What are the causes of high hematocrit. How is erythrocytosis different from polycythemia vera. What are the symptoms, diagnosis, and treatment options for polycythemia vera. How does the JAK2 mutation affect blood cell production.

Understanding Erythrocytosis and Its Impact on Blood Composition

Erythrocytosis is a condition characterized by an increase in red blood cell (RBC) mass, typically accompanied by elevated hematocrit (HCT) and hemoglobin concentration. While often used interchangeably with polycythemia, these terms are not synonymous. Polycythemia refers to an increased number of any hematopoietic cell in the blood, including RBCs, platelets, or leukocytes.

What distinguishes erythrocytosis from other blood disorders? Erythrocytosis specifically pertains to an increase in red blood cell mass, which can be either absolute or relative. Absolute erythrocytosis occurs when there is a true increase in RBC production, while relative erythrocytosis results from a decrease in plasma volume without an actual increase in RBC mass.

Types of Erythrocytosis

• Primary Erythrocytosis: Caused by intrinsic factors within the red blood cell precursors
• Secondary Erythrocytosis: Results from external factors stimulating increased RBC production
• Idiopathic Erythrocytosis: No identifiable cause can be determined

How does erythrocytosis affect blood viscosity? The increased red blood cell mass in erythrocytosis leads to thickening of the blood, which can impair circulation and increase the risk of blood clots. This change in blood composition can have significant implications for overall health and requires careful management.

Polycythemia Vera: A Closer Look at a Myeloproliferative Neoplasm

Polycythemia vera (PCV) is a slow-developing, chronic myeloproliferative neoplasm characterized by the overproduction of red blood cells. This condition leads to blood thickening and is often associated with elevated platelet counts and an enlarged spleen. PCV is linked to a mutation in the JAK2 gene, which plays a crucial role in regulating blood cell production.

Is polycythemia vera hereditary? Unlike some genetic disorders, PCV is not an inherited condition. It is an acquired disease that typically occurs later in life, with the JAK2 mutation developing over time rather than being passed down from parents to children.

Key Characteristics of Polycythemia Vera

• Overproduction of red blood cells
• Thickening of the blood
• Potential elevation of white blood cells and platelets
• Progressive nature of the disease
• Association with JAK2 gene mutation

Why is understanding the underlying cause of PCV important? While the exact trigger for PCV remains unknown, recognizing its association with the JAK2 mutation has opened new avenues for research and targeted treatments, offering hope for more effective management of the condition in the future.

Recognizing the Symptoms of Polycythemia Vera

Polycythemia vera can present with a wide range of symptoms, although some patients may be asymptomatic and only discover the condition during routine blood tests. The symptoms of PCV are often subtle and can develop gradually over time, making early detection challenging.

Common Symptoms of Polycythemia Vera

• Headache
• Excessive sweating, particularly at night
• Tinnitus (ringing in the ears)
• Visual disturbances, including blurred vision or blind spots
• Dizziness
• Reddish or purplish skin coloration
• Unexplained weight loss
• Bleeding or clotting issues
• Persistent feeling of fullness
• Itching, especially after bathing
• Burning sensation and redness in hands or feet
• Fatigue
• Bone pain

How can patients differentiate PCV symptoms from other conditions? Many of these symptoms can be attributed to various health issues, which is why it’s crucial to consult a healthcare professional for proper diagnosis. The combination of symptoms, along with blood tests and genetic screening, can help identify PCV accurately.

Diagnostic Approaches for Polycythemia Vera

Diagnosing polycythemia vera involves a combination of clinical observation, blood tests, and genetic screening. Often, the initial suspicion arises from routine blood work that reveals elevated red blood cell counts. However, a comprehensive diagnostic process is necessary to confirm PCV and rule out other conditions that may cause similar blood abnormalities.

Key Diagnostic Tests for Polycythemia Vera

1. Complete Blood Count (CBC): This test reveals increases in red blood cells, and potentially white blood cells and platelets.
2. Genetic Testing: Screening for the JAK2 mutation, which is positive in approximately 95% of PCV patients.
3. Erythropoietin Level Test: Checking for low levels of this hormone, which is involved in red blood cell production.
4. Bone Marrow Biopsy: Examining the bone marrow for proliferation of blood cell precursors.

Why is a multi-faceted diagnostic approach important for PCV? Given the complexity of myeloproliferative neoplasms, using a combination of tests helps ensure accurate diagnosis and differentiation from other blood disorders. This comprehensive approach also provides valuable information for treatment planning and prognosis.

