Digital class 11. Myeloproliferative syndromes - Recursos Educativos Abiertos

Portada » Digital class 11. Myeloproliferative syndromes

Myeloproliferative syndromes

Introduction

Hello, welcome to this 11th class of the Hematology course provided by the University of Guanajuato. In this class we are going to review some basic concepts of myeloproliferative syndromes. We should remember that myeloid refers to the bone marrow and proliferative means «overproduction», so myeloproliferative syndromes are a group of disorders in which the overproduction of bone marrow cells occurs.

These disorders are closely related to each other; there are transitional forms and, in many patients, an evolution from one entity to another occurs in the course of the disease.

Polycythemia vera, essential thrombocytosis, and myelofibrosis are collectively known as the «non-leukemic myeloproliferative syndromes.» Chronic myeloid leukemia is also a myeloproliferative syndrome but with different characteristics than those mentioned above.

Content developement

Myeloproliferative syndromes describe a group of entities characterized by the endogenous proliferation of one or more hemopoietic components in the bone marrow and, in many cases, in the liver and spleen.

Polycythemia vera

It is a disease of the hematopoietic stem cell, of insidious onset, chronic course and unknown cause.
It is characterized by excessive and sustained proliferation in the bone marrow of erythroid, granulocytic, and megakaryocytic cells.
The erythroid proliferation is dominant, not influenced by its specific growth factor, and is expressed by an absolute increase in erythrocyte volume.
An increase in the number of erythrocytes and hemoglobin can occur for different reasons other than polycythemia vera:
Due to a compensatory increase in erythropoietin in:

High altitudes

Cardiovascular disease, especially congenital with cyanosis
Lung disease and alveolar hypoventilation
Hemoglobin with increased affinity (familial polycythemia)
Heavy smoking
Methemoglobinemia (rarely)
Everything that causes a hypoxia state and generates an increase in the production of erythropoietin and therefore a stimulation in the production of erythrocytes, does not correspond to a polycythemia vera.
It can also increase the number of erythrocytes for other reasons that are also not due to a clonal alteration of the erythroblasts:
Relative
“stress» or «spurine» polycythemia
Dehydration: loss of water, vomiting
Loss of plasma: burns, enteropathy.

*Clinical characteristics

This is a disease of the elderly with the same incidence in men and women.
Although it is not an eminently fatal disease, it does affect the quality of life of patients who suffer from it.
The clinical and laboratory alterations that can be seen are:

Persistent leukocytosis.
Persistent thrombocytosis.
Microcytosis due to Fe deficiency.
Splenomegaly.
Generalized itching (after bathing)
Unusual thromboses.
Erythromelalgia.

The most severe complications in PV include thrombosis and bleeding, the leading causes of morbidity and mortality.

Thromboses occur both in the microcirculation and in the great vessels.

Up to 20% of patients may have a thrombotic episode:

Occlusion of the vein or artery of the retina,
Coronary ischemia,
Thrombosis of the portal or hepatic vein,
Deep vein thrombosis
Digital ischemia

Bleeding complications are less frequent, and their appearance is almost always related to the use of NSAIDs.

The transformation of the disease into Acute Myeloid Leukemia is a possible complication that can occur, leading the patient to a fatal evolution.

Diagnostic criteria for polycythemia vera according to WHO (2001)

A1 Red cell mass> 25% of the calculated normal value, or Hb> 185g / L (men),> 165 g / L (women), or> 99% of the reference value according to age, sex and altitude of residence.

A2 Absence of cause of secondary erythrocytosis, influencing:
Familial absence of red blood cells
Absence of increased erythropoietin due to:

hypoxia (PO, arterial> 92%)
high affinity hemoglobin for oxygen
erythropoietin receptor truncation
inappropriate erythropoietin product, neoplastic in origin.

A3 Splenomegaly
A4 Clonal genetic abnormality other than the Ph chromosome or the BCR / ABL fusion gene, in bone marrow cells
A5 In vitro endogenous growth of erythroid colonies

B1 Thrombocytosis (> 400×109/L)
B2 Leukocytosis (> 12×109/L)
B3 Medullary biopsy demonstrating panmyelosis with primitive erythroid and megakaryocytic proliferation.
B4 Decreased serum erythropoietin.

