Its main characteristics are the cytoplasmic prolongations which give the cells a hairy aspect. Although there are different studies showing a link between exposure to certain agents and HCL, its etiology has not been clearly established, which could be explained due to its low incidence. Amongst the agents which have proven a positive link are: exposition to pesticides, 4 herbicides, mineral oils, working as a carpenter, or a farmer.
There are new cases reported per year in the U. Median age at diagnosis is 52 years old and it is more common in men than in women, with a ratio; with a higher incidence in the white population, especially among Ashkenazi Jews. However, in the north of the country it represents up to 1. HCL is a chronic, lymphoproliferative B-cell disorder. However, its cells do not have the appearance of any B-cell sub-population, and its origin has been a matter of debate.
Evidence suggests an origin post germinal center in memory B-cells, due to their genomic expression profile. This represents a point against the hypothesis of its origin in memory B-cells.
HCL cells show an expression profile similar to the spleen's marginal zone. HCL's characteristic look is due to the beta-actin expression, which is polymerized to F-actin, located in the cortical cytoskeleton.
The disease's clinical course is indolent. Most patients usually present weakness and fatigue as the predominant symptoms during the onset of the disease. These swollen lymph nodes are rarely observed in the periphery; nonetheless, they are generally present in the abdomen and detected by imaging studies. However, this is uncommon because of the availability and effectiveness of treatment. HCL must be differentiated from other indolent lymphoid malignancies such as prolymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma and HCL variant HCL-v.
HCL diagnosis is commonly made with a biopsy and bone marrow aspiration combined with immunophenotypic characterization through flow cytometry. A strong expression for CD is characteristic of HCL and may be useful in the diagnosis of difficult cases. Andrulis et al. Moreover, a study conducted by Uppal et al. HCL regularly has an indolent evolution. Waiting and observing is a good option for asymptomatic patients, since early treatment does not offer any sort of benefit in the survival rates of these cases.
Anyway, the progression of the disease in most patients will lead to complications as a result of cytopenias and splenomegaly; i. In general practice, treatment must be started if any of the criteria listed in Table 2 occur. Chart for the management of a patient with hairy cell leukemia. After treatment with purine analogues, deoxyadenosine triphosphate accumulation results in rupture and inhibition of the DNA repair, which translates into cellular apoptosis.
In Table 3 , 37,39,43,44 specific studies show response rates to pentostatin. Studies on the effectiveness of pentostatin in HCL cases. Flinn et al. It is known as 2-chlorodeoxyadenosine CdA. In Table 4 , 49—52 studies indicate its effectiveness.
The most used scheme consists of administering 0. In a non-randomized study, there was evidence proving that there was no statistically significant difference in the response and toxicity ranges between infusions 24 h and 2 h. Weekly subcutaneous programs have similar response and toxicity rates as daily ones. Studies on the effectiveness of cladribine in HCL cases.
Until now, there are no randomized prospective studies comparing pentostatin versus cladribine, in part because of the great efficiency of both drugs and due to low HCL incidence. Even so, there are retrospective studies proving the fact that both drugs have a similar efficacy, in terms of complete response and free-of-disease survival.
Purine analogues remain the first line of treatment but new discoveries regarding HCL pathophysiology have led to the creation of drugs with different therapeutic targets. These drugs are under research and some have shown promising results. This is less expensive and is usually effective, especially when is combined with interferon.
Rivandi et al. Therefore, it is a therapeutic target which has been studied in recent years. Tiacci et al. The adverse effects were rash, arthralgia and arthritis. Since a positive relation has been observed between the use of Vemurafenib and the onset of dermatological malignancies, frequent explorations of the skin are recommended.
A selective and irreversible inhibitor of the Burton's tyrosine kinase intervenes in the B-cell signaling pathway. Preliminary efficacy and safety data show adverse effects such as eruptions, diarrhea and arthralgia.