Risk Factors Associated with Polycythemia Vera

While the exact cause of polycythemia vera remains unknown, several risk factors have been identified that may increase an individual’s likelihood of developing this condition. Understanding these risk factors can help in early detection and management of PCV.

Primary Risk Factors for Polycythemia Vera

• Gender: Men have a slightly higher risk compared to women.
• Age: PCV is most commonly diagnosed in individuals over 60, although it can occur at any age.
• Radiation Exposure: Intense radiation exposure may increase the risk of developing PCV.
• Environmental Toxins: While not definitively proven, there is speculation about a potential link between toxic substance exposure and PCV development.
• Genetic Factors: The presence of the JAK2 mutation is a significant risk factor, found in 95% of PCV cases.

How does understanding risk factors contribute to PCV management? Recognizing these risk factors allows for targeted screening and earlier intervention, potentially improving outcomes for individuals at higher risk of developing polycythemia vera. It also guides research efforts towards understanding the underlying mechanisms of the disease.

Treatment Strategies for Polycythemia Vera

Managing polycythemia vera is a long-term process aimed at controlling symptoms, reducing complications, and improving quality of life. Treatment approaches are often tailored to the individual patient, considering factors such as age, overall health, and the severity of the condition.

Primary Treatment Options for PCV

1. Phlebotomy: Regular blood removal to reduce overall blood cell count and improve blood flow.
2. Low-dose Aspirin: Used to prevent blood clots and reduce the risk of cardiovascular events.
3. Hydroxyurea: A medication that helps control hematocrit levels when phlebotomy alone is insufficient.
4. Pegylated Interferon: A therapy that alters the growth and survival of abnormal polycythemia cells.
5. Ruxolitinib (Jakafi): A targeted therapy that inhibits the JAK2 protein, approved for patients who don’t respond well to hydroxyurea.

What is the primary goal of PCV treatment? The main objective is to maintain the hematocrit (HCT) below 45%, as this has been shown to improve survival rates and reduce complications. Treatment strategies are adjusted based on patient response and the progression of the disease.

Complications and Long-term Outlook for Polycythemia Vera Patients

Polycythemia vera is a chronic condition that requires ongoing management. While many patients can achieve good quality of life with proper treatment, PCV does carry risks of complications and can progress to more serious conditions in some cases.

Potential Complications of Polycythemia Vera

• Cardiovascular Events: Increased risk of stroke, mini-stroke (TIA), and heart attack.
• Venous Thrombosis: Higher likelihood of deep vein thrombosis and pulmonary embolism.
• Myelofibrosis: Approximately 15% of PCV patients may develop this progressive bone marrow disorder.
• Acute Myeloid Leukemia (AML): In rare cases, PCV can progress to AML.

How does proper management impact the long-term outlook for PCV patients? With appropriate treatment and regular monitoring, many individuals with polycythemia vera can lead relatively normal lives. However, the chronic nature of the disease necessitates ongoing medical care and vigilance for potential complications.

The discovery of the JAK2 mutation’s role in PCV has opened new avenues for research and treatment development. As our understanding of the disease mechanisms improves, there is hope for more targeted and effective therapies in the future, potentially improving outcomes and quality of life for those affected by polycythemia vera.

Polycythemia Vera (PCV) Diagnosis & Treatment – NYC | Herbert Irving Comprehensive Cancer Center (HICCC)

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In polycythemia vera (PCV), the body makes too many red blood cells, leading to a thickening of the blood. It can be associated with an elevated platelet count and an enlarged spleen. 

This slow-developing disease is linked to a mutation in the gene JAK2, which regulates the production of blood cells. This is an acquired disease, not an inherited genetic problem, occurring later in life.

PCV is both chronic and progressive. No one knows its cause.

Symptoms

Patients may not have any symptoms or they may have the kind of complaints that are discovered during a routine physical exam, including:

• Headache
• Sweating during the day or night
• Ringing in the ears
• Blurred vision or blind spots
• Dizziness
• Reddish or purplish skin
• Unexpected weight loss
• Problems with bleeding or clotting
• A perennial feeling of fullness
• Itching, especially after taking a shower
• Burning and redness of the hands or feet
• Fatigue
• Bone pain

Diagnosis

In many cases, a routine complete blood count reveals an increase in the red blood cells along with an increase in the white blood cells or platelets. A physician may also recognize certain signs of this disease during an ordinary office visit, including a redness of the complexion or an increase in the size of the spleen.

