'''Chronic myelogenous leukemia''' ('''CML''') is a form of [[leukemia]] characterized by the increased and unregulated growth of predominantly [[myeloid]] cells in the [[bone marrow]] and the accumulation of these cells in the blood. CML is a clonal bone marrow [[stem cell]] disorder in which proliferation of mature [[granulocyte]]s ([[neutrophil]]s, [[eosinophil]]s, and [[basophil]]s) and their precursors is the main finding. It is a type of [[myeloproliferative disease]] associated with a characteristic [[chromosomal translocation]] called the [[Philadelphia chromosome]]. Historically, it has been treated with [[chemotherapy]], [[interferon]] and [[bone marrow transplantation]], although [[targeted therapy|targeted therapies]] introduced at the beginning of the 21st century have radically changed the management of CML.
CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual [[incidence (epidemiology)|incidence]] is 1–2 per 100,000 people, and slightly more men than women are affected. CML represents about 15–20% of all cases of adult leukemia in Western populations.<ref name="Faderl1990">{{cite journal|title=Chronic myelogenous leukemia: biology and therapy.|author=Faderl S, Talpaz M, Estrov Z, Kantarjian HM|journal=Annals of Internal Medicine|date=1999|volume=131|issue=3|pages=207-219|pmid=10428738}}</ref> The only well-described risk factor for CML is exposure to [[ionizing radiation]]; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.<ref>{{cite journal|title=Radiogenic leukemia revisited|author=Moloney WC|date=1987|journal=Blood|volume=70|issue=4|pages=905-908|pmid=3477299}}</ref>
==[[Chronic myelogenous leukemia differential diagnosis|Differentiating Chronic myelogenous leukemia from other Diseases]]==
==[[Chronic myelogenous leukemia epidemiology and demographics|Epidemiology and Demographics]]==
Patients are often [[asymptomatic]] at diagnosis, presenting incidentally with an elevated [[white blood cell]] count on a routine laboratory test. In this setting, CML must be distinguished from a [[leukemoid reaction]], which can have a similar appearance on a [[blood film|blood smear]]. Symptoms of CML may include: [[malaise]], [[low-grade fever]], [[gout]], increased susceptibility to [[infection]]s, [[anemia]], and [[thrombocytopenia]] with easy [[bruising]] (although an ''increased'' [[platelet]] count ([[thrombocytosis]]) may also occur in CML). [[Splenomegaly]] may also be seen.<ref name="Faderl1990"/><ref name="Tefferi">{{cite journal|title=Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era|author=Tefferi A|journal=Hematology Am Soc Hematol Educ Program|date=2006|pages=240-245|pmid=17124067}}</ref>
==[[Chronic myelogenous leukemia natural history|Natural History, Complications and Prognosis]]==
==Pathophysiology==
CML was the first malignancy to be linked to a clear genetic abnormality, the [[chromosomal translocation]] known as the [[Philadelphia chromosome]]. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania: Peter Nowell of the University of Pennsylvania and David Hungerford of the [[Fox Chase Cancer Center]]. <ref>{{cite journal|title=Discovery of the Philadelphia chromosome: a personal perspective|author=Nowell PC|date=2007|journal=Journal of Clinical Investigation|volume=117|issue=8|pages=2033-2035|pmid=17671636}}</ref>
In this translocation, parts of two chromosomes (the 9<sup>th</sup> and 22<sup>nd</sup> by conventional [[karyotype|karyotypic]] numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a [[tyrosine kinase]]), the bcr-abl fusion gene product is also a tyrosine kinase.<ref name="Faderl1990"/><ref name="Hehlmann">{{cite journal|title=Chronic myeloid leukaemia|author=Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet|journal=Lancet|volume=370|issue=9584|pages=342-50|date=2007|pmid=17662883}}</ref>
The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, bcr-abl activates a cascade of proteins which control the [[cell cycle]], speeding up cell division. Moreover, the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the bcr-abl protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the bcr-abl protein and its action as a tyrosine kinase, [[targeted therapy|targeted therapies]] have been developed (the first of which was [[imatinib mesylate]]) which specifically inhibit the activity of the bcr-abl protein. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.<ref name="Hehlmann"/>
[[Image:CDR526538-571.jpg|600px|center|thumb|Blood cell development. A blood stem cell goes through several steps to become a [[red blood cell]], [[platelet]], or [[white blood cell]]. [http://www.cancer.gov/cancertopics/pdq/treatment/CML/patient/ Source].]]
