How Would an Expert Manage His Own Acute Myelogenous Leukemia: an Update

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Previously, our Curious Dr. George asked leukemia expert Adam Asch, MD, how he would handle his own hypothetical case of acute myelogenous leukemia (AML). Now, Dr. Asch provides an updated answer, highlighting the new option of clinical trials offering novel targeted therapies for some AML patients. Dr. Asch is Professor of Medicine and Nancy Johnson Records Chair of Oncology at the University of Oklahoma College of Medicine.

Curious Dr. George: Please consider this hypothetical scenario: You are an active clinical oncologist in generally good health, but lately, you have lacked energy, have been feeling a little more tired than usual, have some dizziness on exertion, have been bruising easily, and have lost a bit of weight without dieting. So, you decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and feels the tip of your spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, white blood cells (WBCs) 49,000 per microliter with many blasts, many promyelocytes, myelocytes, eosinophils, and basophils. Platelets are low. A diagnosis of acute myelogenous leukemia (AML) is made. How would you proceed?

Adam Asch, MD: This would be a fascinating case to discuss in the abstract. But in the first person, as you have been exploring in your Curious Dr. George series, diagnosis and therapy take on a special and sometimes personal urgency. For this 70-year-old oncologist, the hypothetical is a timely one and for the field a relevant one, since AML is, in so many ways, a disease of aging.

For most AML patients, I find that the most important question to ask is if there is a curative intervention. For some, chemotherapy induction and consolidation may lead to a prolonged remission and perhaps cure. But for some disease categories—notoriously, p53-mutated disease—response to traditional chemotherapy is poor. Second, assuming an initial remission follows an induction regimen, how a remission is consolidated is another critical question. For people with high-risk AML (complex cytogenetics, FLT3-mutated) or intermediate-risk AML, allogeneic transplant remains the best means of consolidating a remission and offering a cure to many.

To a great extent, treatment for AML is informed by genetic and molecular studies that have become standard in the field. Cytogenetics to assess chromosomal defects, molecular analysis to identify potentially targetable mutations, and multi-channel flow cytometry to identify a blast phenotype that can be followed to assess measurable residual disease post induction and consolidation are all standard. Translocation 15;17 or “acute promyelocytic leukemia” (APL)—once considered to be the worst type of AML prognostically—is now routinely treated with all-trans retinoic acid and arsenic trioxide, with long-term survival now approaching 90%. The clinical presentation in this hypothetical case does not sound like APL, though the bruising raises the question, and a coagulation profile, if indicative of disseminated intravascular coagulation, might make that more of a question.

Other good prognostic cytogenetics include the translocation of chromosomes 8 and 21—also known as t(8;21)—and inversion of chromosome 16. Each of these has a historical long-term survival rate of about 60 to 70% with standard induction chemotherapy. All other cytogenetic features are classified as intermediate risk or poor risk, with long-term survival rates of 30 to 40% or 10%, respectively. For each of these latter risk groups, transplant remains the only real chance of relapse-free, long-term survival.

Now, before we discuss treatment regimens for AML in general, there are some features of my presentation that would lead me to ask for some additional data. The presence of a spleen tip and the presence of early myeloid forms, eosinophils, and basophils in addition to blasts raise the possibility that my disease is a Ph+ blast crisis rather than de novo AML. If so, treatment with a kinase inhibitor directed at the BCR-ABL kinase—after initial cytoreduction of the elevated blast count—would be a reasonable initial approach to getting control of the disease. But without allogeneic transplant as consolidation, this would not offer me long-term control of the disease. So, more on transplant in a bit.

Standard induction for “fit” patients with AML has remained largely unchanged for several decades—until recently. The chemotherapy combination of 7+3 (7 days of cytosine arabinoside and 3 days of an anthracycline) has been the backbone of induction in the U.S. Consolidation chemotherapy with 3 to 4 subsequent cycles of high-dose cytosine arabinoside has been common practice. The development of a liposomal preparation containing a defined ratio of cytosine arabinoside and daunorubicin has shown increased efficacy in AML that arises from a pre-existing condition known as myelodysplastic syndrome (MDS). Also, drugs targeting specific mutations in genes such as FLT3, IDH1, or IDH2 are additional options that can now be used in combination with standard approaches—or alone in some instances. But perhaps most impressive has been the incorporation of the BCL2 inhibitor venetoclax in combination with azacytidine as a low-intensity regimen now approved by the U.S. Food and Drug Administration (FDA) for elderly and unfit patients with MDS.

Response rates appear to essentially equal those of the standard high-intensity induction regimens. Importantly, this regimen generally has lower toxicity and is most often administered outpatient. Recent data show that patients achieving a complete response with this regimen do as well with allogeneic transplant as folks who received more intensive induction. And for younger, fit patients, venetoclax added to more intensive regimens is producing results that are likely significant improvements over the old 7+3.

So, getting back to the first question I posed, am I looking at the possibility of a cure? Possibly. It is not likely, at my age, that cytogenetics would be favorable. Complex cytogenetics and AML arising from MDS are much more prevalent. Even if this were to be a Ph+ AML blast crisis, my long-term survival would depend on allogeneic transplant as consolidation post remission.

Am I a candidate at 70 for an allogeneic transplant? Possibly. Recent studies show that arbitrary age limits on allo transplantation have virtually disappeared across transplant centers. Less ablative regimens and improved supportive care around infection control and prevention of graft-versus-host disease have led to a situation where transplantation for older patients is a viable option with reasonable outcomes. Unfortunately, it is one that is currently afforded to only about 5% of older AML patients.

So, what would I want in this situation? I would, of course, look for any relevant clinical trials, as all advances in the field are dependent on trials of novel therapies. There are now several trials looking at the addition of novel targeted therapies as a component of induction therapy for patients with appropriate molecular features. But in the absence of an appropriate trial, for my intermediate- or poor-risk AML, I would likely opt for azacytidine and venetoclax as an induction/consolidation regimen, which would give me a better chance of escaping potentially debilitating complications of induction and consolidation that might put a definitive transplant out of reach. And, I would consider transplant as consolidation if in complete remission and still in good shape.

Some reality here: if these approaches didn’t get me to a complete remission, my discussions would center on defining the best way to preserve quality of life with family and friends during my remaining time.

Dr. Asch can be reached at adam-asch@ouhsc.edu.

Related links:

• How Would an Expert Manage His Own Acute Myelogenous Leukemia?
• SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment
• Treating Pancreatic Cancer: Could Metabolism—Not Genomics—Be the Key?

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