL) is made.[17] Less commonly, the disease comes to light only after the cancerous cells overwhelm the bone marrow, resulting in low red blood cells, neutrophils, or platelets.[9] Symptoms can be fever, night sweats, weight loss, and tiredness.[9]

CLL can be grouped with

liter (i.e. 0.5x9/L) while high-count CLL/SLL MBL has blood monoclonal B-cell counts ≥0.5x9/L but <5x109/L.[21] Individuals with blood counts of these monoclonal B-cells >5x9/L are diagnosed as having CLL. Low-count CLL/SLL MBL rarely if ever progresses to CLL while high-count CLL/SLL MBL does so at a rate of 1-2% per year. Thus, CLL may present in individuals with a long history of having high-count CLL/SLL MBL. There is no established treatment for these individuals except monitoring for development of the disorder's various complications (see treatment of MBL complications) and for their progression to CLL.[22][13]

Complications

Complications include a low level of antibodies in the bloodstream (

salivary gland tumors, and Kaposi's sarcomas.[28] While some of these conversions have been termed RTs, the World Health Organization[29] and most reviews[23] have defined RT as a conversion of CLL/SLL into a disease with DLBCL or HL histopathology. The incidence of this transformation is estimated to be around 5% in people with CLL.[30]

Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.[31]

Cause

CLL can also be caused by a number of epigenetic changes, which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of three different methyl subgroups (naïve B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed.[32][33] Some relevant genetic mutations may be inherited. Since there is no one single mutation that is associated with CLL in all cases, an individual's susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of CLL are co-inherited.[34] Up until 2020, 45 susceptibility loci have been identified. Of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling.[35] Exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk.[36] There is no clear association between ionizing radiation exposure and the risk of developing CLL.[36] Blood transfusions have been ruled out as a risk factor.[4]

Diagnosis

Micrograph of a lymph node affected by B-CLL showing a characteristic proliferation center (right of image), composed of larger, lighter-staining, cells, H&E stain

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. CLL is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 5000 cells per microliter (µl) of blood but can be much higher.[13] The presence of lymphocytosis in a person who is elderly should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.[37]

Molecular examination of peripheral blood and flow cytometry

The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by

flow cytometer instrument can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules, with fluorescent tags recognized by the instrument.[citation needed
]

In CLL, the lymphocytes are all genetically identical since they are derived from the same B cell lineage, expressing common B-cell markers CD19 and CD20, with abnormal expression of surface markers CD5 and CD23.[36] These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells and can indicate the presence of the disease.[38] Smudge cells are due to cancer cells lacking in vimentin, a type of cytoskeleton proteins which is a structural component in a cell which maintains the cell's internal shape and mechanical resilience).[39]: 1899 [40]

Smudge cells in peripheral blood

Surface markers

The atypical molecular pattern on the surface of the cell includes the coexpression of cell surface markers

FMC7
, CD22, and immunoglobulin light chain) Matutes's CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and mantle cell lymphoma (MCL malignant B cells).[42] Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54[43] and CD200.[44] Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. In contrast, FMC7 expression can surprisingly be misleading for borderline cases.[45]

Clinical staging

Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details[2]) and is based primarily on the presence of a low platelet or red cell count. Early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.[46]: 1441 

Rai staging system[47][48] (most commonly used in the United States) [49]

  • Stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia
  • Stage I: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia
  • Stage II: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy
  • Stage III: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly
  • Stage IV: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia

Binet classification[50] (most commonly used in Europe) [49]

  • Clinical stage A: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II)
  • Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II)
  • Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV)

Array-based karyotyping

Main article: Virtual karyotype

Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.[51][52][53][54][55][excessive citations]

Related diseases

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemias (T-PLL).[56][57] An accurate diagnosis of T-PLL is important as it is a rare and aggressive disease.[58]

CLL should not be confused with acute lymphoblastic leukemia, a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting.

Differential diagnosis

Lymphoid disorders that can present as chronic leukemia and can be confused with typical B-cell chronic lymphoid leukemia[59]
Follicular lymphoma
Splenic marginal zone lymphoma
Nodal marginal zone B cell lymphoma
Mantle cell lymphoma
Hairy cell leukemia
Prolymphocytic leukemia (B cell or T cell)
Lymphoplasmacytic lymphoma
Sézary syndrome
Smoldering
adult T cell leukemia/lymphoma

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.