Common diagnostic tests include:

• Complete blood count to check for an increase in the hemoglobin (along with the white blood cells or platelets)
• Genetic testing for the JAK2 mutation (positive in 95% of PCV patients)
• Further blood tests to look for a low erythropoietin level (a hormone involved in red blood cell production)
• Bone marrow biopsy to look for proliferation of precursors to red blood platelets, red blood cells, and white blood cells

Risk Factors

• Gender. Men are slightly more likely than women to develop the condition.
• Age. Though PCV can be diagnosed at any age, it is most commonly found in patients over 60.
• Exposure to intense radiation. This may also increase the risk for PCV.
• Environmental toxins. There is speculation that PCV may be triggered by exposure to toxic substances, but there have been no definitive studies in this area. A cluster of PCV cases has been reported in three counties in Pennsylvania adjacent to a Superfund Cleanup site and is under study now.
• Gene mutations. Ninety-five percent of patients with PCV have a mutation in the JAK2 gene. The discovery of this mutation has inspired research that will hopefully lead to new and effective treatments.

Treatments

For most patients, this disease is chronic. That means they tend to live longer than other patients with myeloproflierative neoplasms (MPN) but have to deal with ongoing symptoms, including itching after bathing, general fatigue, or blood clotting. Complications of this disease may include cardiovascular events such as a stroke, mini-stroke, or heart attack or problems in the veins, including deep vein thrombosis, pulmonary embolus, and blood clots.

Roughly 15% of patients suffer from myelofibrosis, a progressive bone marrow disorder that results in bone marrow scarring, severe anemia, and enlargement of the liver and spleen. In a few cases, PCV may progress to acute leukemia (AML).

The progression of this disease varies with each patient, as does the treatment. Getting the hematocrit (HCT), a measure of the red blood count, to less than 45 has been shown to improve survival and is the goal of treatment.

Treatment options may include:

• Phlebotomy—Removal of blood to reduce the overall number of blood cells. With fewer cells, the blood “thins” and flows more easily and symptoms generally improve.
• Low-dose aspirin—Aspirin keeps platelets from sticking together and can prevent life-threatening blood clots causing heart attacks and strokes.
• Hydroxyurea—a drug that can help to control the HCT in patients when phlebotomy does not work completely.
• Pegylated interferon—a therapy that alters the growth and survival of the abnormal polycythemia cells.
• Ruxolitinib (Jakafi)—a drug that targets the JAK2 protein. This drug was approved by the FDA for patients who no longer respond to hydroxyurea or have too many side effects from hydroxyurea. 

Erythrocytosis | eClinpath

Erythrocytosis is defined as an increase in red blood cell (RBC) mass, usually absolute, and is also associated with an increased hematocrit (HCT) and hemoglobin concentration. Although some use the term polycythemia interchangeably with erythrocytosis, the two are not synonymous. Polycythemia in precise terms refers to an increased number of any hematopoietic cell in blood, be it RBCs, platelets or leukocytes. An increase in RBC number (whether relative to changes in body water or an absolute increase in RBC mass) is more precisely called erythrocythemia, but this term is not in general use and we are currently using the term erythrocytosis instead of polycythemia for a general increase in RBCs (whether relative or absolute), even if not completely correct. Complicating matters is the term polycythemia vera, which specifically refers to a type of chronic myeloid leukemia that only affects the erythroid lineage or, in other words, a chronic erythroid leukemia.

High HCT algorithm

An increased HCT or RBC count can be relative (proportional changes of RBC numbers in relation to plasma water) or absolute (a true increase in RBC numbers due to erythropoiesis, i.e. erythrocytosis). The different causes of an increased HCT or RBC count can be distinguished on the basis of clinical signs and signalment (dehydration, young horse), response to fluid therapy (relative increases should correct with appropriate fluid treatment), total protein concentration (usually only increased with relative increases due to dehydration), detection of hypoxia (arterial blood gas analysis), cardiovascular and pulmonary evaluation, and searching for underlying causes of increased RBC production, which would result in a true increase in RBC mass or erythrocytosis (such as liver and renal disease, including neoplasia). Measurement of erythropoietin concentrations are rarely performed and usually not informative (i.e. not helpful in distinguishing between causes). Bone marrow aspiration is usually not worthwhile as the marrow shows an erythroid hyperplasia in all causes of erythrocytosis.

