Chronic Myeloproliferative Neoplasms (MPNs)

Chronic myeloid leukemia (CML) is a rare disease, with an annual incidence of approximately 2 cases per 100,000 people. It occurs predominantly in older adults, with about half of all diagnoses made in individuals aged 65 years or older. The disease is slightly more common in men than in women.

Chronic myeloid leukemia (CML) most commonly presents in the chronic phase, which is often asymptomatic or associated with mild symptoms such as fever, marked fatigue (asthenia), and weight loss.

Patients may also develop splenomegaly (enlargement of the spleen), which can be asymptomatic or, when significant, may cause early satiety after meals, pain or discomfort in the left upper abdomen, and abdominal distension.

In a minority of cases, the disease presents in or progresses to a more advanced stage characterized by an increased number of blasts, the immature precursor cells of white blood cells.

The advanced stages of CML are classified as accelerated phase or blast crisis, based on the percentage of blasts and other biological features, including platelet counts and the presence of additional chromosomal abnormalities.

In the vast majority of patients, chronic myeloid leukemia (CML) is diagnosed during the chronic phase, often incidentally following routine blood tests performed for unrelated reasons.

A complete blood count (CBC) typically shows an increased number of white blood cells (leukocytosis) and, in many cases, an elevated platelet count (thrombocytosis). Less commonly, platelet levels may be reduced (thrombocytopenia).

Confirmation of the diagnosis requires a combination of laboratory and bone marrow investigations, including:

• Blood tests to evaluate the CBC, lactate dehydrogenase (LDH) levels, liver and kidney function, and uric acid levels.
• Bone marrow aspiration and bone marrow biopsy, performed to examine the tissue responsible for the production of red blood cells, white blood cells, and platelets. The procedure is usually carried out under local anesthesia at the level of the posterior superior iliac crest. Bone marrow cells are aspirated, and a small core of bone tissue is collected for histological analysis by the pathology laboratory.
• Microscopic examination of peripheral blood and bone marrow smears to assess cell morphology and determine the proportion of immature abnormal cells (blasts).
• Cytogenetic analysis and fluorescence in situ hybridization (FISH) on bone marrow samples to identify chromosomal abnormalities, including the Philadelphia chromosome (Ph+), whose presence is diagnostic of CML.
• Molecular analysis of peripheral blood to detect and quantify the BCR::ABL1 transcript. This test is essential both for confirming the diagnosis and for monitoring response to treatment by measuring residual leukemic disease.
• Imaging studies, including chest X ray, ultrasound, and, in selected cases, abdominal CT scan, which may be used to complete the diagnostic assessment.

The treatment of chronic myeloid leukemia (CML) has been transformed by the introduction of tyrosine kinase inhibitors (TKIs), which marked the beginning of the era of targeted therapies. These drugs specifically inhibit the abnormal protein produced by the BCR/ABL fusion gene associated with the Philadelphia chromosome (Ph+).

Imatinib was the first TKI introduced into clinical practice. Since then, several additional agents have become available, including dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. These therapies target the same molecular pathway and are administered orally.

The choice of treatment is individualized and depends on several factors, including the safety profile of each drug, the patient’s comorbidities, and the biological characteristics of the disease, such as the presence of specific BCR/ABL mutations.

Assessment of treatment response is based on clinical, hematological, cytogenetic, and molecular parameters, allowing physicians to evaluate treatment effectiveness and guide ongoing management.

The effectiveness of treatment is initially assessed through peripheral blood tests to confirm the achievement of a complete hematologic response. These evaluations are repeated at intervals ranging from one week to three months to monitor both treatment response and potential toxicity.

Once a complete hematologic response has been achieved, cytogenetic and molecular assessments are used to evaluate residual disease at 3, 6, and 12 months after treatment initiation and subsequently every 3 to 6 months.

