Philadelphia Chromosome Positive

Philadelphia chromosome positive is a genetic abnormality that occurs when two chromosomes in the body swap pieces, creating a harmful protein that causes certain blood cancers. This condition is found in most cases of chronic myeloid leukemia and in some cases of acute lymphoblastic leukemia, primarily affecting adults.

Table of contents

• What Is the Philadelphia Chromosome
• Associated Blood Cancers
• How the Philadelphia Chromosome Develops
• Symptoms
• Diagnosis and Testing
• Treatment Options
• Monitoring Treatment Response
• Outlook

What Is the Philadelphia Chromosome

The Philadelphia chromosome is an abnormal, shortened version of chromosome 22 that results when pieces of two different chromosomes switch places^[1]. Human cells normally contain 23 pairs of chromosomes that carry genetic information. This abnormality occurs when part of chromosome 9 breaks off and attaches to chromosome 22, while a piece of chromosome 22 attaches to chromosome 9^[4].

The name “Philadelphia chromosome” comes from the city where it was discovered. This genetic change creates a fusion of two genes called BCR (breakpoint cluster region) and ABL1 (Abelson murine leukemia), forming a new abnormal gene called BCR-ABL1^[1].

The BCR-ABL1 gene produces an abnormal protein called tyrosine kinase, which is always active or “turned on”^[1]. This protein overactivates the bone marrow and causes young white blood cells to reproduce too quickly, leading to the development of leukemia^[1].

Ph chromosome, Ph+ chromosome, Philadelphia translocation

Associated Blood Cancers

The Philadelphia chromosome is present in the bone marrow cells of patients with specific blood cancers. It occurs in approximately 90% of people with chronic myeloid leukemia (CML)^[3]. CML makes up about 20% of all cases of adult leukemia^[3].

The Philadelphia chromosome is also the most frequent genetic abnormality in adult patients with acute lymphoblastic leukemia (ALL), occurring in approximately 20% to 30% of adults with this disease^[6]. However, it occurs in only about 5% of children with ALL^[6]. The incidence rises with age, and it occurs in approximately 50% of patients older than 50 years^[6].

In Philadelphia chromosome positive ALL, also called Ph+ ALL, only about 1 to 5 percent of children have this genetic change compared to 11 to 30 percent of adults with ALL^[5]. The condition can also be observed in patients with acute myelogenous leukemia (AML) and mixed-phenotype acute leukemia^[4].

• Bone marrow
• Blood
• Spleen

How the Philadelphia Chromosome Develops

The Philadelphia chromosome forms during cell division when cells make mistakes copying their genetic information^[3]. When cells multiply, they create copies of themselves, including all chromosomes. Sometimes during this process, errors occur.

The formation happens when pieces of chromosomes 9 and 22 break away and change places, creating what doctors call a reciprocal translocation^[4]. The shorthand way doctors write this is t(9;22)(q34;q11), which shows exactly where on each chromosome the breaks occur.

Depending on where the breakpoint occurs within the BCR gene, two major varieties of the cancer-causing protein can form. The smaller P190bcr-abl protein is found in over two-thirds of patients with Ph+ ALL, while the larger p210bcr-abl protein, which is typical of chronic myeloid leukemia, is found in about a third of Ph+ ALL patients^[6]. In laboratory studies, the p190bcr-abl protein has higher tyrosine kinase activity and is more efficient in stimulating the growth of lymphoid cells^[6].

The abnormal cells containing the Philadelphia chromosome can duplicate and build up in the bone marrow and travel through the body via the bloodstream^[3]. Over time, these cells may take the space of healthy white and red blood cells and platelets (blood cells that help with clotting), leading to physical symptoms^[3].

Symptoms

Philadelphia chromosome positive conditions often share similar symptoms, though they may not cause symptoms in early stages. Chronic myeloid leukemia, for example, might be detected during a routine blood test before symptoms appear^[8].

Ph+ ALL shares its symptoms with standard ALL^[15]. When symptoms do occur, they may include:

• Enlarged liver or spleen
• Swollen lymph nodes
• Pale skin
• Fever
• Easy bruising or bleeding
• Weight loss without trying
• Bone pain
• Abnormal blood cell counts
• Fatigue
• Loss of appetite
• Pain or fullness below the ribs on the left side
• Excessive sweating during sleep
• Blurry vision caused by bleeding in the back of the eye

These symptoms often mimic other illnesses, like viral infections such as mononucleosis, making specialized tests essential for a correct diagnosis^[15].