==Diagnosis==
==Diagnosis==
CML is often suspected on the basis on the [[complete blood count]], which shows increased [[granulocyte]]s of all types, typically including immature myeloid cells. [[Basophil]]s and [[eosinophil]]s are almost universally increased; this feature may help differentiate CML from a [[leukemoid reaction]]. A [[bone marrow biopsy]] is often performed as part of the evaluation for CML, but bone marrow morphology alone is insufficient to diagnose CML.<ref name="Hehlmann"/><ref name="Tefferi"/>
[[Chronic myelogenous leukemia diagnostic study of choice|Diagnostic Study of Choice]] | [[Chronic myelogenous leukemia staging|Staging]] | [[Chronic myelogenous leukemia history and symptoms|History and Symptoms]] | [[Chronic myelogenous leukemia physical examination|Physical Examination]] | [[Chronic myelogenous leukemia laboratory tests|Laboratory Findings]] | [[Chronic myelogenous leukemia electrocardiogram|Electrocardiogram]] | [[Chronic myelogenous leukemia chest x ray|Chest X Ray]] | [[Chronic myelogenous leukemia CT|CT]] | [[Chronic myelogenous leukemia MRI|MRI]] | [[Chronic myelogenous leukemia ultrasound|Ultrasound]] | [[Chronic myelogenous leukemia other imaging findings|Other Imaging Findings]] | [[Chronic myelogenous leukemia other diagnostic studies|Other Diagnostic Studies]]
[[Image:CDR554337-274.jpg|center|thumb|450px|Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope. [http://www.cancer.gov/cancertopics/pdq/treatment/CML/patient/ Source]]]
Ultimately, CML is diagnosed by detecting the [[Philadelphia chromosome]]. This characteristic chromosomal abnormality can be detected by routine [[cytogenetics]], by [[fluorescent in situ hybridization]], or by [[PCR]] for the bcr-abl fusion gene.<ref name="Tefferi"/>
[[Image:CDR533336-571.jpg|thumb|center|450px|[[Philadelphia chromosome]]. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the [[Philadelphia chromosome]] [http://www.cancer.gov/cancertopics/pdq/treatment/CML/patient/ Source].]]
Controversy exists over so-called ''Ph-negative'' CML, or cases of suspected CML in which the Philadelphia chromosome cannot be detected. Many such patients in fact have complex chromosomal abnormalities which mask the (9;22) translocation, or have evidence of the translocation by [[fluorescent in situ hybridization|FISH]] or [[RT-PCR]] in spite of normal routine karyotyping.<ref>{{cite journal|title=Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period|author=Savage DG; Szydlo RM; Goldman JM|journal=Br J Haematol|date=1997|volume=96|issue=1|pages=111-116|pmid=9012696}}</ref> The small subset of patients without detectable molecular evidence of bcr-abl fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML.<ref name="WHO">{{cite journal|title=Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert pane|author=Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW|date=2007|journal=Blood|volume=110|issue=4|pages=1092-1097|pmid=17488875}}</ref>
CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention, CML typically begins in the ''chronic'' phase, and over the course of several years progresses to an ''accelerated'' phase and ultimately to a ''blast crisis''. Blast crisis is the terminal phase of CML and clinically behaves like an [[acute leukemia]]. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome).<ref name="Faderl1990"/> Some patients may already be in the accelerated phase or blast crisis by the time they are diagnosed.<ref name="Tefferi"/>
===Chronic phase===
Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness. The duration of chronic phase is variable and depends on how early the disease was diagnosed as well as the therapies used. Ultimately, in the absence of curative treatment, the disease progresses to an accelerated phase.<ref name="Tefferi"/>
===Accelerated phase===