The primary goals of treatment for chronic myeloid leukemia (CML) are:

• Achievement of a complete hematologic response, with normalization of blood counts.
• Achievement of a complete cytogenetic response, with disappearance of the Philadelphia chromosome (Ph+) from bone marrow cells.
• Achievement of a molecular response, with a marked reduction or disappearance of the BCR/ABL1 transcript in peripheral blood.

In patients who achieve a deep and stable molecular response, demonstrated by a sustained reduction in residual leukemic cells, discontinuation of tyrosine kinase inhibitor (TKI) therapy may be considered after a prolonged treatment period, typically at least five years, with careful clinical and laboratory monitoring.

If the initial TKI fails to produce an adequate response or causes unacceptable toxicity, treatment can be switched to an alternative TKI capable of overcoming potential resistance mechanisms. In patients who do not achieve a satisfactory response despite these strategies, or whose disease progresses to an advanced phase, allogeneic stem cell transplantation may be considered as a treatment option.

Polycythemia vera (PV) occurs in approximately 1 to 2 cases per 100,000 people.

Patients with polycythemia vera (PV) may be asymptomatic or present symptoms related to increased blood viscosity, including headache, visual disturbances, pruritus after bathing or showering, and redness, warmth, and burning of the hands and feet (erythromelalgia).

Hepatosplenomegaly may also occur, as the liver and spleen may contribute to blood cell production.

In addition, polycythemia vera is associated with an increased risk of arterial and venous thrombotic events, including cerebral and cardiac ischemia. In some cases, thrombosis may represent the first clinical manifestation of the disease.

PV is a chronic condition that, with current treatment strategies, is associated with prolonged survival. Only a minority of patients progress over time to a more advanced myeloproliferative disease such as myelofibrosis, and an even smaller proportion develop acute leukemia.

The diagnosis of polycythemia vera (PV) is typically suggested by complete blood count (CBC) findings showing increased levels of red blood cells, hemoglobin, and hematocrit, sometimes accompanied by elevated platelet and white blood cell counts.

A careful clinical history, including evaluation of family history and previous or concurrent diseases, is essential to exclude other causes of erythrocytosis, such as secondary erythrocytosis or rare congenital forms.

The main diagnostic tests include:

• Serum erythropoietin (EPO) levels, a hormone produced by the kidney that stimulates red blood cell production. In PV, EPO levels are typically below normal, while they may be normal or elevated in secondary erythrocytosis.
• Molecular testing for JAK2 mutations on peripheral blood, which are present in almost all patients with PV.
• Testing for additional mutations associated with myeloproliferative neoplasms, including BCR::ABL1, CALR, and MPL.
• Bone marrow aspiration and biopsy, performed under local anesthesia at the level of the posterior superior iliac crest. The procedure involves aspiration of bone marrow and collection of a small bone core, which is then processed for histological examination. In PV, the bone marrow typically shows panmyelosis, characterized by hyperplasia of all three hematopoietic lineages: red blood cells, white blood cells, and platelets.

The primary goal in the treatment of polycythemia vera (PV) is to reduce the risk of thrombotic events.

For this purpose, antiplatelet therapy is used, such as acetylsalicylic acid or, in patients with a history of deep vein thrombosis, anticoagulant therapy such as warfarin or direct oral anticoagulants (DOACs).

To reduce the number of circulating red blood cells, periodic phlebotomy (bloodletting) can be performed. This involves removing approximately 400 mL of blood and replacing it with an equivalent volume of saline solution, with the aim of maintaining the hematocrit below 45%.

In patients older than 60 years or with a history of thrombotic events, or in those who do not achieve adequate blood count control with phlebotomy alone (for example due to elevated white blood cells and platelets), cytoreductive therapy is used to reduce blood cell production.

The first line treatment is usually hydroxyurea, an oral drug that reduces cellular replication and is administered chronically at doses adjusted individually for each patient.

If hydroxyurea is ineffective or not tolerated, alternative treatments include interferon, JAK2 inhibitors, or, in older patients, alkylating agents such as busulfan.