Diagnosis of PV if:

A1 + A2 and another criterion A
A1 + A2 + 2 criterion B

Therapy

Treatment is intended to maintain a normal blood count.
The hematocrit should be less than 50%, preferably around 45% or less.

Phlebotomy.

This form of treatment is particularly effective when it is required to rapidly decrease blood volume, for example, when initiating therapy. It is especially indicated in younger patients and those with mild disease. Iron deficiency obtained alone can limit erythropoiesis. Phlebotomy does not control the number of platelets.

Cytotoxic myelosuppression.

Continuous therapy with high daily or intermittent doses of busulfan or hydroxyurea. This treatment requires close monitoring and regular blood counts to avoid an overdose.

Therapy with phosphorus32

This is an excellent treatment for patients with severe disease. (P32) emits beta rays and has a half-life of 14.3 days. It is concentrated in the bone and is the most effective myelosuppressive agent. The usual time of remission after a single dose is two years.

-Hydroxyurea (HU)

It is an antineoplastic agent that appears to act specifically in the S phase of the cell cycle, affecting the division of cells.

Hydroxyurea is carcinogenic in animals and may be associated with an increased risk of developing secondary carcinomas in humans.

Patients undergoing treatment may experience amenorrhea or azoospermia due to gonadal suppression, which appears to be related to the dose and duration of treatment and may be irreversible.

It is recommended to avoid its use during the first trimester of pregnancy since it is teratogenic in animals, and the fetus can suffer the adverse effects observed in adults.

Anagrelide: It acts in the postmitotic phase of the megakaryocyte, inhibiting its maturation.

• Recombinant interferon-alpha (IFaR):

Leukocytes secrete endogenous alpha-interferons in response to viral infection or various synthetic and biological inducers.

Antiviral, antiproliferative effects, immunomodulatory effects.

Busulfan belongs to the pharmacological group of antineoplastic agents, alkylating agents. It works by slowing or stopping the growth of cancer cells in the body.

Course and prognosis

Thrombosis and bleeding are common, and strokes are a common cause of death.

Increased viscosity, vascular stasis, and high platelet levels can contribute to thrombosis.

Vascular distention, small vessel infarcts, and impaired platelet function can stimulate bleeding.

The transition from PV to myelofibrosis occurs in 30% to acute leukemia in approximately 15% of patients; 32P was attributed to the high conversion rate.

Transition is part of the natural history of PV, and the high incidence in 32P treated patients results from their more prolonged survival.

ESSENTIAL THROMBOCYTEMIA

The proliferation of megakaryocytes and the excessive production of platelets is the dominant feature of this disorder; there is a sustained increase in platelets greater than 1,000,000 uL (1 million platelets, average values 150,000 to 400,000).

Recurrent bleeding and thrombosis are the main clinical manifestations.

Splenic enlargement is expected in the early phase: however, in many patients, splenic atrophy is seen because platelets obstruct microcirculation in the spleen.

Most patients are asymptomatic, but the main symptoms are the product of thromboembolic and microvascular phenomena.

Life expectancy is indicated the same as the general population, but in young patients, this is diminished, as well as the quality of life. Progression to acute leukemia is a possibility over the years and can occur in its natural history or related to the type of treatment used.

• Thrombocytosis, in general, is produced by three fundamental causes:

They can be reactive or secondary, they can be familial thrombocytosis, or they can be clonal. ET is diagnosed by excluding other causes of thrombocytosis.

Causes of Thrombocytosis that ARE NOT ESSENTIAL THROMBOCYTHEMIA

• Reactive thrombocytosis

Faith deficit
Chronic infections or inflammations (connective tissue diseases, temporal arteritis, tuberculosis, chronic bronchial diseases, vasculitis)
Acute infections and inflammations.
Acute bleeding
Hemolytic anemias
Response to exercise
Post-splenectomy
Tissue damage (surgery, acute myocardial infarction, pancreatitis, trauma)
Neoplasms
Recovery from thrombocytopenia (rebound)
Response to drugs (vincristine, retinoic acid, epinephrine, growth factor)

Clinical and biological aspects

In most patients, thrombocytosis is detected incidentally in routine examinations, these being asymptomatic.

In those with symptoms, thrombo-hemorrhagic manifestations and microcirculation alterations predominate. The former is the primary cause of morbidity and mortality, together with the malignant transformation in the natural history of the disease or due to the type of treatment carried out.

