Philadelphia Positive Acute Lymphocytic Leukaemia

Philadelphia positive acute lymphocytic leukaemia is a serious blood cancer that has seen dramatic improvements in treatment and survival rates thanks to modern targeted therapies that have transformed what was once considered nearly incurable into a disease with much better outcomes.

Table of contents

• What is Philadelphia positive acute lymphocytic leukaemia?
• Understanding the Philadelphia chromosome
• How common is this condition?
• Signs and symptoms
• How doctors diagnose Ph+ ALL
• Treatment approaches
• Prognosis and survival

What is Philadelphia positive acute lymphocytic leukaemia?

Philadelphia positive acute lymphocytic leukaemia (Ph+ ALL) is a specific type of blood cancer that affects white blood cells called lymphocytes^[1]. It is a subtype of acute lymphoblastic leukaemia, which starts in the bone marrow (the soft inner part of bones where new blood cells are made) and spreads throughout the body^[3].

The word “acute” means that this leukaemia develops quickly over days or weeks, which is different from chronic leukaemia that usually develops very slowly^[3]. People with Ph+ ALL usually need to start treatment quite quickly after being diagnosed^[3].

In Ph+ ALL, the bone marrow makes too many abnormal white blood cells. These abnormal cells, often called blast cells, are not fully developed and cannot work normally^[3]. They grow and divide quickly, building up in the bone marrow and stopping healthy blood cells from developing. They also spill out into the blood and can spread to other parts of the body including the lymph nodes, liver, spleen, brain, spinal cord, and rarely the testicles^[3].

Understanding the Philadelphia chromosome

What makes Philadelphia positive ALL different from other types of acute lymphoblastic leukaemia is the presence of an unusual genetic change called the Philadelphia chromosome^[1]. This abnormality happens when a gene called ABL1 on chromosome 9 breaks off and sticks to a gene called BCR on chromosome 22^[3].

This unusual joining creates a new gene called BCR-ABL1, which causes cells to make too much of a protein called tyrosine kinase^[3]. This protein encourages leukaemia cells to grow and multiply uncontrollably^[10].

The Philadelphia chromosome is the most common genetic abnormality in adult patients with acute lymphoblastic leukaemia, occurring in about 20% to 30% of all cases^[1]. Researchers believe that between 20 and 30 out of every 100 people with ALL have this Philadelphia positive type^[3].

How common is this condition?

Philadelphia positive ALL is more common in older people. The incidence increases with age and occurs in up to 50% of ALL diagnosed in individuals who are 50 years old or older^[1]. Philadelphia positive ALL is more common in older people, happening more often as age increases^[3].

While acute lymphoblastic leukaemia is the most common type of leukaemia to affect children, Ph+ ALL specifically is rare in children but appears more frequently in adults with ALL^[7].

Signs and symptoms

Symptoms of Ph+ ALL are generally similar to other types of acute lymphoblastic leukaemia^[4]. They develop because excess blast cells in the bone marrow mean there is not enough room for other healthy blood cells to grow^[4].

Common symptoms include:

• Fatigue or feeling very tired
• Easily bruising or bleeding
• Frequent infections
• Unexplained weight loss
• Swollen lymph nodes
• Shortness of breath
• Pale skin
• Fever or high temperature
• Bone or joint pain
• Night sweats
• Loss of appetite

It is important to note that these symptoms can occur due to other conditions^[4]. If you experience any of these symptoms for longer than two weeks, you should contact your doctor for an accurate diagnosis.

Patients with Ph+ ALL have an increased risk for involvement of the central nervous system (the brain and spinal cord) and typically have an aggressive clinical course^[1].

How doctors diagnose Ph+ ALL

Numerous tests are necessary to diagnose ALL and identify whether it is the Philadelphia positive subtype^[4]. A doctor will start with a physical examination and ask about your symptoms, how long they have lasted, and how they interfere with your everyday life^[4].

Tests that may be ordered include:

• A complete blood count with differential to measure the amount of red blood cells, white blood cells, and platelets in the blood^[4]
• Bone marrow aspiration and biopsy, usually taken from the hip bone^[4]
• Biomarker testing, which involves looking for changes in chromosomes, genes, and proteins^[4]

Biomarker tests that can help confirm the diagnosis include immunophenotyping, which looks at proteins on the surface of cells, and genetic tests to identify the Philadelphia chromosome^[4]. According to medical experts, doctors can classify around 75% of ALL cases in adults into subtypes because of genetic mutations and chromosomal abnormalities^[4].