Interferon is an immunomodulatory agent that reduces the production of red blood cells, white blood cells, and platelets by acting on the immune system. Currently, pegylated (extended release) formulations are used, administered subcutaneously at intervals of two or more weeks depending on response (for example, ropeginterferon alfa-2b).

In patients who are intolerant or resistant to hydroxyurea, ruxolitinib, a targeted agent that inhibits the JAK2 signaling pathway, may also be used.

The incidence is estimated at approximately 1.5–2.4 cases per 100,000 people. The disease is more common in women, and the average age at diagnosis is around 60 years, although about 20% of patients are diagnosed before the age of 40. 

Essential thrombocythemia (ET) may be asymptomatic or associated with clinical manifestations related to altered blood flow or, in some cases, to ischemic or thrombotic events caused by vascular occlusion due to blood clots (thrombi).

The most common symptoms include headache, paresthesia or abnormal sensations in the fingers, hands, and feet, chest pain, visual disturbances (including transient vision loss or seeing spots), weakness, dizziness, and bleeding, usually mild. Bleeding manifestations may include epistaxis, easy bruising, mild gum bleeding, or gastrointestinal bleeding.

Despite the increased platelet count, hemorrhagic events may occur, often related to platelet interference with von Willebrand factor, an essential protein in the coagulation process.

Splenomegaly (enlargement of the spleen) may be present, although it is not common.

The life expectancy of patients with ET is close to normal, and the overall clinical course is generally benign. Approximately 10% of cases may progress to a more advanced disease form such as myelofibrosis, while transformation to acute leukemia is rare, occurring in 1–3% of cases.

The diagnosis of essential thrombocythemia (ET) is based on clinical evaluation and laboratory findings, in particular the detection of elevated platelet counts in the blood count, together with the exclusion of causes of reactive thrombocytosis, such as blood loss, trauma, infection, other neoplasms, or splenectomy.

The disease is associated with acquired genetic mutations, most commonly involving JAK2, the thrombopoietin receptor gene (MPL), or the CALR gene, which regulates platelet production. Identification of a mutation in one of these genes supports the diagnosis of ET, although the absence of detectable mutations does not exclude it.

To differentiate ET from other myeloproliferative neoplasms, it is also necessary to perform testing for BCR/ABL and to carry out a bone marrow biopsy (osteomedullary biopsy) with histological examination.

Thrombotic risk in essential thrombocythemia (ET) is stratified using the IPSET (International Prognostic Score for Thrombosis in Essential Thrombocythemia) score, which considers four main factors: age over 60 years, history of thrombotic events, presence of cardiovascular risk factors (such as smoking, hypertension, and diabetes), and the JAK2 V617F mutation.

Based on these variables, patients are classified into low-, intermediate-, or high-risk categories for thrombosis. This stratification supports the selection of the most appropriate therapy to prevent complications.

Low-risk patients (no risk factors) generally do not require antiplatelet or anticoagulant therapy, unless individually indicated.

In patients at intermediate or high risk (presence of one or more risk factors), low-dose acetylsalicylic acid is recommended to reduce the risk of thrombotic events, or anticoagulant therapy in cases with a history of thrombosis. In addition, high-risk patients require cytoreductive therapy to control platelet counts.

Cytoreductive treatment options include hydroxyurea, anagrelide, or, particularly in younger patients, pegylated interferon.

The incidence of the disease is low, estimated at approximately 0.5–1.3 cases per 100,000 people, and it is classified as a rare disease. The average age at diagnosis is around 65 years. 

Idiopathic myelofibrosis may initially be asymptomatic. Over time, symptoms related to splenomegaly, reduced complete blood count (CBC) values, and so called constitutional symptoms may appear, including weight loss, general malaise, fever, and night sweats.

Splenomegaly may cause abdominal distension, postprandial fullness, and left flank pain.

Anemia may lead to fatigue, weakness, and dyspnea on exertion.

Alterations in platelet counts, which may be either increased or decreased, can result in thrombotic or hemorrhagic events.

A reduction in white blood cells increases susceptibility to infections.