• Relative increase in HCT or RBC count: This is due to changes in RBC numbers with respect to plasma (i.e. not a true increase in RBC mass). This can be due to loss of intravascular water, which is the most common cause of a relative increase, or proportionally increased numbers of RBC in circulation. In theory, this should not be called an erythr0cytosis.
  • Loss or redistribution of intravascular water (hemoconcentration): Causes are fluid depletion and increased vascular permeability (secondary to endotoxemia). The total protein, with both albumin and globulin, concentrations will usually be increased due to water losses in excess of RBCs (albumin is a more specific indicator of hemoconcentration than globulins because the latter will go up with inflammation or antigenic stimulation). With moderate to marked external losses of water, the animal usually displays clinical signs and laboratory features of dehydration (increased total protein and albumin concentrations, perhaps increased sodium and chloride concentrations). With internal losses, there may be evidence of fluid accumulation in internal sites (e.g. peritonitis, sequestration of fluid in a non-functioning or blocked gastrointestinal tract) or of endotoxemia (inflammatory leukogram, thrombocytopenia). With endotoxemia, the alterations in HCT are usually mild and the animal does not show clinical signs of dehydration (unless there is concurrent fluid losses or sequestration), although they may show signs of endotoxic shock.
  • Splenic contraction: Up to 30% of RBCs can be stored in the spleen and these RBCs can be released upon splenic contraction. Contraction occurs during extreme excitement or fear and is likely epinephrine-mediated (Deniau et al 2013). This is usually seen in young horses (usually hot-blooded breeds, such as Arabians, Thoroughbreds, Appaloosas and Standardbreds), since horses have a muscular spleen, and is less likely in ruminants, dogs and cats. One study in goats showed a 20% increase in packed cell volume (from a mean of 29% to 35%) within 5 minutes of epinephrine injection (2 mg), which was absent in splenectomized animals. This returned to baseline within 15-30 minutes (Abdelatif and Abdalla et al 2012). Splenic contraction is associated with a relative increase in RBCs in relation to water but, unlike hemoconcentration, will not be associated with an increase in total protein concentrations. Splenic contraction and a component of hemoconcentration may also explain the increase in HCT seen in horses subjected to strenuous exercise (Rose et al 1983, Snow et al 1983).
• Absolute increase in HCT or RBC mass (erythrocytosis): This is due to increased erythropoiesis and can be primary (a bone marrow disorder) or secondary, due to appropriate or inappropriate production of the erythropoietic cytokine, erythropoietin.
  • Primary erythrocytosis: This can be a familial disorder or neoplastic.
    • Familial erythrocytosis has been reported in Jersey cattle (Tennant et al 1967). A congenital condition could have been the cause of a persistently increased HCT in a 2 year old Arabian gelding (McFarlane et al 1996). 
    • Polycythemia vera: This is a chronic myeloproliferative disorder (chronic erythroid leukemia) and is a neoplastic condition in which RBC production is autonomous and independent of erythropoietin concentrations. In human patients, this has been shown to be largely due to a mutation in Janus-activated kinase 2 (JAK2). JAK2 is a non-receptor tyrosine kinase that is downstream of the erythropoietin receptor and directs the signaling cascade triggered by erythropoietin binding to its receptor on RBC precursors in the bone marrow. The signaling then drives cell division and erythropoiesis. Normally, JAK2 is only activated (by phosphorylation of tyrosine residues) when erythropoietin binds to its receptor. However, up to 90% of patients with polycythemia vera have a homozygous single amino acid mutation in JAK2 (valine is substituted for a phenylalanine in amino acid 617), which makes the enzyme constitutively active. This drives erythropoiesis, either independently of erythropoietin or because RBC precursors become hypersensitive to normal concentrations of erythropoietin. Polycythemia vera is rarely reported in animals and a genetic mutation in JAK2 has not been identified in affected animals. Polycythemia vera is usually a diagnosis of elimination, ruling out other causes of secondary erythrocytosis or a relative increase in HCT.
  • Secondary erythrocytosis: This is usually due to increased erythropoietin production. The physiologic stimulus for erythropoietin production is hypoxia, therefore erythropoietin production can be appropriate (in response to hypoxia), albeit excessive, or inappropriate (independent of hypoxia).
    • Appropriate secondary erythrocytosis: There is an appropriate stimulus for erythropoietin production, which is principally hypoxia, e.g. cardiovascular or respiratory disease, increased affinity of hemoglobin (carbon monoxide poisoning).
    • Inappropriate secondary erythrocytosis: This is due to enhanced erythropoiesis that is independent of a hypoxic stimulus, and is usually mediated via erythropoietin. This has been reported with erythropoietin-producing neoplasms (renal and non-renal tumors, including carcinomas and sarcomas, in dogs and cats [Peterson and Zanjani 1981, Couto et al 1989, Durno et al 2011, Troia et al 2017, Won Seo et al 2018, Grimes et al 2019], hepatoblastoma, endocrine/neuroendocrine carcinoma, and renal lymphoma in horses [Cook et al 1995, Koch et al 2006, Gold et al 2008, Tirosh et al 2019]) or renal disease (hydronephrosis, renal cysts in humans and experimental animal models [Hirsch and Leiter 1983, Fasolino et al 2022]), which for some reason stimulate erythropoietin production without hypoxia. For most of these tumors, increased erythropoietin production makes sense because erythropoietin can be produced in the kidney (main site) or liver. However, tumors can ectopically secrete cytokines, which may explain erythropoietin production in tumors in unexpected sites (e. g. nasal tumor). Epinephrine-producing neoplasms, such as pheochromocytoma, can also result in a fluid-unresponsive erythrocytosis in horses (but this may not be a true increase in RBC mass). Similarly, mild increases in RBC numbers can be seen in some dogs and cats with endocrine disorders, such as dogs with hyperadrenocorticism or excess androgens and cats with hyperthyroidism and acromegaly. This may be mediated through erythropoietin. Horses with severe non-neoplastic liver disease (e.g. fibrosis) can also have a persistent erythrocytosis, which is not responsive to fluid therapy (Steiger and Feige 1995, anectdotal reports). The mechanism is unclear, but could be due to aberrant erythropoietin release from the diseased liver.