The mean age at diagnosis is 60 years, and there is a slight predominance of the female sex. With the introduction of automated platelet counters, asymptomatic young patients have increased. Exceptional cases have been described in childhood.

Diagnostic criteria

The diagnosis is by exclusion. There are no specific criteria for diagnosis.

Platelet count> 600,000 uL.
Hemoglobin <13 g / dL or normal blood volume
No iron deficiency (presence of hemosiderin in the marrow).
Absence of the Philadelphia chromosome.
Collagenous fibrosis in bone marrow absent or if present: less than a third of the biopsy area, without splenomegaly or leucoerythroblastic reaction
Absence of causes of secondary thrombocytosis.

– Generally, in the event of persistent and unexplained thrombocytosis in a non-splenectomized patient, with normal serum ferritin and C-reactive protein values, with a bone marrow examination cytogenetic and molecular studies that exclude CML, myelodysplastic syndromes, and PM, can raise a TE.

Treatment

The main objective of the treatment is to reach a figure of 450 thousand platelets.

Hydroxyurea (HU): 85% response. Reduces the number of platelets in 4 weeks. A maintenance dose is then assessed.

Recombinant interferon-alpha (IFaR)

Anagrelide: It acts in the postmitotic phase of the megakaryocyte, inhibiting its maturation. 93% response. Fundamental side effects (headache, tachycardia with palpitations, water retention, gastrointestinal intolerance).

It should be used with caution in pregnant women because it crosses the placental barrier.

Pipobroman: has a chemical structure similar to alkylating agents. 95% response.
Busulfan: Transformation to acute leukemia.
Radioactive phosphorus: Development of second neoplasms
Melphalan: Related to transformation to acute leukemia.

Therapeutic apheresis of platelets:

Extraction of whole blood from a donor or patient, followed by the separation of its components, conservation of the desired element and return of those not required to the donor or patient. Specialized and automated continuous flow machine.

Antiplatelet treatment

Candidates for this treatment are those with microvascular symptoms in addition to patients with recent previous major thrombosis:

Ticlopidine
Clopidrogel
Indomethacin
Dipyridamole

MYELOFIBROSIS This disorder has many names: myelosclerosis (chronic), myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia (MMM).
Hemopoietic stem cell proliferation is more generalized and there is splenic, and liver involvement.
There is secondary fibrosis in the bone marrow.

Clinical manifestations

i) An insidious onset with symptoms of anemia is typical in elderly patients.
ii) Symptoms caused by massive splenomegaly (e.g. abdominal discomfort, pain, or indigestion) are common; splenomegaly is the primary physical finding
iii) Weight loss, anorexia, and night sweats are common.
iv) There are bleeding problems, bone pain, or gout in a minority of patients.

Myelosclerosis and chronic granulocytic leukemia cause most cases of massive splenic growth (> 20 cm).

Laboratory investigations

i) Anemia is common: intermediate myeloproliferative disease
ii) Onset: high leukocytes and platelets. Posterior: leukopenia and thrombocytopenia.
iii) Teardrop-shaped erythrocytes.
iv) Bone marrow cannot be obtained by aspiration. A needle biopsy can reveal a hypercellular bone marrow with an increased pattern of reticulin fibers. Megakaryocyte increase. Bone radiographs reveal the increased bone formation and density.
v) Extramedullary erythropoiesis can be verified by radioactive iron studies or by liver biopsy.

Clinical features

In young patients, the course of the disease is almost always more aggressive than in adults
About 25% of patients are asymptomatic at the time of diagnosis, which is made by the detection of splenomegaly or hematological abnormalities in a medical examination for another reason.
Sometimes, the patient goes to the doctor to notice a mass in the abdomen or for symptoms attributable to splenomegaly, such as discomfort or pain.

Splenic infarcts, perisplenitis, or subcapsular hematomas can occur, causing severe pain in the left upper quadrant of the abdomen and/or the shoulder on that side. Other symptoms related to splenomegaly are diarrhea due to compression of the colon, an early sensation of fullness with food due to gastric reduction, and edema in the lower limbs.