The clinical course of primary myelofibrosis is variable: some patients experience a slow and stable evolution, while others show a more rapid progression.

Risk stratification systems, based on clinical findings, laboratory data, and genetic information, are used to define prognostic groups and guide the most appropriate therapeutic approach for each patient.

Idiopathic myelofibrosis should be suspected in patients presenting with splenomegaly and abnormalities in the blood count, which may include either increases or decreases in white blood cells, red blood cells, and platelets.

When the disease is suspected, in addition to the complete blood count (CBC), the following investigations are indicated:

• Peripheral blood smear, to evaluate red blood cell morphology and quantify immature circulating cells. Characteristic findings may include abnormally shaped red blood cells (e.g., dacryocytes) as well as circulating precursors of white blood cells (myeloblasts) and red blood cells (erythroblasts).
• Lactate dehydrogenase (LDH) levels, which are often elevated.
• Bone marrow aspiration and biopsy (osteomedullary biopsy), essential for histological evaluation and for assessing the degree of fibrosis.
• Molecular testing for JAK2, CALR, and MPL mutations.
• Extended molecular profiling using next generation sequencing (NGS) on peripheral or bone marrow blood to identify additional mutations associated with increased risk of leukemic transformation. This analysis is particularly relevant for prognostic assessment, especially in younger patients who may be candidates for hematopoietic stem cell transplantation.
• Abdominal ultrasound or, if necessary, abdominal CT scan, to evaluate liver and spleen size and to exclude thrombotic involvement of abdominal vessels.

Therapy is aimed at controlling symptoms and complications. Some patients may be observed without treatment.

Patients with systemic symptoms, increased spleen, white blood cells or platelets should receive cytoreductive therapy.

Depending on age, concomitant diseases, general condition, and risk of disease progression as determined by the major prognostic scores (IPSS, DIPSS, DIPSS-plus, MYSEC, MIPPS), patients may receive either therapy with hydroxyurea, or with drugs -target that inhibit the JAK2 signaling pathway (JAK2 inhibitors) by reducing symptoms and splenomegaly, or be referred to an allogeneic stem cell transplantation pathway.

For intermediate-high risk MFI with increased spleen, JAk2 inhibitors (ruxolitinib, momelotinib or fedratinib) are the drugs of first choice. They are administered by mouth chronically and are able to reduce symptoms associated with myelofibrosis and splenomegaly in a good percentage of patients. Momelotinib can also improve anemia when present at diagnosis. If therapy with these drugs fails, patients should be evaluated for experimental therapies; in fact, new JAK2 inhibitors and drugs that act on other cellular mechanisms are under advanced study.

Low-dose corticosteroids may be used in conjunction with the drugs listed above or when they have failed or are contraindicated to control symptoms; androgens, erythropoietin, and transfusions to correct anemia; splenic radiotherapy to try to reduce spleen size when JAK2 inhibitors have failed or are contraindicated.

Patients with high-risk myelofibrosis with age <70-75 years should be evaluated early for allogeneic transplant candidacy, and be referred to an oncohematologist experienced in cell therapy. The procedure involves first administering preparatory chemotherapy that destroys all bone marrow cells and then infusing the patient with healthy stem cells from the donor, which are responsible for repopulating the blood and marrow itself. INOC – Istituto Nazionale Oncologico Candiolo is equipped with a Transplant Center and a transplantology program.

Treatment for rare sarcomas and tumors may be associated with side effects that can variably impact quality of life. However, these effects can often be mitigated, and in some cases prevented, through specific treatments and appropriate lifestyle measures.

At INOC – Istituto Nazionale Oncologico Candiolo, physicians and nurses within the multidisciplinary team are available to provide patients with comprehensive support in managing the side effects that may occur during the course of treatment.

The cancer patient is often a vulnerable individual who requires continuous support throughout the disease course. When new symptoms arise, whether related to the underlying disease or to treatment-related adverse effects, it is essential that timely specialist evaluation is ensured through a dedicated “fast track” pathway.