Diagnosis and Testing

Doctors usually identify Philadelphia chromosome positive disease after confirming a leukemia diagnosis. Advanced genetic testing identifies the Philadelphia chromosome and related mutations in cancer cells^[15]. These tests help customize treatment by revealing how genetic abnormalities affect the cancer’s response to therapies.

Cytogenetic testing helps detect the presence of altered chromosomes, such as the Philadelphia chromosome, in the body^[1]. Molecular testing measures the levels of BCR-ABL1 in the body^[1]. One type of molecular test is called RT-qPCR, and it can be used to determine how well treatment is working.

In most cases, patients learn they have Philadelphia chromosome positive disease about one to two weeks after their initial diagnosis, once genetic testing provides detailed results^[15].

Treatment Options

Tyrosine kinase inhibitors (TKIs) are targeted therapies used to treat Philadelphia chromosome positive leukemia. They work by blocking the BCR-ABL1 protein and helping to stop the rapid spread of abnormal blood cells^[1].

For newly diagnosed adults with Ph+ ALL, one approach is using a TKI in combination with chemotherapy. Until recently, there was no FDA-approved TKI treatment for use with chemotherapy in adults with newly diagnosed Ph+ ALL^[1]. The introduction of TKIs from the beginning of the 2000s dramatically improved the outlook for Philadelphia chromosome positive patients, with complete response rates above 90%, deep molecular responses, and prolonged survival^[10].

TKIs became the cornerstone of Ph+ ALL management, and their effectiveness led to the development of reduced-intensity chemotherapy approaches^[10]. The introduction of newer treatments, including a medication called blinatumomab, allowed development of chemotherapy-free strategies^[10].

ICLUSIG is one TKI that is the only one approved to treat people with Ph+ ALL who have the T315I mutation^[1]. Different generations of TKIs, including first, second, and third-generation drugs, have revolutionized patient outcomes^[7].

In the past, standard chemotherapy alone led to poor survival rates for pediatric Ph+ ALL—just 30%. Recent advances have dramatically improved outcomes. Imatinib (Gleevec), a prominent TKI, is now paired with chemotherapy, doubling survival rates to around 70%^[15].

Allogeneic hematopoietic cell transplantation (also called stem cell transplant) remains an important treatment option for some patients. This procedure, followed during the first complete remission, has been a standard approach for eligible patients^[12]. However, whether transplant is necessary for all patients, especially those achieving early deep remissions with newer treatments, remains an area of ongoing research and discussion^[7].

Monitoring Treatment Response

Throughout treatment, doctors monitor how well the body is responding. This involves performing different types of tests to check for the presence of cancer cells and the BCR-ABL1 protein^[1].

Today, the goal in Ph+ ALL treatment is a deep remission in the bone marrow and disease control^[1]. MRD stands for minimal residual disease, and CR stands for complete remission. Doctors may call a deep remission an MRD-negative CR.

MRD-negative CR is a more robust response than complete remission alone. This means that no or very low levels of cancerous blood cells and BCR-ABL1 are detected, even with advanced tests^[1]. When MRD-negative CR is reached, remission of disease is possible.

Regular testing for mutations is important because changes called mutations can appear in the BCR-ABL1 protein during treatment with a TKI^[1]. Mutations may affect the condition and cause treatment to stop working, so it’s important for doctors to test regularly for mutations.

If a mutation develops while on a current TKI, doctors may recommend changing to a different TKI that may work better against the mutation^[1]. The T315I mutation is a type that can occur in Ph+ ALL and is one reason why treatment might stop working.

Outlook

The outlook for Philadelphia chromosome positive diseases has improved dramatically over recent decades. Prior to the introduction of tyrosine kinase inhibitors, the outcome was poor. Although complete remission could be achieved in the majority of patients (60%–90%), the duration of remission was considerably shorter than that seen in patients without the Philadelphia chromosome^[6].

With modern treatments, outcomes have significantly improved. Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure^[13]. The combination of powerful TKIs and newer immunotherapy agents has led to remarkable advances in treating this condition.

Despite promising results, survival rates for Ph+ ALL still fall behind the 85%+ rates seen in most pediatric ALL cases^[15]. Researchers are focusing on developing new drugs that more effectively target the Philadelphia chromosome and creating alternative treatments for patients who don’t respond to current therapies or experience relapse.

Some people will need to change their TKI treatment over time. There are two main reasons why a person may need to change their treatment—resistance and intolerance^[1]. Resistance occurs when the disease no longer responds to a TKI treatment, which can happen if new mutations develop. Intolerance means side effects from the current TKI make it difficult or impossible to continue taking the treatment.