  • B cell prolymphocytic leukemia, a related, but more aggressive disorder, has cells with similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differ from CLL.[60]
  • Hairy cell leukemia is also a neoplasm of B lymphocytes, but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression.[61]

All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow, and occasionally lymph node cells by a

FISH.[62]

Treatment

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. In those without or only minimal symptoms watchful waiting is generally appropriate.[2]

CLL is treated by

bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy – removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).[citation needed
]

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. Any of dozens of agents may be used for CLL therapy.[2]

Decision to treat

While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, asymptomatic early-stage CLL (Rai 0, Binet A) is, in general, not treated since it is believed that early-stage CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern.[2][63][64]

There are two widely used staging systems in CLL to determine when and how to treat the patient: The Rai staging system, used in the United States, and the Binet system in Europe. Both these systems attempt to characterize the disease based on the bulk and marrow failure.[2][49] A "watchful waiting" strategy is used for most patients with CLL.[49] The International Workshop on CLL (iwCLL) has issued guidelines with specific markers that should be met to initiate treatment, generally based on evidence for progressive symptomatic disease (summarized as "active disease").[64]

Chemotherapy

Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and longer progression-free survival than single agents:

Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy,[68][69] no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.

Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness.[70] This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of people with CLL.[citation needed]

Alkylating agents approved for CLL include bendamustine and cyclophosphamide.[citation needed
]

Targeted therapy

monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab).[2][71] Notably, some of the effects of the targeted therapies such as BCR inhibitors can be attributed to disrupting the interaction of CLL cells with tumour promoting T cells.[citation needed
]

Stem cell transplantation

allogeneic stem cell transplantation, may be better tolerated by older or frail patients.[72][73]

Refractory CLL

"Refractory" CLL is a disease that no longer responds favorably to treatment within six months following the last cancer therapy.[64] In this case, more aggressive targeted therapies, such as BCR or BCL2 pathway inhibitors, have been associated with increased survival.[74]

During pregnancy

Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women.

first trimester.[75]

Prognosis

Prognosis can be affected by the type of genetic mutation that the person with CLL has.[76] Some examples of genetic mutations and their prognoses are: mutations in the IGHV region are associated with a median overall survival (OS) of more than 20–25 years, while no mutations in this region is associated with a median OS of 8–10 years; deletion of chromosome 13q is associated with a median OS of 17 years; and trisomy of chromosome 12, as well as deletion of chromosome 11q, is associated with a median OS of 9–11 years.[2] While prognosis is highly variable and dependent on various factors including these mutations, the average 5-year relative survival is 86.1%.[77] Telomere length has been suggested to be a valuable prognostic indicator of survival.[78] In addition, a person's sex has been found to have an impact on CLL prognosis and treatment efficacy. More specifically, females have been found to survive longer (without disease progression) than males, when treated with certain medications.[79]

Epidemiology

CLL is the most common type of leukaemia in the Western world compared to non-Western regions such as Asia, Latin America, and Africa.[80] It is observed globally that males are twice as likely than females to acquire CLL.[80] CLL is primarily a disease of older adults, with 9 out of 10 cases occurring after the age of 50 years.[81] The median age of diagnosis is 70 years.[81] In young people, new cases of CLL are twice as likely to be diagnosed in men than in women.[82] In older people, however, this difference becomes less pronounced: after the age of 80 years, new cases of CLL are diagnosed equally between men and women.[82]

According to the American Cancer Society, in the United States, 13,040 males and 8,210 females (total of 21,250 people) are expected to be newly diagnosed with CLL in 2021.[83] In that same year, 2,620 males and 1,700 females (total of 4,320 people) are expected to die from CLL.[83] Because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy,[2] the prevalence (number of people living with the disease) is much higher than the incidence (new diagnoses). CLL is the most common type of leukemia in the UK, accounting for 38% of all leukemia cases. Approximately 3,200 people were diagnosed with the disease in 2011.[84]