Criteria for diagnosing transition into the accelerated phase are somewhat variable; the most widely used criteria are those put forward by investigators at M.D. Anderson Cancer Center,<ref>{{cite journal | author = Kantarjian H, Dixon D, Keating M, Talpaz M, Walters R, McCredie K, Freireich E | title = Characteristics of accelerated disease in chronic myelogenous leukemia. | journal = Cancer | volume = 61 | issue = 7 | pages = 1441-6 | year = 1988 |pmid=3162181}}</ref> by Sokal et al,<ref>{{cite journal | author = Sokal J, Baccarani M, Russo D, Tura S | title = Staging and prognosis in chronic myelogenous leukemia. | journal = Semin Hematol | volume = 25 | issue = 1 | pages = 49-61 | year = 1988 | id = PMID 3279515}}</ref> and the [[World Health Organization]].<ref>{{cite journal | author = Vardiman J, Harris N, Brunning R | title = The World Health Organization (WHO) classification of the myeloid neoplasms. | journal = Blood | volume = 100 | issue = 7 | pages = 2292-302 | year = 2002 |pmid=12239137|url=http://www.bloodjournal.org/cgi/content/full/100/7/2292|accessdate=2007-09-22}}</ref><ref name="WHO"/> The WHO criteria are perhaps most widely used, and include:
*10–19% [[myeloblast]]s in the blood or [[bone marrow]]
*>20% [[basophil]]s in the blood or bone marrow
*[[Platelet]] count <100,000, unrelated to therapy
*Platelet count >1,000,000, unresponsive to therapy
*Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome
*Increasing [[splenomegaly]] or white blood cell count, unresponsive to therapy
The patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent.<ref name="WHO"/>
===Blast crisis===
Blast crisis is the final phase in the evolution of CML, and behaves like an [[acute leukemia]], with rapid progression and short survival.<ref name="Tefferi"/> Blast crisis is diagnosed if any of the following are present in a patient with CML:<ref>{{cite journal|title=Blastic phase of chronic myelogenous leukemia|author=Karbasian Esfahani M, Morris EL, Dutcher JP, Wiernik PH|date=2006|journal=Current Treatment Options in Oncology|volume=7|issue=3|pages=189-199|pmid= 16615875}}</ref>
*>20% [[myeloblast]]s or [[lymphoblast]]s in the blood or bone marrow
*Large clusters of blasts in the bone marrow on [[bone marrow biopsy|biopsy]]
*Development of a [[chloroma]] (solid focus of leukemia outside the bone marrow)
==Treatment==
==Treatment==
===Overview===
In June of 2006, the Food and Drug Administration (FDA) approved the oral tyrosine kinase inhibitor dasatinib (Sprycel(tm)) to treat CML that does not respond to other therapy.
One treatment that does impact on CML survival is allogeneic bone marrow transplantation, the use of high dose chemotherapy and radiation followed by infusion of a donor bone marrow. This procedure removes the chromosomal abnormality in a large percentage of patients and for them is curative. In addition, there is treatment with interferon (INF). About 20% to 30% of patients taking interferon show elimination of the abnormal chromosome and improved survival. Recent findings also suggest that low-dose cytarabine (ara-C), in combination with interferon, may be more beneficial than interferon alone. For patients who do not respond to interferon, autologous or allogeneic stem cell transplantation is the only alternative.
Patients with advanced-phase disease may be treated with cytotoxic drugs. For example, individuals showing myeloid transformation may be given drugs that are used to induce remission in AML - that is, daunorubicin and cytarabine, with or without 6-thioguanine or etoposide. Blast cell numbers will be reduced temporarily, but they will increase again within 3 to 6 weeks. Individuals showing lymphoid transformation have a slightly better outlook. They are treated with drugs used in the management of acute lymphocytic leukemia (ALL) - that is, prednisone, vincristine, and daunorubicin, with or without L-asparaginase.
New drugs that are being studied in clinical trials of CML include homoherringtonine with interferon-alpha (INF-a), paclitaxel (Taxol®), QS21 (a plant extract that heightens immune responses), and amifostin (a chemical that lessens some side effects of chemotherapy). In addition, clinical trials are evaluating the potential benefits of substances such as vaccines, monoclonal antibodies (immunologic substances that can direct the patient's immune system to kill cancer cells), and hormones (e.g., growth factors, interleukins).