Additional tests may include imaging tests such as CT scans, PET scans, or MRI, lymph node biopsy, or a spinal tap to check if leukaemia has spread to the central nervous system^[4].

Treatment approaches

Tyrosine kinase inhibitors: A breakthrough in treatment

The integration of drugs called tyrosine kinase inhibitors (TKIs) into treatment was a breakthrough in Philadelphia positive acute lymphoblastic leukaemia^[13]. These are targeted cancer drugs that work to stop the BCR-ABL protein and help stop the rapid spread of abnormal white blood cells^[10].

TKIs targeting the BCR-ABL protein have been incorporated into treatment regimens used to treat patients with Ph+ ALL^[1]. Doctors treat Philadelphia positive ALL with a targeted cancer drug called imatinib^[3]. Imatinib has been the most widely used TKI, with several published trials showing it produced better outcomes when combined with chemotherapy^[1].

Dasatinib, a more potent inhibitor than imatinib, has also been evaluated with promising results^[1]. Additional newer third-generation TKIs are also being used in treatment strategies^[1].

Standard treatment approach

For Ph+ ALL, tyrosine kinase inhibitors are the most important components of treatment protocols, while the intensity of chemotherapy may be reduced compared to other types of ALL^[11]. Current treatments include first, second, and third-generation TKIs that have revolutionized patient outcomes including molecular remission and overall survival^[2].

One way to treat Ph+ ALL in newly diagnosed adults is by using a TKI in combination with chemotherapy^[10]. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL, as these regimens can achieve high rates of complete remission while causing fewer deaths during the induction phase^[13].

Stem cell transplantation

Despite promising results, relapses still occur at a high rate, and allogeneic stem cell transplant (a transplant using stem cells from a donor) has been considered a better curative option during first remission^[1]. Allogeneic stem cell transplantation from either an HLA-matched sibling, unrelated donor, or haploidentical donor should be considered for patients with high estimated risk of relapse^[11].

However, there is ongoing controversy regarding the ability to omit consolidation with allogeneic stem cell transplantation, specifically for patients achieving early molecular remission^[2]. The future role of stem cell transplantation in the context of newer treatment approaches appears uncertain^[11].

Newer treatment options

Chemotherapy-free regimens such as combining blinatumomab with dasatinib or ponatinib offer exciting possibilities^[2]. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease and serves as an excellent salvage therapy^[13]. Patients with detectable measurable residual disease (MRD) should be treated with blinatumomab^[11].

Results of clinical studies using frontline dasatinib or ponatinib in sequence or in combination with blinatumomab are very promising, and such strategies may allow the avoidance of systemic chemotherapy^[11].

Monitoring treatment response

Throughout treatment, doctors monitor how well the body is responding using two types of tests^[10]. Cytogenetic testing helps detect the presence of altered chromosomes (such as the Philadelphia chromosome) in the body, while molecular testing measures the levels of BCR-ABL1 in the body^[10].

Monitoring measurable residual disease is now a cornerstone of treatment, particularly using next-generation sequencing for accurate assessment^[2]. Inadequate response at the level of measurable residual disease is the strongest adverse prognostic factor^[11].

Prognosis and survival

Historically, patients with Ph+ ALL had an inferior outcome when compared with their Philadelphia-negative counterparts^[1]. Prior to the advent of tyrosine kinase inhibitors, patients with Ph+ ALL who were treated with combination chemotherapy regimens were able to achieve complete response rates of 45% to 90%, but most relapsed^[1].

However, recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure^[13]. The incorporation of tyrosine kinase inhibitors into frontline treatment significantly improved clinical outcomes^[12].

In the past, having leukaemia cells with the Philadelphia chromosome (referred to as Ph+ ALL) used to mean a less favourable prognosis. Today, targeted therapy drugs are used to treat Ph+ ALL, so the prognosis for this cancer is more favourable^[16].

The response to chemotherapy is measured as the time it takes to reach a complete remission. When complete remission is reached within 4 weeks of starting chemotherapy, the prognosis is more favourable^[16].

Today, the goal in Ph+ ALL treatment is a deep remission in the bone marrow and disease control. This means that no or very low levels of cancerous blood cells and BCR-ABL1 are detected, even with advanced tests^[10]. When this level of remission is reached, remission of disease is possible.

Ph+ ALL, Philadelphia chromosome-positive acute lymphoblastic leukemia, Philadelphia-positive ALL

• Bone marrow
• Blood
• Lymph nodes
• Liver
• Spleen
• Brain
• Spinal cord