In Western populations, subclinical "disease" can be identified in 3.5% of normal adults,[85] and in up to 8% of individuals over the age of 70.[86] That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

In contrast, CLL is rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions.[46]: 1432 [87] A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.[46]

Of all cancers involving the same class of blood cell, 7% of cases are CLL/SLL.[88][needs update]

People who live near areas with considerable industrial pollution have an elevated risk of developing leukemia, particularly CLL.[89]

Research directions

In light of new therapies such as targeted agents, the role of

bone marrow transplants is decreasing.[90] Bone marrow transplants are not recommended as a front-line therapy, and only recommended in specific cases where front-line therapies have either failed or there is a lack of response to BCL-2 inhibitors.[91]

Wikinews has related news:

Researchers at the

remission, while the presence of leukemia in the third patient reduced by 70%.[95][96][non-primary source needed][needs update
]

One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared.[97][needs update] The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return.[95] This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease".[98]

Research is also investigating therapies targeting

Syk inhibitors fostamatinib and entospletinib are currently in trials.[99][100] The trial of a combination of ibrutinib and venetoclax had encouraging results in a small number of people.[101]

People with CLL undergoing immunotherapy with

chimeric antigen receptor T cells have been found to have a high response rate.[102]

See also

References

  1. ISBN 9781420068962
    .
  2. ^ a b c d e f g h i j k l m n o p q r "Chronic Lymphocytic Leukemia Treatment". National Cancer Institute. 26 October 2017. Retrieved 19 December 2017.
  3. ^ a b c d "Chronic Lymphocytic Leukemia - Cancer Stat Facts". seer.cancer.gov. Retrieved 9 September 2022.
  4. ^
    PMID 28102226
    .
  5. ^
    ISBN 9780323529570
    .
  6. ^
    PMID 27733282
    .
  7. ^
    PMID 27733281
    .
  8. PMID 19331210
    .
  9. ^
    S2CID 3517733
    .
  10. ^
    PMID 25993154
    .
  11. S2CID 199000131
    .
  12. PMID 33902665
    .
  13. ^
    PMID 28782884
    .
  14. ^ "Key Statistics for Chronic Lymphocytic Leukemia". www.cancer.org. Retrieved 2021-11-29.
  15. ^ "Genes and Cancer". Archived from the original on 2021-11-16.
  16. PMID 33147729
    .
  17. PMID 32735048
    .
  18. ^
    PMID 26690614
    .
  19. PMID 30573042
    .
  20. S2CID 52892403
    .
  21. PMID 30855005
    .
  22. S2CID 52963674
    .
  23. ^
    S2CID 247975378
    .
  24. PMID 36012912
    .
  25. S2CID 212677249
    .
  26. S2CID 232301854
    .
  27. PMID 1512794
    .
  28. PMID 31570695
    .
  29. S2CID 205171057
    .
  30. S2CID 21552054
    .
  31. ^ Bitetto AM, Lamba G, Cadavid G, Shah D, Forlenza T, Rotatori F, Rafiyath SM. Colonic perforation secondary to chronic lymphocytic leukemia infiltration without Richter transformation. Leuk Lymphoma. 2011 May;52(5):930-3.
  32. S2CID 73483725
    .
  33. OCLC 1011064243
    .
  34. S2CID 207510537
    .
  35. PMID 33054046
    .
  36. ^
    PMID 29728204
    .
  37. ^ "Chronic Lymphocytic Leukemia". The Lecturio Medical Concept Library. Retrieved 9 July 2021.
  38. ISBN 978-1-4051-4265-6
    .
  39. ISBN 978-1451172683
    .
  40. PMID 32992303
    .
  41. S2CID 30952923
    .
  42. PMID 7523797
    .
  43. PMID 18263793
    .