===Chronic phase===
Chronic phase CML is treated with inhibitors of [[tyrosine kinase]] , the first of which was [[Imatinib|imatinib mesylate]] (marketed as Gleevec® or Glivec®; previously known as STI-571). In the past, antimetabolites (e.g. [[cytarabine]], [[hydroxyurea]]), [[alkylating antineoplastic agent|alkylating agent]]s, [[Interferon|interferon alfa 2b]], and [[steroid]]s were used, but these drugs have been replaced by imatinib. Imatinib was approved by the United States [[Food and Drug Administration|FDA]] in 2001 and specifically targets BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by the [[Philadelphia chromosome]] translocation. It is better tolerated and more effective than previous therapies. [[Bone marrow transplant|Bone marrow transplantation]] was also used as initial treatment for CML in younger patients before the advent of imatinib, and while it can often be curative, there is a high rate of transplant-related mortality.<ref name="Hehlmann"/>
To overcome imatinib resistance and to increase responsiveness to TK inhibitors, two novel agents are currently undergoing [[clinical trials]]. The first, [[dasatinib]], is a TK inhibitor that blocks several oncogenic proteins and has been recently approved by the US FDA to treat CML patients who are either resistant to or intolerant of imatinib. Dasatanib and Imatinib resistance is caused by the T315I mutation. One drug to overcome this resistance is being developed by Merck (MK-0457, formerly known as VX-680), however, enrollments in this clinical trial are currently suspended, pending a full analysis of all efficacy and safety data <ref>FDANEWS.Nov 26 volume5 (230)</ref>. Another drug in development for the T315I mutation is Omacetaxine (formerly known as Ceflatonin®). Clinical data from the first 21 patients enrolled in a Phase 2/3 trial were presented at the American Society of Hematology (ASH) Annual Meeting <ref> Khoury, HJ. et al. Safety and Efficacy Study of Subcutenous Homoharringtonine(SC HHT) in Imatinib (IM)-Resistanct Chronic Myeloid Leukemia (CML) with the T315I Mutation-Intial report of a Phase II Trial (2007)Blood. 110(11):318a</ref>. Another agent, nilotinib, is a selective kinase inhibitor, but is currently undergoing clinical development and testing. Nilotinib is designed to bind more tightly than imatinib to the Bcr-Abl abnormal fusion protein responsible for chronic myeloid leukemia. [[Stem cell treatments|Stem cell transplantation]] is a secondary option for treatment of CML.<ref name=Jabbour>{{cite journal|title=Current and emerging treatment options in chronic myeloid leukemia|author=Jabbour E, Cortes JE, Giles FJ, O'Brien S, Kantarjian HM|journal=Cancer|date=2007|volume=109|issue=11|pages=2171-2181|pmid=17431887}}</ref><ref>{{cite journal|title=New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia|author=Kimura S, Ashihara E, Maekawa T|date=2006|journal=Current Pharmaceutical Biotechnology|volume=7|issue=5|pages=371-379|pmid=17076652}}</ref>
In 2005 favourable results of [[vaccination]] were reported with the ''BCR/abl'' p210 fusion protein in patients with stable disease, with [[GM-CSF]] as an adjuvant.<ref>{{cite journal|author=Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F|title=Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial|journal=Lancet|date=2005|volume=365|issue=9460|pages=657-62|pmid= 15721470}}</ref>
===Blast crisis===
''Blast crisis'' carries all the symptoms and characteristics of either [[acute myelogenous leukemia]] or [[acute lymphoblastic leukemia]], and has a very high [[death|mortality]] rate. This stage can most effectively be treated by a [[bone marrow transplant]] after high-dose [[chemotherapy]]. In young patients in the accelerated phase, a transplant may also be an option. However the likelihood of relapse after a bone marrow transplant is higher in patients in blast crisis or in the accelerated phase as compared to patients in the chronic phase.<ref name="Jabbour"/>
===There are different types of treatment for patients with chronic myelogenous leukemia===
Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
===Leukapheresis===
It is also known as a peripheral blood stem cell transplant, with stem cell cryopreservation (frozen storage) prior to any other treatment. The patient's blood is passed through a machine that removes the stem cells and then returns the blood to the patient. Leukapheresis usually takes 3 or 4 hours to complete. The stem cells may or may not be treated with drugs to kill any cancer cells. The stem cells then are stored until they are transplanted back into the patient.