This clinical assay is currently taking place in several centers in the U. In order to increase monoclonal antibody cytotoxicity, techniques that facilitate the production of antibody—toxin or antibody—drug conjugates have been created.
An immunotoxin is the fusion between a bacterial toxin i. Pseudomonas exotoxin or diphtheria and the variable fraction of a monoclonal antibody, whose specific target is found on the surface of neoplastic cells like CD25 or CD This toxin is released in the neoplastic cell's interior and interferes with protein synthesis. BL22 is an immunotoxin against CD22 fused with a truncated shape of the P. Two patients developed uremic hemolytic syndrome without the need to recur to plasmapheresis.
Even though HCL is treated in most developed countries with cladribine and pentostatin, it is a fact that these drugs are not only expensive, they are not available in Mexico and in many countries with limited resources. So, in these types of circumstances, there are other affordable therapeutic options with favorable results.
Interferon alpha for HCL patient treatment was first introduced in On the other hand, in countries with low economic resources, it is an inexpensive option and one which has proved similar results to those of cladribine in terms of global survival. Ruiz-Delgado et al. All patients had a hematological remission before 12 weeks of treatment. This therapeutic option is cheaper, effective and comparable to other forms of therapy with IFN in the treatment and maintenance of patients with this type of leukemia.
Splenectomy was the first intervention that significantly changed the survival in patients. Today, it is rarely used. An interesting finding when comparing both groups was that no statistically significant differences were observed regarding leukemia-free survival and global survival.
Survival time in patients after diagnosis was 4 years before a treatment was known, due to complications derived from cytopenias, including hemorrhages and infections. Then, alfa interferon was utilized as the first drug with benefits in the treatment of HCL.
The challenge is to identify this malignancy as early as possible and treat it properly using available resources. The authors have no conflicts of interest to declare. Inicio Medicina Universitaria Hairy cell leukemia, an uncommon B-cell lymphoid neoplasia.
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Download PDF. Garza-Ledezma , C. Tellez-Hinojosa , E. Corresponding author. This item has received. Under a Creative Commons license. Article information. Table 1. Clinical manifestations.. Show more Show less. The majority of patients initially present weakness and fatigue, pancytopenia and splenomegaly. These pharmaceuticals are currently undergoing testing. Hairy cell leukemia. Full Text. Etiology Although there are different studies showing a link between exposure to certain agents and HCL, its etiology has not been clearly established, which could be explained due to its low incidence.
Clinical manifestations. Spleen Liver Bone marrow Lymph nodes The cells accumulate in the red pulp and atrophy the white pulp. Here, they accumulate in the liver sinusoids as well as in the portal tract. There is fibrosis in the latter due to the abundant hyaluronic acid, which stimulates the hairy cells to produce fibronectin, with its corresponding fibrosis.
In this area, there is extensive production of fibrosis and suppression of hematopoiesis. The key factor is the interaction of the hairy cells with the hyaluronic acid of the extracellular matrix, generating fibroblastic growth factors FGF and stimulating the malign cells to produce and secrete fibronectin.
Generally, absent of the disease. Lack of receptors for entry of hairy cells. Table 2. Criteria to begin treatment. Symptomatic splenomegaly 2. Severe infections. Algorithm 1. Table 3. Table 4. Leukemic reticuloendotheliosis hairy cell leukemia. Blood, 53 , pp.
Schrek, W. Blood, 27 , pp. Swerdlow, E. Campo, N. Harris, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Clavel, L.
Mandereau, S. Cordier, et al. Hairy cell leukaemia, occupation, and smoking. Br J Haematol, 91 , pp. Monnereau, S. Slager, A. Hughes, et al. Medical history, lifestyle, and occupational risk factors for hairy cell leukemia: the interlymph non-Hodgkin lymphoma subtypes project. J Natl Cancer Inst Monogr, , pp. Oloske, H. Golomb, M. Farber, et al. A case control inquiry into the etiology of hairy cell leukemia. Am J Epidemiol, , pp.
