When the Philadelphia Chromosome Strikes

by Guest Author: Dr. Namitha A Kumar
OPFORD project, Strand Life Foundation

Hospitals are places where human drama of illness, pain, suffering, turmoil and turbulence play out. A keen observer can learn a lot just watching human emotions on the faces of those who come to the hospital either as patients or patient families and friends. Sorrow, grief, sometimes happiness when there is hope and relief when things are settled. Perhaps no other department or ward contains as much suffering, pain and grief as oncology. The Big C is one of the worst human trials to go through. What must it be to be given a terminal verdict? What is it like to cling to a few rays of hope? What is it like to live through intense uncertainty not knowing which way the ball will roll? What is it like for the body to be racked by intense physical pain? How does it feel to be in remission yet live in dread in case Big C is still lurking around the corner?

On my recent visit to the hematology OPD in one of the big hospitals in Bangalore, I met a family waiting with their 3-year-old daughter. They were extremely distressed and troubled. The child looked ill and weak. We started chatting while waiting to see the doctor. The parents had come from Jaipur to seek treatment for their little girl who was diagnosed with Chronic Myeloid Leukemia (CML). She was currently being dosed with the targeted therapy drug Gleevec (imatinib). She had been evaluated to undergo a bone marrow transplant with her 14 year old brother, who was a 10/10 HLA match, as a donor. The family had been staying in Bangalore to get the child treated. They clung on to the hope that the child would totally kick Big C after the transplant. They were determined to find all routes to cure their little girl.

As we talked, I was shocked to know the medical history of this family. They had another little girl in 2010 who was diagnosed with Acute Lymphoblastic Leukemia in 2012. Despite treatment in Delhi, the girl did not survive and succumbed in 2013. They had the second girl in 2015 and were confident she would be healthy. Unfortunately the little girl was struck with a similar form of blood cancer. Alarm bells rang and the parents thought it was better to seek treatment in Bangalore and they brought her to the current onco-hematologist. This time the onco-hematologist was very thorough and after listening to the family medical history asked to test the girl for the BCR-ABL1 mutation. True enough the test came back positive for the mutation!

The BCR-ABL1 mutation also known as the Philadelphia chromosome or Philadelphia translocation (Ph) is a genetic abnormality in chromosome 22. There is a translocation of genetic material between chromosome 9 and chromosome 22 resulting in a fusion gene – BCR-ABL1. This translocation disrupts the tyrosine kinase signalling protein pathway and causes uncontrolled division of cells leading to leukemias. Almost all cases of CML are positive for BCR-ABL1. However, this gene fusion is also present in cases of Acute Lymphoblastic Leukemia (ALL) and sometimes in Acute Myelogenous Leukemia (AML). CML, ALL, and AML are usually treated with tyrosine kinase inhibitors like imatinib and other recent inhibitors like dasatinib or nilotinib. Hence, the little girl was being treated with imatinib.

The parents were extremely angry and obviously upset that their child had been affected with cancer, that too caused by a genetic mutation. They thought their first daughter too must have had the same erroneous genetic mutation. They had treated her in Delhi and were indignant that the oncologist had not bothered to ask for a genetic test. They were even angrier since no one had informed them about prenatal testing for the second child. That too, when the doctors knew the first child had succumbed to leukemia. They had informed the gynecologist that their first daughter had died of leukemia when they were trying for another child. They were not informed that a prenatal test could rule out if the second child had the disease mutation too. They had no clue that cancer could be genetic and their children could be susceptible to such disease mutations. As the mother sadly put it, had they known the second daughter too had such a mutation, they would have spared her of the pain and agony she was now going through. In fact the whole family was traumatized by the fact that two children in the family had similar cancers.

The parents were not educated enough to understand the genetic basis of cancer and they were relying on doctors to guide them. Sadly many oncologists shy away from genetic sequencing of cancers wrongly believing that they are saving money for the patient. Nothing could be further from the truth. Genetic sequencing can in fact be the best investment for a cancer patient allowing him/her to seek targeted therapies for specific mutations. In the case of this little girl, if her older sister’s DNA had been sequenced and she had tested positive for the Philadelphia chromosome with the BCR-ABL1 fusion gene, the knowledge could have helped the parents take a decision on going in for a second child.

The father said they would have adopted a child if they had known there was a risk of inheriting cancer-causing genetic mutations in the family. He squarely blamed the gynecologist who should have seen a red flag and asked them to rule out such a risk. Unfortunately in our country, even gynecologists shy away from genetic testing. Some of them feel it is an unnecessary expense. However, this one expense can prevent a lifetime of expenses when a child is diagnosed with hereditary cancer or a rare disease. Not to mention the pain, suffering and grief caused to the patient and families.

Genetic sequencing of cancers and prenatal testing provides critical genetic information which can be used to take important decisions. Whether it is to opt for better targeted therapies or plan for a healthy baby. Forewarned is forearmed. It is better to know than be in the dark and face the consequences later. Oncologists and gynecologists must take into account the fact that they could be helping the patient and families if they recommend genetic sequencing of cancers or prenatal testing by improving health outcomes for the patient and preventing life-threatening genetic disorders in families. The decision whether to test or not will always lie with the patient or the parents, but as a basic minimum, doctors should mention and suggest testing whenever it is indicated.