I think that there is value in bringing the maximum information to bear in every case. One must be careful in the application of the ideas that emerge
I recently saw a 50 year old woman. She was very Northwest. Atheletic, her profession was environmental preservation. I could feel that she had a life that was filled with love , the outdoors, living an ethical and healthy life. She had an annual blood test, a Complete Blood Count (CBC). In modern machines, the concentration of various white blood cells is reported. This patient had an excess of lymphocytes.
Lymphocytes make me wince. The word denotes a cell, present in the blood, with a single,nonsegmented, mature appearing nucleus. T-cells, B cells, natural killer cells, are all classes of cells with this appearance. In addition T cells and B cells come in at least 300,000 varieties, defined by DNA rearrangements that determine their targets. This array of distinct cells and classes of cells is lumped together and called lymphocytes.
The most common disease caused by a abnormal proliferation of "lymphocytes" is B cell CLL. B cells, under the appropriate conditions, become factories for the production of antibodies. Leukemic cells do not progress, they are abnormal. CLL B cells have T cell markers that identify them as abnormal.
In my patient, the typical abnormal pattern for chronic lymphocytic leukemia was identified. An elevation of CD38 was also identified. Increased CD38 is associated with a poorer prognosis in CLL. It predicts for more extensive nodal disease and earlier progression from the time of diagnosis.
But sometimes negative prognostic factors are targets for new therapies; and the new therapies turn the negative into a positive. A drug called Daratumumab was recently approved by the FDA for multiple myeloma ,a disease that is distantly related to CLL, It is directed against CD 38. Multiple myeloma is a malignancy of plasma cells. Plasma cells are the antibody producing cells that the B lymphocytes mature into, after they are stimulated. Plasma cells have CD38. Daratumumab has not been approved for chronic lymphocytic leukemia. Research into the use of this drug is just beginning for chronic lymphocytic leukemia.
In order to characterize the patient's disease further, we had sent an analysis of the Chromosomal changes that are often seen in chronic lymphocytic leukemia. This test brought another result that needed explanation. Her CLL was missing one copy of the ATM gene. This is another negative prognostic marker. But a closer look might turn the situation.
ATM is one of several genes that are involved in DNA repair. A class of drugs, including some that are FDA approved, makes the mutation in ATM into an Achilles heel. The drug turns this defect in DNA repair ( which probably contributed to the malignant process by increasing mutations) into a lethal problem for the cells that carry it. Drugs that target DNA repair defects are approved for breast and ovarian cancer, not for CLL or other cancers . However, a clinical trial in prostate cancer showed that a drug in this class prolonged survival along a spectrum of DNA repair defects, including ATM. Studies have begun to investigate the utility of this approach in CLL and related diseases.
On the horizon, CART cells are now being tested for refractory cases. These are genetically modified immune cells directed at a chemical that is on the surface of the malignant ( and some normal) cells. This technique, newly approved for acute leukemia, has had dramatic success.
There is value in bringing our expanded understanding of disease and the wider range of treatment options to bear on every case. The safest and best outcome for the patient must always be the top priority. It is important to avoid seduction by your own thoughts. "Don't let the sound of your own wheels drive you crazy" ( The Eagles)
I recently saw a 50 year old woman. She was very Northwest. Atheletic, her profession was environmental preservation. I could feel that she had a life that was filled with love , the outdoors, living an ethical and healthy life. She had an annual blood test, a Complete Blood Count (CBC). In modern machines, the concentration of various white blood cells is reported. This patient had an excess of lymphocytes.
Lymphocytes make me wince. The word denotes a cell, present in the blood, with a single,nonsegmented, mature appearing nucleus. T-cells, B cells, natural killer cells, are all classes of cells with this appearance. In addition T cells and B cells come in at least 300,000 varieties, defined by DNA rearrangements that determine their targets. This array of distinct cells and classes of cells is lumped together and called lymphocytes.
The most common disease caused by a abnormal proliferation of "lymphocytes" is B cell CLL. B cells, under the appropriate conditions, become factories for the production of antibodies. Leukemic cells do not progress, they are abnormal. CLL B cells have T cell markers that identify them as abnormal.
In my patient, the typical abnormal pattern for chronic lymphocytic leukemia was identified. An elevation of CD38 was also identified. Increased CD38 is associated with a poorer prognosis in CLL. It predicts for more extensive nodal disease and earlier progression from the time of diagnosis.
But sometimes negative prognostic factors are targets for new therapies; and the new therapies turn the negative into a positive. A drug called Daratumumab was recently approved by the FDA for multiple myeloma ,a disease that is distantly related to CLL, It is directed against CD 38. Multiple myeloma is a malignancy of plasma cells. Plasma cells are the antibody producing cells that the B lymphocytes mature into, after they are stimulated. Plasma cells have CD38. Daratumumab has not been approved for chronic lymphocytic leukemia. Research into the use of this drug is just beginning for chronic lymphocytic leukemia.
In order to characterize the patient's disease further, we had sent an analysis of the Chromosomal changes that are often seen in chronic lymphocytic leukemia. This test brought another result that needed explanation. Her CLL was missing one copy of the ATM gene. This is another negative prognostic marker. But a closer look might turn the situation.
ATM is one of several genes that are involved in DNA repair. A class of drugs, including some that are FDA approved, makes the mutation in ATM into an Achilles heel. The drug turns this defect in DNA repair ( which probably contributed to the malignant process by increasing mutations) into a lethal problem for the cells that carry it. Drugs that target DNA repair defects are approved for breast and ovarian cancer, not for CLL or other cancers . However, a clinical trial in prostate cancer showed that a drug in this class prolonged survival along a spectrum of DNA repair defects, including ATM. Studies have begun to investigate the utility of this approach in CLL and related diseases.
The relevance of all this biology is not clear because the treatment of CLL, regardless of negative prognostic factors, has improved so much... and it continues to improve. In the past year , the FDA has approved ibrutinib (response rate 85%), venetoclax ( response rate 84%, complete response rate 50%) and idelalisib (resposne rate 50 % CR 15%) . These drugs target enzymes that are common to (almost) all CLL cells. They are approved because they are known to be tolerable and effective
On the horizon, CART cells are now being tested for refractory cases. These are genetically modified immune cells directed at a chemical that is on the surface of the malignant ( and some normal) cells. This technique, newly approved for acute leukemia, has had dramatic success.
There is value in bringing our expanded understanding of disease and the wider range of treatment options to bear on every case. The safest and best outcome for the patient must always be the top priority. It is important to avoid seduction by your own thoughts. "Don't let the sound of your own wheels drive you crazy" ( The Eagles)
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