Hardell, A. Magnuson, et al. Occupational exposures, animal exposure and smoking as risk factors for hairy cell leukaemia evaluated in a case—control study. Br J Cancer, 77 , pp. Staines, R. Hairy cell leukaemia: descriptive epidemiology and a case—control study. Br J Haematol, 85 , pp. Effects of cigarette smoke on the immune system. Nat Rev Immunol, 2 , pp. Oloris, A. Frazer-Abel, C. Jubala, et al. Nicotine-mediated signals modulate cell death and survival of T lymphocytes.
Toxicol Appl Pharmacol, , pp. Bernstein, P. Newton, R. Epidemiology of hairy cell leukemia in Los Angeles County. Cancer Res, 50 , pp. Ruiz-Arguelles, O. Cantu-Rodriguez, D. Gomez-Almaguer, et al. Hairy cell leukemia is infrequent in Mexico and has a geographic distribution. Am J Hematol, , pp. Pascual, Y. Liu, A. Magalski, et al. Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med, , pp. Forconi, S. Sahota, D. Raspadori, et al. Hairy cell leukemia: at the crossroad of somatic mutation and isotype switch.
Blood, , pp. Arons, J. Sunshine, T. Suntum, et al. Somatic hypermutation and VH gene usage in hairy cell leukaemia. Br J Haematol, , pp. Liu, F. Malisan, O. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation.
Immunity, 4 , pp. Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing.
Blood, 98 , pp. Arons, L. Roth, J. Sapolsky, et al. Evidence of canonical somatic hypermutation in hairy cell leukemia. Basso, A.
Liso, E. Tiacci, et al. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors.
Tiacci, A. Liso, M. Piris, et al. Evolving concepts in the pathogenesis of hairy-cell leukaemia. Nat Rev Cancer, 6 , pp. Forconi, D. Raspadori, M. Lenoci, et al. Absence of surface CD27 distinguishes hairy cell leukemia from other leukemic B-cell malignancies.
Haematologica, 90 , pp. Fecteau, G. J Immunol, , pp. Vanhentenrijk, C. De Wolf-Peeters, I. Comparative expressed sequence hybridization studies of hairy cell leukemia show uniform expression profile and imprint of spleen signature.
Park, M. Elsevier Inc. Miyoshi, P. Stewart, P. Kincade, et al. Aberrant expression and localization of the cytoskeleton-binding pp52 LSP1 protein in hairy cell leukemia. Leuk Res, 25 , pp. Chung, E. Kim, J. Park, et al. Sci Transl Med, 6 , pp. Tiacci, V. Trifonov, G. Schiavoni, et al. N Engl J Med, , pp. Tiacci, G.
Schiavoni, M. Martelli, et al. Haematologica, 98 , pp. Hematology: basic principles and practice, 6th ed. Jain, N. Pemmaraju, F. The choice will largely depend on the physician and patient and most are given as outpatient treatment. Both drugs are generally well tolerated but are associated with a temporary reduction in normal blood counts, which need to be monitored closely weekly initially until recovery.
Sometimes recovery of the reduced blood counts is delayed for a much longer time, but eventually they improve. Pentostatin and cladribine may also cause a more prolonged suppression of the immune system, and patients should be informed of this possibility and be made aware of signs and symptoms of possible infection. Infections should always be taken seriously as prompt treatment is important.
In the case of cladribine, it is better to start these agents after the 1-week course of treatment has been given, since rashes can sometimes occur when the drugs are given concurrently.
Blood transfusions, if ever required, should be with irradiated blood. Splenectomy is rarely performed nowadays since the agents used today are very effective in reducing the size of the spleen.
The spleen is often enlarged at the time of diagnosis. Interferon was used in the past, but is rarely used today. It is not well tolerated and much less effective than the purine analogues, but occasionally may still be useful if patients fail initial therapy. Rituximab used as a single agent in first line treatment of HCL is not as effective in inducing remissions as the purine analogues.
