Chronic myeloproliferative neoplasms

CML is a rare disease that affects about 2 in 100,000 people each year. It is a disease that occurs mainly in old age: and about half of the cases are diagnosed in people aged 65 years or older, with a slight prevalence in men.

Chronic myeloid leukemia generally presents in a chronic phase, typically asymptomatic or with mild clinical symptoms such as fever, marked fatigue (asthenia), and weight loss.

An enlargement of the spleen (splenomegaly) can also be found, which can be asymptomatic or, if important, determining postprandial sense of repletion, left flank pain, and increased volume of the abdomen.

In a minority of cases, the disease occurs or evolves into a more advanced stage, characterized by an increase in immature cells that give rise to white blood cells, the so-called blasts. The advanced phase of CML is distinguished into accelerated phase or blastic crisis based on the number of blasts and other biological features, such as the number of platelets or the presence of other chromosomal abnormalities.

In almost all patients, the diagnosis is made during the chronic phase, often absolutely randomly through the normal blood tests, performed for routine or other causes.

The blood count shows an increased number of white blood cells (leukocytosis) and/or increased platelets (plateletosis or thrombocytosis), although in some cases platelets may be reduced (plateletopenia).

Confirmation of the diagnosis is through:

• blood tests, to evaluate the CBC, LDH value, liver and kidney function, and uric acid assay;
• bone marrow analysiso, which is the factory of red blood cells, white blood cells, and platelets, by means of a sampling (osteomidullary biopsy), which is usually performed under local anesthesia, at the level of the postero-superior iliac crest of the pelvis (at the top of the buttock). In such a procedure, bone marrow blood is aspirated and a small cylinder of bone is taken. The histological specimen is processed and analyzed at the pathology laboratory;
• The microscopic analysis of peripheral and bone marrow blood smear to see cell morphology and count the number of immature abnormal cells (blasts);
• cytogenetic examination and a FISH (fluorescent in situ hybridization) on bone marrow blood to study chromosomes and highlight the Ph+ chromosome, the presence of which is diagnostic for CML;
• The molecular analysis on peripheral blood which makes it possible to assess the presence and quantify the transcript of the BCR-ABL gene and thus residual leukemic cells, and is useful for monitoring response to therapy;
• chest X-ray, ultrasound and in selected cases CT scan of the abdomen, useful for diagnostic completion. These are examinations that are performed at the Division of Radiodiagnostics.

CML therapy has been completely revolutionized by the advent of the Tyrosine kinase inhibitors (TKIs), which ushered in the era of targeted therapies. These are specifically directed against the abnormal protein produced by the Ph+ chromosome.

Imatinib was the progenitor of this family of drugs, but to date we have other 2nd, 3rd, and 4th generation tyrosine kinase inhibitors available, such as dasatinib, nilotinib, bosutinib, ponatinib, and asciminib, which act on the same target and are all taken orally.

The physician will choose the most appropriate therapy for each patient depending on the toxicity profile of each drug, the patient’s associated diseases, and the biological characteristics of the disease (e.g., the presence of BCR/ABL mutations).

The effectiveness of therapy is assessed initially by examination of peripheral venous blood, to verify the achievement of a complete hematologic response. This examination is repeated at intervals ranging from one week to three months to check toxicity and to monitor response.

Once a complete hematologic response is obtained, cytogenetics and molecular biology are used to determine residual disease levels at the 3rd, 6th, and 12th months of therapy and then at intervals ranging from 3 to 6 months.

The goal of CML therapy is to achieve early a complete hematologic response, that is, normalization of CBC values, and later disappearance of the Philadelphia chromosome from bone marrow cells (complete cytogenetic response) and finally reduction to disappearance of the BCR-ABL transcript from peripheral blood (molecular response).

In patients who achieve a profound molecular response with a significant and stable reduction in leukemic cells as measured by BCR/ABL transcript, discontinuation of the tyrosine kinase inhibitor can be attempted after a prolonged period of treatment (typically at least 5 years), with close clinical-laboratory monitoring.