===Tyrosine kinase inhibitor therapy===
A drug called imatinib mesylate is used as initial treatment for certain types of chronic myelogenous leukemia in newly diagnosed patients. It blocks an enzyme called tyrosine kinase that causes stem cells to develop into more white blood cells (granulocytes or blasts) than the body needs. Another tyrosine kinase inhibitor called dasatinib is used to treat patients with certain types of CML that have progressed, and is being studied as an initial treatment.
===Chemotherapy===
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
===Biologic therapy===
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
===High-dose chemotherapy with stem cell transplant===
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
===Donor lymphocyte infusion (DLI)===
Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant. Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.
===Surgery===
Splenectomy is surgery to remove the spleen.
==Current Treatment Protocols for CML==
===Chronic Phase Chronic Myelogenous Leukemia===
Treatment of chronic phase chronic myelogenous leukemia may include the following:
* Drug therapy with a tyrosine kinase inhibitor.
* High-dose chemotherapy with donor stem cell transplant.
* Biologic therapy (interferon) with or without chemotherapy.
Treatment of accelerated phase chronic myelogenous leukemia may include the following:
* Stem cell transplant.
* Drug therapy with a tyrosine kinase inhibitor.
* Biologic therapy (interferon) with or without chemotherapy.
* High-dose chemotherapy.
* Chemotherapy.
* Transfusion therapy to replace red blood cells, platelets, and sometimes white blood cells, to relieve symptoms and improve quality of life.
===Blastic Phase Chronic Myelogenous Leukemia===
[[Chronic myelogenous leukemia medical therapy|Medical Therapy]] | [[Chronic myelogenous leukemia surgery|Surgery]] | [[Chronic myelogenous leukemia primary prevention|Primary Prevention]] | [[Chronic myelogenous leukemia secondary prevention|Secondary Prevention]] | [[Chronic myelogenous leukemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Chronic myelogenous leukemia future or investigational therapies|Future or Investigational Therapies]]
Treatment of blastic phase chronic myelogenous leukemia may include the following:
* Drug therapy with a tyrosine kinase inhibitor.
* Chemotherapy using one or more drugs.
* High-dose chemotherapy.
* Donor stem cell transplant.
* Chemotherapy as palliative therapy to relieve symptoms and improve quality of life.
===Relapsed Chronic Myelogenous Leukemia===
Treatment of relapsed chronic myelogenous leukemia may include the following:
* Drug therapy with a tyrosine kinase inhibitor.
* Donor stem cell transplant.
* Donor lymphocyte infusion.
* Biologic therapy (interferon).
==Prognosis==
In one analysis of several clinical studies, three different risk groups were identified based on a prognostic scoring system that includes several variables: age, spleen size, blast count, platelet count, eosinophil count and basophil count. In the lowest risk group, the median survival time was 98 months. In the middle group, the median was 65 months, and in the highest risk group, the median was about 42 months. Of all patients analyzed, the longest survival time was 117 months.<ref>{{cite journal|title=A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group|author=Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H|date=1998|journal=Journal of the National Cancer Institute|volume=90|issue=11|pages=850-858|pmid=9625174}}</ref> However, this study pre-dates the advent of treatments using targetted therapy. A follow-up on patients using imatinib published in the New England Journal of Medicine shows an overall survival rate of 89% after five years.<ref>{{cite journal|title=Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia|author=Druker BJ, Guilhot F, O'Brien SG et al |date=2006|volume=355|issue=20| pages=2408-2417|doi=10.1056/NEJMoa062867| url=http://content.nejm.org/cgi/content/full/355/23/2408|pmid=17151364}}</ref>
The prognosis (chance of recovery) and treatment options depend on the following:
* The patient’s age.
* The phase of CML.
* The amount of blasts in the blood or bone marrow.
* The size of the spleen at diagnosis.
* The patient’s general health.