Its use would be reserved for patients unable to tolerate purine analogues. There is evidence that better remissions may be achieved with the combination of rituximab and a purine analogue pentostatin or cladribine.
Because of the very good results with purine analogues alone for most patients, the addition of rituximab is often reserved for those HCL patients who do not achieve a complete remission or who relapse earlier than expected. Currently, these therapies have been examined in relapsed or refractory HCL and only in a very small number of patients for whom purine analogues cannot be given as first line therapy.
A number of clinical trials are ongoing to evaluate these drugs further in hopes of sparing the immunosuppressive effects of purine analogues. Moxetumumab pasudotox Lumoxiti is administered as an intravenous infusion over 30 minutes on days 1, 3, and 5 of each day cycle. Lumoxiti may cause serious side effects, including capillary leak syndrome and hemolytic uremic syndrome. HCL is a rare disease and there are very few clinical studies being undertaken worldwide.
To continue to make progress in new therapies, it is important for patients at every stage of treatment to consider participation in clinical trials. We encourage patients to visit our clinical trials page to learn about trials underway that may be right for them. Usually within a few weeks of receiving treatment, the blood counts begin to recover and will often return to completely normal levels. However, to assess response to anti-HCL treatment, a bone marrow examination is necessary.
This is usually done months after cladribine therapy to assess the full impact of therapy. The bone marrow procedure is not pleasant for patients, but does provide important information about the quality of response to the treatment given and whether or not more or different therapy is needed.
Studies have shown that in those patients who have obtained a clinical complete remission, the response lasts longer. There are other more sensitive laboratory methods which can assess for any measurable minimal residual disease MRD. MRD may be present even if patients are in complete remission.
It remains to be determined what effect the presence of MRD has on outcome and this is an area of ongoing research. Regular monitoring by a hematologist takes place, usually once or twice a year for patients in stable remission. Relapse is usually suspected in patients who have falling blood counts and should be confirmed by examination of the bone marrow. Re-treatment is often successful although the subsequent remissions tend to last for a shorter period of time, when the same therapeutic agents are given again.
Hairy cell leukemia most commonly affects the bone marrow and spleen. However, because HCL travels between the bone marrow, spleen, liver and lymph nodes via the bloodstream, it may potentially affect any part of the body that the blood circulates to.
Therefore, other medical problems have been described that are likely a direct or indirect result of the hairy cell leukemia. This section will provide a brief review of both the common and uncommon complications of HCL. When hairy cell leukemia is present in the bone marrow, it slowly increases over time until it begins to prevent normal blood cell production.
Many of the symptoms and complications of HCL are a direct result of low blood cell counts. In some patients, hairy cells will begin to circulate in the blood stream and when this happens the white blood count may be higher than normal. Some patients with hairy cell leukemia have an elevated white blood cell count due to the presence of hairy cells in the bloodstream, but these are not normally functioning white blood cells and do not protect against infection.
Whether the white blood count is high or low, patients with HCL are overall at increased risk of infection. In fact, infection is one of the leading causes of illness and death for patients with hairy cell leukemia.
Infections can be caused by bacteria, viruses, or fungal diseases. In addition, some medications used to treat HCL can temporarily increase the risk of infection by decreasing the white blood cell numbers or normal functioning. For example, the chemotherapy agents most commonly used for the initial treatment of hairy cell leukemia - pentostatin and cladribine - can lower the number of normal lymphocytes. Patients with HCL should not receive the older Herpes Zoster shingles vaccine called Zostavax from their physicians, as it is a live virus vaccine that might result in causing the very condition that it is intended to prevent.
However, immunizations using killed virus vaccines, such as the influenza vaccine, are safe and may provide important protection for HCL patients. A newer, non-live shingles vaccine called Shingrix has more recently been introduced and patients with HCL should discuss this option with their doctors.