Therapy

i) In cases of anemia, supportive blood transfusions are administered, as well as regular folic acid therapy
ii) Those patients with global myeloproliferation and hypermetabolism are treated with alkylating agents, such as busulfan or hydroxyurea.
iii) Splenic radiation can also temporarily reduce myeloproliferation; it manages to reduce the spleen’s size and reduces the symptoms caused by hypermetabolism and splenomegaly.
iv) Splenectomy is considered for those patients with:

a) Unacceptable transfusion requirements;
b) Massive splenomegaly that causes symptoms and cannot be controlled by radiation therapy or chemotherapy
c) Severe thrombocytopenia that is associated with recurrent bleeding.

In an advanced stage of the disease, where there is massive splenomegaly, the operation carries considerable risk; the general condition of the patients is poor, so there is a high mortality rate due to postoperative bleeding and infection.
Thrombocytosis after splenectomy carries a high risk of thromboembolism.

Course and prognosis

Median survival is approximately 3 to 4 years, although many patients live ten years or more.
Death usually occurs from bleeding, infection, heart or kidney failure.
Less than 10% of patients develop terminal blast transformation (acute leukemia)

Chronic myeloid leukemia

It is a chronic myeloproliferative syndrome in which the proliferation of the myeloid series predominates.
Like other myeloproliferative syndromes, it appears in middle-aged people with no known apparent cause.
It is related to a cytogenetic marker, the Philadelphia chromosome, which appears in up to 95% of cases.
Hypermetabolic syndrome accompanied by hepatosplenomegaly and a progressive.

Diagnosis

Peripherally blood.
Increase in white blood cells in all its manifestations (predominantly neutrophils and eosinophils, basophils, some blasts, and even monocytes).
Red series: there is usually normochromic normocytic anemia with a not high number of reticulocytes.
The platelet series can present from thrombopenia to thrombocytosis.
The decrease in some neutrophil enzymes, such as leukocyte alkaline phosphatase and myeloperoxidase or lactoferrin, is characteristic.

Bone marrow.

It is characteristically hypercellular, with an increased myeloid/erythroid ratio.

Characteristics of the evolutionary phases

The initial phase of CML or chronic phase
It has an average duration of 2 to 5 years; it is relatively indolent, with less than 5% blasts in the blood and marrow, and generally responds well to treatment.

Characteristics of the evolutionary phases

All cases at diagnosis have a leukocytosis that can vary from 10,000 to 100,000 / uL.

The predominant cell is the neutrophil, with the presence of all cells of the granulopoietic line, including myeloblasts, and basophilia and eosinophilia are also common.
In a third of the patients, there is anemia, which is generally moderate.
The bone marrow is hypercellular, with marked granulocytic hyperplasia and occasionally an increase in reticulin fibers.
The essential biochemical abnormalities in CML include:
Marked reduction in leukocyte alkaline phosphatase index (ALP).
Increase in serum levels of LDH, urates, and lysozyme.
By cytogenetic techniques, it is possible to detect the t (9,22) translocation.
Due to molecular biology rearrangement of the BCR/ABL gene characteristic of the disease.

The second phase or accelerated phase (duration 6 to 18 months)
It is characterized by a series of clinical-biological manifestations that show a change in the evolution of the disease with a tendency to leukocytosis with progressive difficulty in controlling it with the initial treatment.

Unexplained fever, general symptoms, and progressive splenomegaly
Anemia, thrombocytopenia, or persistent thrombocytosis despite chemotherapy
Increase in the number of basophils (> 20%) and eosinophils in the peripheral blood.
Changes in previously found chromosomal alterations.

Progressive anemia and increased hepatosplenomegaly, infiltration of organs by leukemic cells.

Granulocytic sarcomas or chloromas: malignant leukemic cells located in other organs.

When the percentage of blast cells is increased, both in the bone marrow and in the peripheral blood, this manifestation is called accelerated phase, which means that chronic myeloid leukemia is approaching the blast phase or phase of acute leukemia, defined when the percentage of blasts in bone marrow is more significant than 5% and is close to 20% (greater than or equal to 15% in peripheral blood).

In 25% of cases, this transformation can be acute lymphoblastic leukemia. It has a worse prognosis than de novo acute leukemias.

Non-favorable prognostic factors

General

Old age
Spleen size
Severe leukocytosis
% blasts in peripheral blood
Additional cytogenetic abnormalities

Young patients (in addition to the above)

Male gender
Anemia

Treatment

Induction to remission will be started depending on the clinical phase in which the patient is:

Chronic phase

Initial treatment (3 drugs can be used)
Hydroxyurea (HU)
It is one of the preferred drugs for initial treatment.