==References==
{{reflist|2}}
== External links ==
* [http://www.leukemia-lymphoma.org/all_page?item_id=8501 The Leukemia & Lymphoma Society]
* [http://www.bmtinfonet.org/ Blood & Marrow Transplant Information Network]
* [http://leukemia.acor.org/ Association of Cancer Online Resource (ACOR) Leukemia Links]
Pernicious anemia (also called Addison's anemia) is a type of red blood cell disorder caused by impaired vitamin B12 metabolism. Vitamin B12 is primarily absorbed by the small intestine, after being bound to intrinsic factor secreted by parietal cells of gastric mucosa. When this process is disrupted by conditions like atrophic gastritis, celiac disease, small bowel resection etc, B12 deficiency ensues.
Historical perspective
Pernicious anemia was first discovered by Thomas Addison, hence it is also known as addison's anemia.
Loss of life from large volume blood loss in the people fighting in the first world war inspired George Whipple to investigate blood forming components such as arsenic, iron pills etc, but found liver to be the most effective. He bled dogs until they had clinical anemia and fed them cooked liver which showed an improvement in symptoms and hematopoeisis. [1]
In 1948, Smith, Rickles et al., isolated the anti-pernicious factor from liver extract and named it Vitamin B12. They showed that even small amounts of this factor can be used to treat and to prevent pernicious anemia. [2]
Pathophysiology
Vitamin B12 is an essential vitamin for humans and animals because we cannot synthesise it on our own. B12 is a cofactor in DNA synthesis and other important biochemical reactions. Vitamin B12 deficiency manifests as anemia because hematopoetic stem cells in the bone marrow which are rapidly dividing need B12 for division and DNA production. This process is impaired leading to ineffective hematopoeisis. Vitamin B12 is also necessary for production of myelin which is an important component in the covering sheath of nerves. Deficiency results in improper nerve conduction due to nerve destabilisation. [3]
Physiology
Vitamin B12 is also called cobalamin because it contains cobalt at the core of its structure. Dietary sources of vitamin B12 include meat, fish and eggs.[4]
When consumed through its dietary source, B12 is bound to protein till it enters the stomach.
In the stomach, B12 is uncoupled from its carrier protein due to the presence of gastric acid, which is why vitamin B12 deficiency is so commonly seen among those on chronic antacid medication. [5]
Once in the stomach, it is then bound to gastric R binder, a glycoprotein secreted by the salivary glands till it reaches the duodenum.[6]
In the duodenum and jejunum, the pancreatic enzymes digest the gastric R binder and cobalamin is bound to intrinsic factor (IF).
Intrinsic factor is secreted by the gastric parietal cells. Once bound to IF, vitamin B12 travels up to the ileum where IF is removed and B12 binds with carrier proteins called transcobalamins and this complex is taken up by the liver and bone marrow, among other tissues.
Inside the cells, the transcobalamin-B12 complex is dissolved and cobalamin is reduced to methylcobalamin which serves as a cofactor and coenzyme in many important biochemical reactions[7].
The two major reactions involving B12 in the human body are:
Vitamin B12 in the from of cyanocobalamin is required in the synthesis of methionine. Methionine is produced from homocysteine and is catalysed by the enzyme methionine synthase. This enzyme utilises cyanocobalamin as a cofactor. Deficiency of vitamin B12 causes a decreased production of methionine and buildup of homocysteine. Hyperhomocysteinemia is implicated as a risk factor in cardiovascular disease.[8]
The Kreb's cycle utilises vitamin B12 in the reaction converting methylmalonyl-CoA to succinyl-CoA. Thus vitamin B12 deficiency causes a buildup of methylmalonic acid, the substrate for the enzyme methylmalonyl coenzyme A mutase. Methylmalonic acid levels are elevated in the urine of people affected with pernicious anemia and other forms of B12 deficiency.
Storage
The human body can store anywhere from 2-5mg of vitamin B12. Most of this is stored in the liver and is recycled via enterohepatic circulation.
Pathogenesis
Pernicious anemia is a type of megaloblastic anemia caused due to improper vitamin B12 absorption by the body. Impaired absorption occurs because of deficiency of intrinsic factor which is produced by the parietal cells of the stomach. The etiology of pernicious anemia can be due to autoimmune causes or genetic disease. In autoimmune disease, the antibodies attack most of the gastric mucosa, but the antrum is spared.