Indicators RDW-SD and RDW-CV in the diagnosis of anisocytosis – Article in Yekaterinburg

Patients who donate blood to the laboratory for analysis often ask for an explanation of the finished result. This situation is popular, because instead of several columns, people see a list of 18 to 22 parameters as a result. Our article will help to understand this issue.

Blood functions

Blood is the most important indicator by whose parameters one can assess the state of the body. It is a liquid medium, which includes plasma and formed elements: platelets, erythrocytes and leukocytes.

Erythrocytes are red corpuscles shaped like a concave disk. These are cells without nuclei. Their size varies from 7.5 to 8.3 microns, and live from 3 to 4 months. Erythrocytes have antigenic properties, on the basis of which there are 4 blood groups.

In addition to mature erythrocytes, young blood cells can be found in the blood. Such cells do not have nuclei and contain a large amount of RNA and ribosomes. They have membrane receptors for transferrin. Reticulocytes lose their RNA and the ability to produce hemoglobin when they become mature cells.

The circulatory system in the body is very important. Since such an environment provides nutrition to organs and tissues, a complete blood count is required constantly. During the study, the color, size and shape of blood cells are taken into account. Changes in shape and size indicate poikilocytosis and anisocytosis occurring in the body.

Anisocytosis: what blood parameters do they pay attention to? An automatic analyzer allows you to get an accurate result, indicating the state of the human body.

At meetings of laboratory assistants, the following question is often asked: “ Which indicators of the hematology analyzer allow us to analyze the patient’s clinical picture? “.

Let’s look into these aspects on the example of interpreting the values ​​of the RDW-SD and RDW-CV indicators in the diagnosis of anisocytosis.

Anisocytosis is a disease in which there is an increase in the number of cells of non-standard sizes. Depending on which bodies have changed in size, there is anisocytosis of platelets and erythrocytes.

Anisocytosis of erythrocytes in the general blood test indicates that the size of red blood cells deviated from the standard. Normally, their value is from 7.5 to 8.3 microns. Red blood cells may be present in the blood, the size of which deviates, but their number should not exceed 30%. According to medical research, it is acceptable when 15% of cells are more than normal, 15% are less than normal. Red blood cells with a diameter of 6.9 microns are called microcytes.

Large cells come in two groups: macrocytes (which vary in size from 8 to 12 microns) and megalocytes with a diameter of more than 12 microns.