Lowering of the red blood cell count, or anemia, is often associated with symptoms of fatigue. Some patients with hairy cell leukemia will require a red blood cell transfusion to correct this problem, although this is a temporary solution until the HCL improves. Lowering of the platelet counts leads to an increased tendency to bleed, and many patients with low platelet counts notice an increased tendency to develop bruising or bleeding from the gums or nose.
If bleeding is severe or the platelet count is very low, a platelet transfusion may be required. However, again this is a temporary solution until treatment is given to improve the underlying HCL. In the past, significant enlargement of the spleen was a very common complication of hairy cell leukemia and was often the initial symptom of the disease. Although patients today are more often diagnosed with HCL on the basis of an abnormal blood count, many patients will still develop an enlarged spleen as part of the disease course.
This may cause symptoms of abdominal pain, abdominal distention, or difficulty eating a full meal due to the pressure that the enlarged spleen exerts on the stomach.
Most of the effective therapies for HCL will decrease the size of the spleen, relieving these discomforts. It is possible to remove the spleen if need be, although this could lead to an increased risk of certain types of infection.
Therefore, removing the spleen is usually only performed if other therapies are not possible or have not proven effective. When the spleen is very enlarged there is an increased risk of splenic rupture due to trauma, such as a car accident. Sudden pain in the abdomen followed by profound weakness should cause the patient to seek immediate medical care in an emergency facility. This is an ongoing issue of debate.
Some studies show that the disease itself may actually increase this risk. Therefore, people with HCL should continue to have their routine cancer screening performed at regular intervals based upon recommendations established by cancer experts. Further defining the more rare complications of hairy cell leukemia is an ongoing research initiative. For example, there is some suggestion that certain types of autoimmune complications many manifest in patients with HCL, such as certain types of arthritis and immune-mediated blood disorders.
Understanding the complications of hairy cell leukemia is one of the main goals of the HCL Patient Data Registry , and the valuable insights gained by this project will add to the understanding of this rare disease. This normally requires flow cytometry of the blood laser-based technology that analyzes characteristics of cells and preferably of the bone marrow. There are specific markers that are characteristically found on the leukemic cells from patients with classic hairy cell leukemia.
The markers on the leukemic cells may provide a clue that the non-responding patient has a variant of hairy cell leukemia. These patients can undergo analysis of the BRAF expression to further delineate whether the patient has either the classic form of the disease or a variant. Confirmation of the underlying diagnosis enables decisions to be made about treatment. Patients with the atypical variant of hairy cell leukemia do not respond as well to the standard agents and may have a short-lived, partial response.
The variant form of hairy cell leukemia is now recognized as a separate clinical entity from the classic disease, and is recognized as being less responsive to therapy with standard treatment. Some patients with the variant form of hairy cell leukemia have responded to the combination of cladribine and rituximab.
In addition, moxetumomab pasudotox was more recently approved by the FDA for the treatment of adult patients with hairy cell leukemia and hairy cell leukemia variant who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog.
For example, in some cases, patients have low blood counts for months after treatment, due to the toxicity of either cladribine or pentostatin. Given time, the patients in these cases may achieve a remission. It is important to understand why the patient is not responding to treatment i.
If the patient is non-responsive to medical therapy, splenectomy may be required. To avoid being retreated too early or unnecessarily, it may be helpful to consult an HCL expert at a Centers of Excellence. Patients who are treated for hairy cell leukemia should have a bone marrow biopsy performed following treatment to determine if a complete response eradication of all evidence of hairy cell leukemia has been achieved.
Among patients who have achieved a complete response, it is not unusual to find minimal residual disease MRD if more sophisticated studies are done to detect a small amount of hairy cells not visible under the regular microscope.
Minimal residual disease may be one reason that some patients ultimately relapse. Patients are usually followed quarterly after they have completed therapy. Routine blood counts are obtained to ensure that the remission is being maintained. If blood counts show a decline, a repeat bone marrow may be obtained to see if the disease is relapsing by identifying a small amount of recurrent hairy cells.