If there is no response to the TKI used in the first line or in case of toxicity, it is possible to replace the current drug with a different tyrosine kinase inhibitor that can overcome any resistance mechanisms of the leukemic cells. In cases where the response is still not achieved or the disease evolves into its acute phase, one treatment option may be stem cell transplantation.

PV occurs in about 1-2 people per 100,000.

Patients with polycythemia vera may be asymptomatic or present with symptoms related to increased blood viscosity, such as headache, vision changes, itching after bathing or showering, redness and warmth of hands and feet, often accompanied by burning (erythromelalgia). The liver and spleen may become enlarged as both begin to produce blood cells.

In addition, Polycythemia Vera is characterized by an increased risk of cerebral or cardiac ischemic events and venous thrombosis, which can sometimes be the onset symptom of the disease.

PV is a chronic disease that with current treatment strategies is associated with prolonged survival. In fact, only a minority of patients develop a more advanced form of myeloproliferative disease, such as myelofibrosis, over the years, and an even smaller percentage develop acute leukemia.

The diagnosis of Polycythemia Vera is usually made by the finding on the CBC of elevated red blood cell, hemoglobin, and hematocrit values, sometimes associated with increased platelet and white blood cell counts.

With a careful medical history (evaluation of family history and previous or concomitant diseases), forms of erythrocytosis caused by other diseases (secondary erythrocytosis) or the very rare congenital forms should be excluded.

The main diagnostic tests are:

• assay of blood levels of erythropoietin, a hormone produced by the kidney that stimulates the bone marrow to produce red blood cells. Erythropoietin levels are usually below normal in PV, while they may be normal or elevated in secondary forms;
• The search for mutations in the JAK2 gene on peripheral venous blood, present in almost all patients;
• The search for other mutations associated with myeloproliferative syndromes such as BCR/ABL, CALR, MPL
• bone marrow analysis, which is the factory of red blood cells, white blood cells and platelets, by means of a sampling (osteomidullary biopsy), which is usually performed under local anesthesia, at the level of the postero-superior iliac crest of the pelvis (at the top of the buttock). In such a procedure, bone marrow blood is aspirated and a small cylinder of bone is taken. The histological specimen is processed and analyzed at the pathology laboratory. Morphologically, in the bone marrow, hyperplasia of all three hematopoietic cell lines, red blood cells, white blood cells, and platelets (panmyeloses), is evident.

The therapy of Polycythemia Vera has as its first goal. to reduce the incidence of thrombotic events.

For this, the following are used antiplatelet drugs, such as acetyl salicylic acid or, in cases of previous deep vein thrombosis, anticoagulant drugs, such as warfarin or direct oral anticoagulants (NAOs).

To reduce the number of circulating red blood cells, the following can be performed periodic bloodlettingi, which consist of taking about 400 cc of blood and reinfusing equal amounts of saline, with the goal of keeping the hematocrit below 45 percent.

In patients older than 60 years of age who have a history of thrombotic events or who fail to normalize blood counts with bloodletting alone (e.g., due to increased white blood cells and platelets), the following are used drugs defined as “cytoreductive”, that is, that lower blood cell values.

The drug of first choice is usually hydroxyurea, which acts on cell replication by reducing it. It is taken chronically by mouth at a dosage that varies from patient to patient.

If hydroxyurea therapy is not effective or is associated with major side effects, other drugs such asinterferon, JAK2 inhibitors, or in elderly patients alkylating drugs (such as busulfan) may be used.

Interferon is an immunomodulatory drug, which acts on the immune system by reducing the number of red blood cells, white blood cells, and platelets. Currently, extended-release (pegylated) interferon formulations are used, which are administered subcutaneously every 2 or more weeks depending on response (e.g., ro-peg-ineterferon alpha2b).

In addition, in patients intolerant or unresponsive to hydroxyurea, ruxolitinib, a drug-target that acts by inhibiting the JAK2 signaling pathway, can be used.