INOC – Istituto Nazionale Oncologico Candiolo provides a dedicated support service, available Monday to Friday from 8:00 a.m. to 5:00 p.m. Patients may contact the Oncology Day Hospital Secretariat at +39 011.993.3775 to report the need for an urgent clinical assessment. The referring specialist is then promptly informed and will contact the patient to ensure timely evaluation and appropriate management.

Cancer patients often face complex needs that extend beyond the treatment of the disease itself, requiring comprehensive, multidisciplinary support to address both medical and quality-of-life challenges.

At INOC – Istituto Nazionale Oncologico Candiolo, patients who need additional support have access to a team of specialists across multiple disciplines. This integrated approach includes nutritional counseling, physical rehabilitation, pain management, and the treatment of other cancer-related conditions, ensuring personalized and holistic care throughout the patient journey.

The impact of cancer in a person’s life also affects the psychological sphere: in fact, falling ill with cancer is always a traumatic event that affects all dimensions of the person and can generate anxiety, fear, anger, depression.

In our institute, alongside cutting-edge therapies, the treatment and care pathway always includes a qualified psycho-oncological support that helps the patient cope positively not only with treatment but also with the delicate phase of physical and psychological recovery.

It is also possible to participate in psychological support groups to engage with other people who have gone through or are going through the same experience.

The Social Service Department of INOC – Istituto Nazionale Oncologico Candiolo, conducts information and orientation interviews for patients and their families on how to access services in the area and how to obtain welfare and social security benefits provided by law (disability, benefits for aids and prostheses, work leave, etc.).

The service operates on Wednesdays and Fridays from 9 a.m. to 1 p.m. – Phone: +39 011.993.30

In many cases, chronic myeloproliferative neoplasms can be safely monitored over time without the need for immediate active treatment.

Throughout the follow-up period, patients undergo regular clinical assessments and diagnostic tests to monitor disease progression, evaluate the effectiveness of therapies, identify potential side effects, and assess overall health and functional recovery.

Follow-up visits play a crucial role in the early detection of disease changes, enabling timely and appropriate intervention when necessary. They also provide patients with an important opportunity to discuss concerns, ask questions, and maintain an ongoing dialogue with their specialist team.

The follow-up plan is personalized for each patient and varies according to the type of chronic myeloproliferative neoplasm, the treatment received, the response achieved, and the patient’s individual clinical characteristics and needs.

Thanks to the large number of cases treated each year, INOC – Istituto Nazionale Oncologico Candiolo is a national reference center for the care of this disease. This extensive experience allows us to manage even the most complex cases, always using a personalized approach, tailored to the clinical and individual profile of each patient.

Establishing a treatment plan always begins with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies, such as ultrasound, contrast-enhanced CT, MRI, and cholangio-RM, which are critical for accurately assessing the extent of the tumor.

Advanced laboratory tests, including molecular analyses, are also available to help define biological features of the disease and guide treatment choices.

When appropriate, surgeries are performed using minimally invasive, laparoscopic or robotic techniques. These approaches involve the use of camera-equipped instruments introduced into the abdomen through small incisions, thus reducing surgical trauma. Benefits to the patient include shorter hospital stay times, faster recovery, and lower risk of complications compared with traditional open surgery.

As an IRCCS (Scientific Institute for Research, Hospitalization, and Healthcare), INOC – Istituto Nazionale Oncologico Candiolo combines clinical care with a strong focus on scientific research. Patients can be considered for participation in active clinical trials, offering access to innovative therapies not yet available in standard practice. This integration of care and research is a distinctive strength that translates into tangible benefits for patients.

The Interdisciplinary Care Group (GIC or MDT) supports the patient at every stage: from diagnosis, through treatment, to follow-up. Special attention is paid to nutritional support, psychological health and reintegration into daily life. The organization of checkups, examinations, and treatment is designed to ensure continuity, serenity, and a humane, caring approach to each patient’s needs.