If, according to the results of the study in the hematological analyzer, little bodies are found, the size of which differs significantly from the specified norm, then the diagnosis is made: “ Increased anisocytosis of erythrocytes “.

Depending on which cell size prevails in the liquid medium, anisocytosis can be of the following types: microcytosis, macrocytosis and mixed type. The latter species is characterized by the presence of bodies of various sizes.

Indicate the degree of heterogeneity using a special index RDW, indicating the width of the distribution of red blood cells. Otherwise, such an indicator is called the erythrocyte anisocytosis index. It shows the difference in the size of the cell population in the tested sample.

The following indexes exist: RDW-CV and RDW-SD . The first index indicates the percentage distribution of cells by size. The second index is the standard deviation, namely the difference in size between large and small bodies.

RDW-CV is determined using a hematology analyzer. The device counts the number of bodies automatically. The result obtained is expressed as a percentage. The index is normal if its value is from 11 to 15%.

As a result of blood, another RDW-CV index can be found, which is determined by a different method. It is measured in femtoliters. It represents the difference between the minimum and maximum cell volume in the test sample. The normal value is from 35 to 60 femtoliters.

Clinical value of the RDW index in the correct diagnosis

The RWD value is interpreted simultaneously by assessing the mean erythrocyte volume. This is due to the fact that the width of the distribution of erythrocytes does not deviate from the norm during microcytosis and macrocytosis.

If the indicator is exceeded, we can talk about the development of the patient:

• Iron deficiency anemia;
• Hemolytic or megaloblastic anemia due to vitamin B deficiency;
• Hemoglobinopathies.

The score will be raised if the patient has liver disease or has recently had a blood transfusion. In the presence of cold agglutinins in the blood, an increase in the index may occur erroneously.

In addition, there are pathological conditions in which the index does not change. These include anemia in severe diseases, spherocytosis, anemia. It is important to pay attention to the fact that in the treatment of iron deficiency anemia, the index does not decrease, but rather increases. This is due to the appearance of new cells, the size of which differs from red blood cells. With the effectiveness of therapy, the anisocytosis index returns to normal.

“Medica-Group” – an online store of laboratory equipment necessary for equipping medical institutions. In the company’s catalog, buyers can purchase bacteriological analyzers and related equipment. The technique examines blood samples and reveals heterogeneity in the size of the red blood cell population.

You can buy on the company’s website various models of analyzers that differ in functionality and technical characteristics. The acquisition of sophisticated medical equipment will provide a clinical diagnostic laboratory of various sizes.

The company offers various forms of payment, selection of equipment depending on the specifics of the clinic, warranty and post-warranty service.

Attention! Medica Group sells automated microbiology analyzers and culture media vials, but does not provide a service to to collect or interpret blood test results.

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Late Effects After Autologous Hematopoietic Cell Transplantation

Linda J. Burns, MD, Associate Professor of Medicine and Fellowship Director of the Hematology, On cology, and Transplantation Program at the University of Minnesota, Minneapolis , MN.

Reported by Edward A. Faber, Jr., DO, MS.

With the improvement of accompanying therapy, the number of patients suffering from early complications of treatment has decreased; therefore, more attention is paid to the causes of complications and mortality in the long term. The increase over the past three decades in the number autologous hematopoietic stem cell transplants (auto-HCT) coincided with a 15% to 2% reduction in transplant-related mortality (TRM). The interpretation of the data is very difficult, since the definition of “distant” varies by researchers, and is also associated with the observed patient cohort, the disease under consideration, the modes of mobilization and transplantation, and the source of stem cells. Methods (relative risk, standardized mortality, actuarial estimate or cumulative rate) usually take into account that the rate of long-term complications over time varies between studies or is not explained in sufficient detail. In addition, the question arises: should comparisons of auto-HCT patients be made against other auto-HCT patients only, or against a “standard” population?

Numerous studies contribute to the current understanding of long-term complications and causes of death in adult patients. A major study designed to elucidate the causes of long-term mortality in patients surviving more than two years after HCT identified the most common cause of non-relapse mortality (NRM) secondary tumors, the incidence of which is increased after the use of carmustine and peripheral blood stem cell transplantation (PBSC ). Studies indicate a level of secondary malignancy ranging from 0.7% to 24%. Research 1193 children and adults have established the risk of developing second tumors. The cumulative rate of prior therapy-associated myelodysplastic syndrome and acute myeloid leukemia has a stable plateau for 10 years after HCT (higher trend with PBSC). On the contrary, the risk of developing solid tumors continued to increase even 20 years after transplantation. Relapses of the underlying disease, previous lines of chemotherapy and age are risk factors for the development of secondary tumors.