Autoimmune causes of pernicious anemia
This is the most common cause of pernicious anemia. In autoimmune pernicious anemia, the body produces antibodies against parietal cells or intrinsic factor.
Antibodies against parietal cells of the gastric mucosa work to inhibit the H+/K(+)-ATPase which is the proton pump present in the parietal cells. The proton pump serves as an auto antigen and activates the cytotoxic CD4+ T cells which proceed to destroy gastric mucosal cells.[9][10]
Intrinsic factor antibodies are present in fewer cases of pernicious anaemia but are highly specific. There are 2 types of IF antibodies. They prevent the binding and absorption of cobalamin in the ileum via its receptor.[11]
Clinical features
The symptoms of pernicious anemia take months, and often years to manifest. Patients most commonly present with symptoms of anemia like lightheadedness, dizziness, shortness of breath etc. The population affected with pernicious anemia is usually the elderly (>60 years) owing to its insidious onset.
Pernicious anemia has hematological, gastrointestinal and neurological manifestations.
Hematological signs are the earliest manifestation of the disease while neurological signs are seen much later.
Patients with pernicious anemia usually have very low levels of hydrochloric acid in the stomach (achlorhydria) and high levels on gastrin (hypergastrinemia).
Differentiating pernicious anemia from other diseases
Pernicious anemia shares many similarities with other forms of megaloblastic anemia like B12 and folate deficiency.
Vitamin B12 deficiency due to insufficient intake (eg veganism) has all the features of pernicious anemia like megaloblasts, hypersegmented neutrophils, neuropsychiatric manifestations. But atrophic gastritis is absent, so achlorhydria, parietal cell antibodies or IF antibodies are absent. Intrinsic factor levels are also normal.[6]
Folic acid deficiency also results in megaloblastic anemia and similar hematological changes as pernicious anemia, but urinary excretion of methylmalonic acid is absent, so are features of pernicious anemia like achlorhydria, antibodies and normal IF levels.
Ileal resection causes B12 deficiency due to decreased absorption.
Certain drugs such as methotrexate, azathioprine cause folate deficiency and result in megaloblastic anemia. This is usually seen in patients taking chemotherapy or other chronic conditions such as rheumatoid arthritis. [12]
Chronic proton pump inhibitor therapy also results in B12 deficiency as vitamin B12 cannot dissociate from its carrier protein in the absence of an acidic environment.[13]
Long term use of metformin, such as in diabetics, is linked to vitamin B12 deficiency and symptoms similar to pernicious anemia, but this can be differentiated from pernicious anemia as it is seen in diabetics on chronic therapy.[14]
Associated Conditions
People affected with pernicious anemia might have other coexisting autoimmune conditions such as autoimmune thyroiditis, autoimmune diabetes, vitiligo etc. Autoimmune thyroiditis is most commonly seen in patients with pernicious anemia, particularly females. HLA DR3 has been implicated in the development of autoimmune diseases such as pernicious anemia[15].
Epidemiology and demographics
Pernicious anemia is a disease of the elderly. The mean age of patients who are symptomatic is >60.[16]
An exception is the genetic form of the disease which is a congenital deficiency of intrinsic factor and is seen in children <10 years of age.
Men and women are equally affected
Prevalence of pernicious anemia is estimated at 0.1% of the population.[17]
Genetics
Some forms of pernicious anemia are congenital and a genetic link has been postulated because of a higher incidence in certain populations.
Affected people have a complete or near total absence of intrinsic factor and the presence of antibodies against intrinsic factor.
The genetic variant is transmitted through an autosomal recessive pattern.[18]
Risk factors
People who have autoimmune conditions like diabetes mellitus, autoimmune thyroiditis are at higher risk of developing pernicious anemia.
Natural History, Complications and Prognosis
In most cases, patients affected with pernicious anemia remain asymptomatic for many years.
Early manifestations include fatigue, shortness of breath, pallor and weakness.
Long standing untreated pernicious anemia results in irreversible neurological damage such as subacute combined degeneration of the spinal cord.
Neurological changes are irreversible once they set in and do not resolve with cobalamin supplementation.