Imatinib Mesylate (Glivec)

It is a drug of recent incorporation to the treatment of CML with excellent results, both in the hematological response and in the molecular response, but with the current drawback of its high cost.
It acts on a molecular scale selectively against abnormal cells, in the same place where the significant alteration of the pathophysiology of the disease occurs, inhibiting the tyrosine kinase created by the BCR / ABL gene, managing to revert to regular modifications in the cell proliferation, differentiation, and apoptosis.
Adverse reactions: water retention, osteoarticular pain, muscle cramps, skin rash, nausea, vomiting and diarrhea, headache, hepatotoxicity.

Busulfan

For many years, this alkylating agent was the drug of choice in the initial treatment of Chronic Myeloid Leukemia in the chronic phase.
It has the disadvantage of its toxicity, as it is associated with cataracts, hyperpigmentation of the skin, pulmonary fibrosis, among other problems. Currently, it is only indicated on special occasions and until remission is obtained. Its use tends to be abandoned.

In the accelerated phase, sequential polychemotherapy can also be used in the form of COAP-TRAP cycles every 15 to 21 days, in a number of 6 cycles each:

– COAP

Cyclophosphamide: 100 mg / m2 SC / day, via IV or V / O
Oncovin: 1.4 mg / m2 SC / day, via IV
Ara- C: 100 mg / m2 SC / day, via IV
Prednisone 40 mg / m2 SC / day, orally
Rest 15 to 21 days and perform another cycle, after a blood count

– TRAP

6 Tiguanine: 100 mg / m2 SC / day, orally
Rubidomycin: 30 mg / m2 SC / day, via IV
Ara C: 100 mg / m2 SC / day, via IV
Prednisone 40 mg / m2 SC / day, orally

Criteria for considering a patient in clinical remission:

Disappearance of symptoms
Absence of visceromegaly
Hemoglobin> 10 g / L
White blood cell count <15,000 / uL

Post remission treatment

– When the patient reaches the initial control of the disease and has siblings, he would undergo compatibility studies through the HLA system to join the protocol for allogeneic transplantation of hematopoietic precursors.

Only allogeneic hematopoietic precursor transplantation is curative, which presents better results in the first two years of the disease.

Transplantation is reserved as the first therapeutic option for patients under 40 years of age and salvage treatment for patients who do not respond to Imatinib.

Treatment of the blast phase is usually unsatisfactory, given the poor prognosis of acute leukemia.

Post-transplant BCR / ABL rearrangement studies:

First year: every 3 months
Second year: every 4 months
Up to 5 years: every 6 months
More than 5 years: annual

– Relapse: 7 – 25%

– Disease-free survival

Chronic phase: 80%
Accelerated phase or 2nd chronic phase: 30 – 35%
Blast crisis: 10 – 20%

Evolution and prognosis

The natural evolution of the disease, once it is detected in the clinic, lasts approximately 3 to 4 years.

The disease initially remains stable and responds adequately and quickly to treatment (chronic phase).

After a few years, the response is erratic, and the disease becomes more aggressive and resistant (accelerated phase). Later, in approximately one year, it becomes an acute disease with numerous blasts in the blood and bone marrow. that finally ends the life of the patient.

Conclusion

The classification of myeloproliferative syndrome is carried out by their clinical, morphological, cytogenetic, and molecular characteristics:

The demonstration of BCR / ABL by the translocation between chromosomes 9 and 22 diagnoses chronic myeloid leukemia (CML), as well as the high number of neutrophils.
The demonstration of an increase in red cell mass in a clonal manner defines polycythemia vera (PV).
The presence of fibrosis in the bone marrow not associated with chronic myeloid leukemia or myelodysplastic syndrome (MDS) suggests myelofibrosis (MF), reticulin fibers, and inability to obtain a bone marrow aspirate.
Essential Thrombocythemia represents a chronic, non-reactive thrombocytosis that is not related to CML, MDS, PV, and MF. That is, it is detected by discard, and the platelets are too high

Introduction

Content developement

Chronic myeloid leukemia

Diagnosis

Conclusion

Information sources