  44. PMID 19230971
    .
  45. PMID 22180480
    .
  46. ^
    ISBN 978-0071621519
    .
  47. ISBN 9780845126585
    .
  48. PMID 1139039
    .
  49. ^ a b c d Woyach, Jennifer A.; Byrd, John C. (2022), Loscalzo, J; Fauci, Anthony S.; Kasper, Dennis L.; Hauser, Stephen L.; Longo, D; Jameson, J (eds.), "Chronic Lymphocytic Leukemia", Harrison's Principles of Internal Medicine (21 ed.), New York, NY: McGraw-Hill Education, retrieved 2023-01-29
  50. S2CID 38619478
    .
  51. S2CID 205651767
    .
  52. PMID 19074592
    .
  53. PMID 14730057
    .
  54. PMID 17053054
    .
  55. PMID 18687794
    .
  56. ^ "T Cell Prolymphocytic Leukemia". AccessMedicine. Archived from the original on 2011-07-07. Retrieved 2009-02-04.
  57. PMID 10442186
    .
  58. PMID 28340878
    .
  59. ISBN 9780071802161
    .
  60. ^ "France - Lymphoproliferative Syndrome B-Cell Prolymphocytic Leukemia |". icgc.org. Retrieved 2016-11-18.
  61. ^ "Hairy Cell Leukemia". The Lecturio Medical Concept Library. Retrieved 24 July 2021.
  62. PMID 6812046
    .
  63. ^ Janssens; et al. (2011). "Rituximab for Chronic Lymphocytic Leukemia in Treatment-Naïve and Treatment-Experienced Patients". Contemporary Oncology. 3 (3): 24–36.
  64. ^
    S2CID 206956090
    .
  65. PMID 16219797
    .
  66. PMID 12393429
    .
  67. PMID 15767648
    .
  68. PMID 11114313
    .
  69. PMID 16856041
    .
  70. S2CID 28834830
    .
  71. S2CID 54473182
    .
  72. PMID 19147079
    .
  73. S2CID 10144544
    .
  74. S2CID 54544330
    .
  75. ^
    PMID 18472198
    .
  76. S2CID 195804409
    .
  77. ^ "Chronic Lymphocytic Leukemia - Cancer Stat Facts". SEER. Retrieved 2020-12-07.
  78. PMID 19340005
    .
  79. S2CID 6542508
    .
  80. ^ a b "Chronic lymphocytic leukaemia - Symptoms, diagnosis and treatment | BMJ Best Practice". bestpractice.bmj.com. Retrieved 2021-11-29.
  81. ^
    OCLC 1264228575.{{cite book}}: CS1 maint: location missing publisher (link
    )
  82. ^
    OCLC 1029074059.{{cite book}}: CS1 maint: location missing publisher (link
    )
  83. ^ a b "Cancer Facts & Figures 2021" (PDF). American Cancer Society. Archived (PDF) from the original on 2021-01-12.
  84. ^ "Chronic lymphocytic leukaemia (CLL) statistics". Cancer Research UK. Retrieved 27 October 2014.
  85. PMID 12091358
    .
  86. ^ "Chronic Lymphocytic Leukemia". Cleveland Clinic. Retrieved 9 July 2021.
  87. PMID 22449365
    .
  88. ISBN 978-0-7817-5007-3
    . Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)
  89. S2CID 221748665
    .
  90. PMID 34068813
    .
  91. PMID 27660167
    .
  92. University of Pennsylvania School of Medicine
    . Retrieved August 12, 2011.
  93. PMID 21830940
    .
  94. PMID 21832238
    .
  95. ^ a b Palca J (August 11, 2011). "Gene Therapy Advance Trains Immune System To Fight Leukemia". NPR. Retrieved August 12, 2011.
  96. ^ Bazell R (August 10, 2011). "New leukemia treatment exceeds 'wildest expectations'". NBC News. Retrieved August 12, 2011.
  97. ^ DeNoon DJ (August 10, 2011). "Gene Therapy Cures Adult Leukemia". WebMD. Retrieved August 12, 2011.
  98. ^ Beasly D (August 10, 2011). "Gene therapy shown to destroy leukemia tumors". Reuters. Retrieved August 12, 2011.
  99. PMID 25050922
    .
  100. S2CID 213941348
    .
  101. ^ Munir T, Rawstron A, Brock K, Vicente S, Yates F, Bishop R, et al. (2017-12-07). "Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy". Blood. 130 (Suppl 1): 428.
  102. S2CID 174808115
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Chronic_lymphocytic_leukemia&oldid=1214008989"