Immunophenotyping studies looking for certain markers on the surface of the lymphocytes to identify hairy cells may be done to look for a small amount of recurrent hairy cells.
If relapse has been documented, careful consideration is given to decide if and when to re-initiate treatment. Just as there is a watchful waiting approach at the time of initial diagnosis, a similar strategy may be followed in patients who have a small amount of recurrent hairy cells, but are without symptoms.
A small decline in the blood counts may not be sufficient to warrant re-treatment since often this disease is slow-growing. However, there is an advantage to re-starting therapy before the counts deteriorate to very low dangerous levels. According to the World Health Organization classification of diseases, it is not biologically related to classic hairy cell leukemia. HCL-V is a more aggressive disease than the classic form.
Hairy cell leukemia variant is a rare disorder accounting for approximately 0. The disease affects the elderly population without sexual predominance. The median age of the patients is 71 years.
The features of hairy cell leukemia variant are intermediate between those of classical HCL and prolymphocytic leukemia PLL.
Patients with HCL-V have elevated white blood cells as well as unique morphology structure and shape and immunophenotype types of markers on the surface of cells.
In contrast to the classic hairy cell leukemia, patients with HCL-V have no monocytopenia deficiency of monocytes, a type of immune cell that is made in the bone marrow , and the leukemic leukocytes lack CD25 antigens. There is currently no curative treatment for hairy cell leukemia variant. The results of therapy with cladribine or pentostatin are rather poor. In addition, the majority of HCL-V patients required more than one cycle to maintain a partial remission.
Rituximab alone or splenectomy followed by rituximab therapy can induce complete remission in patients with hairy cell leukemia variant. More recently, cladribine combined with rituximab was found to be more effective than cladribine alone or rituximab alone. Kreitman et al report a case of 10 patients with HCL-V treated simultaneously with cladribine and rituximab. These results indicate that patients with HCL-V could be initially treated with cladribine combined with rituximab.
Alemtuzumab is an active agent in selected cases with hairy cell leukemia variant. Splenectomy can induce clinical responses and correct cytopenias lower-than-normal number of blood cells in some patients with HCL-V. Moxetumomab pasudotox, an anti-CD22 immunotoxin, was more recently approved by the U.
Food and Drug Administration FDA for the treatment of adult patients with hairy cell leukemia or hairy cell leukemia variant who received at least two prior systemic therapies, including treatment with a purine nucleoside analog. The B-cell antigen receptor BCR signal transduction inhibitors, ibrutinib PCI and idelalisib GS, CAL , represent a promising new strategy for the treatment of hairy cell leukemia and possibly hairy cell leukemia variant.
In , Dr. Bouroncle described the multiple features of hairy cell leukemia, firmly establishing this disease as a unique clinical entity. The malignant cells were identified predominantly in the bone marrow, spleen and other tissues.
While the origin of this malignant cell was often debated, it has ultimately been recognized as a B-cell malignancy with a very distinctive immunophenotypic profile.
For the latter part of the past century, the diagnosis was made by describing these leukemic cells in the peripheral blood and the bone marrow. Classic hairy cell leukemia has been differentiated from the less common variant form of this leukemia, which is now known to be a completely separate clinical entity. The leukemic presentation of the variant form of this disease may be associated with bone marrow failure and significant splenomegaly, but the diagnostic markers differ from the classic form of the disease as does the clinical course and response to therapy.
Tiacci and colleagues described the presence of BRAFVE mutation in leukemic cells from almost every patient with the classic form of hairy cell leukemia. In sharp contrast, this mutation is missing in the variant form of the disease. This observation has provided diagnostic accuracy as well as a novel therapeutic target for patients with the classic form of the disease. In patients who have been unresponsive to standard effective therapy for classic hairy cell leukemia, clinical responses have been observed in patients treated with BRAFVE inhibitors.
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