is important as it is a rare and aggressive disease. 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 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. 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. 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 pathologist with specific training in blood disorders. a flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the dna changes with fluorescent probes by fish. 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. cll is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. symptoms are sometimes treated surgically (splenectomy – removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes). 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. 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. 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. a "watchful waiting" strategy is used for most patients with cll. 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"). 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: fc (fludarabine with cyclophosphamide) fr (fludarabine with rituximab) fcr (fludarabine, cyclophosphamide, and rituximab) although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy, 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. 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. alkylating agents approved for cll include bendamustine and cyclophosphamide. targeted therapy targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. targeted drugs used in cll include venetoclax (a bcl-2 inhibitor), ibrutinib (a bruton's tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against cd20 (rituximab, ofatumumab and obinutuzumab) and cd52 (alemtuzumab). 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. stem cell transplantation autologous stem cell transplantation, using the recipient's own cells, is not curative.: 1458 younger individuals, if at high risk for dying from cll, may consider allogeneic hematopoietic stem cell transplantation (hsct). myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant.: 1458 an intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients. refractory cll "refractory" cll is a disease that no longer responds favorably to treatment within six months following the last cancer therapy. in this case, more aggressive targeted therapies, such as bcr or bcl2 pathway inhibitors, have been associated with increased survival. during pregnancy leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women. treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy. if treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in pregnancy loss or birth defects than treatment during the first trimester. prognosis prognosis can be affected by the type of genetic mutation that the person with cll has. 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. while prognosis is highly variable and dependent on various factors including these mutations, the average 5-year relative survival is 86.1%. telomere length has been suggested to be a valuable prognostic indicator of survival. 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. 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. it is observed globally males are twice as likely than females to acquire cll. cll is primarily a disease of older adults, with 9 out of 10 cases occurring after the age of 50 years. the median age of diagnosis is 70 years. in young people, new cases of cll are twice as likely to be diagnosed in men than in women. 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. 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. in that same year, 2,620 males and 1,700 females (total of 4,320 people) are expected to die from cll. because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy, 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. in western populations, subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. 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.: 1432 a low incidence is seen in japanese immigrants to the us, and in african and asian immigrants to israel. of all cancers involving the same class of blood cell, 7% of cases are cll/sll. people who live near areas with considerable industrial pollution have an elevated risk of developing leukemia, particularly cll. research directions in light of new therapies such as targeted agents, the role of bone marrow transplants is decreasing. 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. wikinews has related news: scientists use gene therapy, patients' own immune systems to fight leukemia researchers at the abramson cancer center of the university of pennsylvania school of medicine reported preliminary success in the use of gene therapy, through genetically modified t cells, to treat cll. the findings, which were published in august 2011, were based on data from three patients who had modified t cells injected into their blood. the t cells had been modified to express genes that would allow the cells to proliferate in the body and destroy b cells including those causing the leukemia. two patients went into remission, while the presence of leukemia in the third patient reduced by 70%. 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. 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. this was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease". research is also investigating therapies targeting b cell receptor signalling. syk inhibitors fostamatinib and entospletinib are currently in trials. the trial of a combination of ibrutinib and venetoclax had encouraging results in a small number of people. people with cll undergoing immunotherapy with chimeric antigen receptor t cells have been found to have a high response rate.