The incidence is estimated to be approx. 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, although about 20% of patients are diagnosed before age 40.

Essential Thrombocythemia may or may not be symptomatic. I symptoms, if present, may be related to alterations in blood circulation or, in some cases, to ischemic or thrombotic events caused by the blockage of certain blood vessels by blood clots (thrombi).

The most common symptoms are headache, tingling and other abnormal sensations of the fingertips, hands, and feet, chest pain, loss of vision or vision of dots, weakness, dizziness, bleeding, usually mild (such as nosebleeds, ease of bruising, mild exudate from the gums, or bleeding in the digestive tract). Despite the increase in platelet numbers, hemorrhagic rather than thrombotic events may occur, related to the interference of platelets with von Willebrand factor, an essential coagulation protein. The spleen may increase in volume, but this event (splenomegaly) is not so common.

Life expectancy is almost normal , and the course of the disease is usually benign. About 10% of cases may evolve into a more advanced form of disease such as myelofibrosis, and evolution to acute leukemia is very rare (1-3%).

The diagnosis of Essential Thrombocythemia is made on the basis of symptoms and after noting theincreased platelets in the blood count and ruling out causes of reactive plateletosis (blood loss, trauma, infection, neoplasm, splenectomy).

The cause lies in a genetic mutation, usually affecting the JAK2 kinase genes, the thrombopoietin receptor (MPL), a growth factor for platelet production, or the CALR gene. Identifying mutation in one of these genes confirms the diagnosis of essential thrombocythemia, but the absence of mutation does not exclude it.

In order to distinguish it from other forms of myeloproliferative disease, it is also necessary to perform BCR/ABl mutation detection and bone marrow examination by osteomedicular biopsy and histological examination.

Thrombotic risk is stratified by the IPSET (International Prognostic Score for Thrombosis in Essential Thrombocythemia) score, which takes into account four main factors: age over 60 years, history of thrombotic events, presence of cardiovascular risk factors (such as smoking, hypertension, diabetes), and the JAK2 V617F genetic mutation. Based on these factors, patients are divided into low-, medium-, or high-risk groups for thrombosis, thus helping the physician choose the most appropriate therapy to prevent complications.

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

In patients at intermediate or high risk (presence of one or more factors), low-dose acetyl salicylic acid is recommended to prevent thrombotic events or anticoagulants in case of previous thrombotic events. In addition, high-risk patients need cytoreductive therapy to normalize platelet counts.

Hydroxyurea, anagrelide, or, in younger patients, interferon in its pegylated form can be used for this purpose.

The incidence of the disease is low (estimated at approx. 0.5-1.3 cases per 100,000 people) and falls within the definition of a rare disease. The average age at diagnosis is around 65 years.

Idiopathic Myelofibrosis initially may be asymptomatic. Next, the following may appear symptoms related to increased spleen (splenomegaly), decreased CBC values or so-called “constitutional symptoms,” such as weight loss, generalized malaise, fever, night sweats.

Splenomegaly may cause sense of abdominal distension, postprandial stuffiness, left flank pain.

Fatigue, weakness, dyspnea on exertion may occur in case of anemia.

In case of altered platelet count, which can be either elevated or reduced, there may be thrombotic or hemorrhagic manifestations.

If the number of white blood cells is reduced, the body is at risk of infection.

Survival in primary myelofibrosis may vary: some patients have a slow and stable course, others may have a more rapid evolution.

Risk stratification systems exist that, by considering clinical data, blood tests and genetic information, help physicians identify different prognostic groups and choose the most appropriate treatment for each patient.

