Drug Resistant Acute Myeloid Leukemia Meets Its Match
Updated: Oct 24, 2021
Among the diseases that hematologist-oncologists regularly treat, acute myelogenous leukemia (AML) can be viewed as a qualified success. With appropriate (induction and consolidation) therapy, 40-50% of adults with this disease can achieve durable remission.
Of the adult leukemias diagnosed each year in the US there are over 21,000 new cases and 10,000 deaths from AML, making this a challenging disease.
Although most patients respond to therapy, the majority relapse and many undergo bone marrow transplantation. Once an AML patient has failed therapy or relapsed, the prospects for durable, complete remission become extremely limited.
Case of 75-Year-Old Woman with Refractory AML
Just such a patient came under my care in early October when I was asked to see a 75-year-old woman with refractory (unresponsive) AML.
Diagnosed in June, 2016 she had received induction and consolidation yet rapidly progressed. After second and third line treatments culminating in the most intensive therapy (high dose Ara-C), her October bone marrow biopsy revealed 50-70% of the marrow to be leukemia.
She had not responded.
I introduced myself to this spry, slender woman who I recognized from the oncology unit where she could be seen on her daily exercise routine making the rounds from one ward to the next. I explained my assay-directed approach and we arranged for a bone marrow aspiration the very next day.
With the leukemic cells isolated in my laboratory from her bone marrow, we were able to study both conventional drugs and experimental combinations.
No Stranger to Leukemia
As an aside, I began my professional career studying leukemia.
My earliest studies of programmed cell death and apoptosis (apoptosis being but one form of programmed cell death) focused on leukemia and I helped in the development of Chlorodeoxyadenosine (2-CdA), a treatment that remains the curative therapy for Hairy Cell Leukemia today.
Two decades later newer compounds have been developed that selectively induce cell death in leukemic cells and I was keenly interested to test these new combinations for this patient.
I first described the activity for 2-CdA in AML in a paper that I wrote for the British Journal of Cancer some years earlier, but it was decades before that observation led to its use in this disease.
Her Functional Profiling Leads to a Two Drug Combo
With this patient’s cancer cells in hand, I reasoned that 2-CdA would be synergistic with a class of drugs known as the BH3 mimetics and combined the BH3 mimetic Venetoclax with 2-CdA in the EVA-PCD assay to interrogate her sensitivity.
The combination of 2-CdA and Venetoclax obliterated her leukemia cells.
The only problem; Venetoclax has only been approved for the treatment of chronic lymphocytic leukemia (CLL), not AML. There is no FDA approval for AML and in the absence of insurance coverage the drug would be prohibitively expensive.
Working with my colleagues we petitioned the drug company and thankfully they granted our request.
Borrowing from the hairy cell leukemia literature and the Venetoclax data we administered a combination of subcutaneous 2-CdA and Venetoclax by mouth.
Her Treatment Results
The patient tolerated the treatment extremely well. In fact there were virtually no toxicities.
By the end of the third week I began to have concerns that the bone marrow recovery was sluggish, the platelet count was still low and I feared that my ideas might have fallen short of the goal.
Although I had intended to wait until day 28 to conduct a repeat bone marrow, I felt compelled to find out sooner for fear that the patient might remain on a treatment that was not as effective as hoped.
The bone marrow aspirate was submitted to my laboratory as we had every intention of restudying the patient if needed. Despite my concerns, the bone marrow was completely normal!
When I then asked the hematopathologist he explained that her bone marrow aspirate was also normal. We submitted the cells for flow cytometry and the result revealed that the previous 70% leukemia from 3 weeks earlier was now 0.59%.
Going Home Finally
With the white count recovering, platelets improving and hemoglobin stable the patient returned home for the first time in two months. She is well, free of symptoms and will now be considered for a consolidation course.
I am gratified by the good outcome and delighted that we had at our disposal an entirely new class of drugs that can selectively induce cell death in AML.
For the first time in over a year, this novel combination had done something that other treatments could not; provide the patient with an highly effective regimen that proved non-toxic to boot.
While we cannot achieve remissions in every patient, these experiences reinvigorate our spirits in this difficult battle.
Smartly administered, correctly selected chemotherapies provide patients with the highest likelihood of benefit at the lowest toxicity. I could not be happier with this patient’s good outcome and I will follow her closely.
For now, after a year of trial and error failures, a complete remission is a very good start.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDX SPEAKER, author of the book OUTLIVING CANCER, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NAGOURNEYCANCERINSTITUTE.COM