Although the 10-year incidence of myelodysplastic syndrome (MDS) after auto-HCT for multiple myeloma was reported to be 1%, patients with low CD34 counts (<3×10 ⁴ /kg and >2 apheresis) and patients with post-HCT consolidation chemotherapy had a higher incidence of secondary myeloid hemoblastoses. Chromosomal damage from >1 previous regimen of chemotherapy or mobilization chemotherapy may predispose to the formation of pre-leukemic stem cell clones.

The influence of HCT timing (pre-HCT, peri-HCT and post-HCT) on the development of secondary malignancy has been raised for more than a decade. Some studies have noted that pre-HCT abnormalities not detected by cytogenetic analysis could be detected by fluorescence in situ hybridization (FISH), suggesting that pre-HCT therapy is the cause of secondary malignancies, especially t-MDS/AML. Two prospective studies demonstrate an association of high cumulative doses of alkylating agents with the development of t-MDS/AML. Conversely, three retrospective studies reported no association with an increased risk of t-MDS/AML. Stem cell treatment with etoposide was associated with a 12.3 increased risk of t-MDS/AML and expected 11q23/21q22 abnormalities, but multivariate analysis failed to show any association with HCT.

Infection-related complications are reported to develop with a median of 28 months. Pulmonary fibrosis has been shown to occur with a median of three years after HCT. Inconclusive long-term effects include endocrine abnormalities (hypogonadism and hypothyroidism), late infectious complications, cataracts, sensorineural impairment, xerostomia, osteoporosis, while cardiac, pulmonary, and renal pathologies can lead to fatal outcomes. Arterial vascular events, especially cerebral and coronary, are more common in patients after allogeneic transplantation (allo-HCT) than after auto-HCT. Factors associated with cardiac events include number of pre-HCT chemotherapy cycles, anthracyclines >250 mg/m ² , comorbid status and female. Chronic renal failure more than a year after HCT has been associated with advanced age and multiple myeloma.

In addition to the factors described above, pre-transplant comorbidity, underlying disease, age, lifestyle, and genetics likely contribute to the development of chronic infections and delayed organ toxicity. With this in mind, it is logical to take steps to eliminate or reduce the impact of factors associated with delayed effects. Perhaps limiting the use of alkylating agents or avoiding regimens involving total therapeutic irradiation will help limit the impact of pre-HCT therapies. Any physician involved in the follow-up of transplant patients should be vigilant for the development of t-MDS/AML and secondary solid tumors, as well as chronic diseases.

References:

1. Baker S, DeFor TE, Burns LJ, et al. New malignancies after blood or marrow stem-cell transplantation in children and adults: Incidence and risk factors. J Clin Oncol. 2003;21:1352-1358.
2. Barlogie B, Tricot G, Haessler J, et al. Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: The Arkansas experience in more than 3,000 patients treated since 1989. Blood. 2008;111:94-100.
3. Bhatia S, Robison LL, Francisco L, et al. Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood. 2005;105:4215-4222.
4. Burns LJ. Late effects after autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;15(1 Suppl):21-24.
5. Forrest DL, Hogge DE, Nevill TJ, et al. High-dose therapy and autologous hematopoietic stem cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin’s lymphoma: A comparison of conventional therapy versus conventional therapy followed by autologous hematopoietic stem cell transplantation. J Clin Oncol. 2005;23:7994-8002.
6. Govindarajan R, Jagannath S, Flick JT, et al. Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol. 1996;95:349-353.
7. Harrison CN, Gregory W, Hudson GV, et al. High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin’s disease is unlikely to be associated with a major increased risk of secondary MDS/AML. BrJ Cancer. 1999;8:476-483.
8. Jantunen E, Ita “la” M, Siitonen T, et al. Late non-relapse mortality among adult autologous stem cell transplant recipients: A nation-wide analysis of 1,482 patients transplanted in 1990-2003. Eur J Haematol. 2006;77:114-119.
9. Krishnan A, Bhatia S, Slovak ML, et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood. 2000;95:1588-1593.
10. Lenz G, Dreyling M, Schiegnitz E, et al.