Idiopathic Myelofibrosis should be suspected in patients with splenomegaly and changes in the blood count that can be either increase or decrease in white blood cells, red blood cells, and platelets. If pathology is suspected, the following investigations should be performed in addition to the CBC:

• the peripheral blood smearo To assess the morphology of red blood cells and determine the number of immature cells. In fact, red blood cells with alterations in shape (e.g., dacryocytes) or precursors of white blood cells (myeloblasts) or red blood cells (erythroblasts) can be found in circulation;
• LDH dosage, which often occurs increased;
• osteomidullary biopsy for histological examination and determination of the degree of fibrosis;
• The search for mutations in JAK2, CALR or MPL;
• The search for other mutations on peripheral venous or medullary blood through a larger panel of next-generation sequencing (NGS) to detect gene mutations associated with increased risk of leukemic transformation. This analysis may be useful for prognosis, especially for younger patients who are candidates for hematopoietic stem cell transplantation;
• abdominal ultrasound or, if necessary, CT scan of the abdomen to measure liver and spleen and exclude thrombotic manifestations 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. The Candiolo Institute is equipped with a Transplant Center and a transplantology program.

All cancer treatments involve side effects that impact the patient’s quality of life more or less severely. Treatments for chronic myeloproliferative syndromes also involve side effects, both physical and psychological, that can change the way people cope with daily life.

At the Candiolo Institute, attention to the patient’s quality of life remains a priority throughout the entire course of treatment: the physicians and nurses of the multidisciplinary team are available to provide the patient with all the support needed to manage the various side effects, particularly through nutritional counseling, psychological support and pain therapy.

To ensure timely and direct support and receive timely answers to concerns and questions, a dedicated support service is in place at the Candiolo Institute for all patients.

From Monday to Friday, from 8 a.m. to 5 p.m., you can contact the secretariat of the oncology day hospital at 011.993.3775, reporting the need for urgent consultation.

The patient will be quickly put in touch with his or her medical specialist, to receive clear answers and immediate support.

The cancer patient is a person with complex needs that requires multidisciplinary support not only for the cancer disease, but also for all related issues.

At the Candiolo Institute, patients who need or require it have access to specialists in different areas to receive nutritional support, physical therapy, pain therapy and management of other associated conditions.

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 the Candiolo Institute conducts information and orientation interviews to 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: 011 9933059).

In many cases, chronic myeloproliferative syndromes only need to be monitored over time, with no need to initiate active treatment.

In each case, during the follow-up period, through a series of examinations and visits, the progress of the disease or the side effects of the therapies given and their effectiveness are monitored, and the patient’s functional recovery is assessed.

Follow-up examinations are especially important to intercept any disease development early, so as to intervene early and appropriately. For the patient, they are also a valuable opportunity for dialogue with their medical specialist.

The follow-up course is planned with different timing and modalities depending on the type of chronic myeloproliferative syndrome, the therapy performed, the response obtained, and the patient’s own characteristics.

Due to the high number of cases treated each year, the Candiolo Institute is a national reference for taking care of esophageal cancer. Our experience enables us to deal with even the most complex situations, always with a personalized approach built on the clinical and personal profile of each patient.

Establishing the treatment plan always starts with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies that allow accurate assessment of the extent of the disease.

In addition, the Institute offers advanced and sophisticated laboratory investigations, including molecular and genomic analyses, which are critical for identifying biological features of cancer and guiding therapeutic decisions.

When indicated, surgery is performed with minimally invasive techniques (laparoscopic or thoracoscopic), which reduce operative trauma, promote faster recovery, and improve postoperative quality of life. Every treatment choice is defined within the GIC, ensuring a consistent and integrated approach.

As an IRCCS, the Candiolo Institute combines clinical practice with a strong vocation for scientific research. Patients can be evaluated for inclusion in active clinical trials, which provide a real opportunity to access innovative therapies not yet available in standard practice. Collaboration between care and research is a distinctive value that translates into concrete opportunities for the patient.

The Interdisciplinary Care Group takes care of the person at every stage: from diagnosis to treatment to follow-up, with attention to nutritional support, psychological health, and reintegration into daily life. The organization of checkups, visits and treatment is designed to ensure continuity and serenity, always valuing the human dimension of care.