Diagnosis
A diagnosis of pernicious anemia is made by a history and physical examination, along with hematological and neurological examination.
Diagnostic criteria
The only specific criteria to diagnose pernicious anemia is an intrinsic factor output of less than 200U/h after pentagastrin stimulation, where normal levels would be >2000U/h. [19]
Symptoms
Symptoms of pernicious anemia are summarised below
Hematological symptoms
Gastrointestinal symptoms
Neurological symptoms
Fatigue
Loss of appetite
Parasthesias
Weakness
Weight loss
Depression
Shortness of breath
Nausea
Gait problems
Dizziness
Burning sensation on tongue
Weakness
Tachycardia
Diarrhea
Loss of balance
Lightheadedness
Vomiting
Confusion
Physical examination findings
Most important physical examination findings are the neurological findings of long standing B12 deficiency which leads to subacute combined degeneration of the spinal cord.
Neurological signs: Vitamin B12 deficiency causes nerve demyelination. B12 deficiency also causes a buildup of methylmalonic acid which is toxic to neuronal cells and causes apoptosis.[21].
The main neurological manifestation of pernicious anemia and vitamin B12 deficiency is subacute combined degeneration. The posterior and lateral columns of the spinal cord are affected. Lateral column demyelination manifests as hyperreflexia and spasticity, while posterior column defects are loss of proprioception and vibration sense. Ataxia and loss of tandem gait are also manifestations of posterior column demyelination.
Recreational or accidental inhalation of nitrous oxide gas (laughing gas) can precipitate subacute combined degeneration in people with low levels of vitamin B12.[22]
Gastrointestinal signs: Upto 25% of people affected with pernicious anemia develop glossitis. The tongue appears red, "beefy" and smooth due to atrophy and blunting of the lingual papillae.[23]
Subacute combined degeneration
Laboratory findings
The first step in diagnosis is a blood vitamin B12 level. Blood levels less than 200 pg/ml are seen in pernicious anemia.
Intrinsic factor antibodies and Parietal cell antibodies.
Gastric mucosal sampling shows parietal cell atrophy with antral sparing.[25]
Increased level of gastrin.
Increased levels of homocysteine and methylmalonyl-CoA.
Decreased folate levels are seen due to "folate trapping" in the form of methyltetrahydrofolate.
Shilling Test
The Shilling test is no longer done to detect an IF deficiency but has historical importance. After a vitamin B12 deficiency is noted, the patient is given radioactively tagged cobalamin to take orally. Soon after this step, the patient is injected with unlabelled cobalamin intramuscularly. Urine is checked for radioactive cobalamin for the next 24 hours. In pernicious anemia, there is an intrinsic factor deficiency, therefore the orally consumed radioactive cobalamin will not be absorbed and can be detected in the urine. In the next step, the patient is given radioactive cobalamin along with intrinsic factor and their urine is checked for traces of radioactive cobalamin. Absence of radioactive cobalamin in the urine points to the deficiency of intrinsic factor in the patients stomach which is the cause of vitamin B12 deficiency[26].
If the cobalamin absorption does not increase even with intrinsic factor supplementation, patient can be given a course of antibiotics as bacterial overgrowth may hinder absorption.
Peripheral smear findings
The most obvious peripheral smear finding is megaloblasts and macrocytes.
Megaloblastic anemia results due to the lagging behind of nuclear development when compared to cytoplasmic development. This is known as nuclear-cytoplasmic asynchrony. Such defective cells are destroyed in the bone marrow (intramedullary hemolysis).
Decreased number of RBCs (erythopenia)
Macrocytosis- the RBCs in pernicious anemia are very large. Macrocytosis is defined as cells that have an MCV >100 femtolitres (normal :80-100fL)
Within the first 3-4 weeks of treatment, marrow changes revert and there is resolution in macrocytosis.
Most patients require lifelong monthly therapy.
Routine follow up should be done with a CBC every few months.
A small percentage of patients develop gastric carcinoma, particularly in the elderly. Regular surveillance helps in early detection and treatment. [29]
Prevention
There is no primary preventive measure for pernicious anemia.
Once sucessfully diagnosed and treated, patients with pernicious anemia are followed up every year for development of stomach cancer[30], or symptoms of anemia.
