Harry Erba, MD, PhD:So, this is clearly a challenging case. First, you have a patient who is over the age of 60 and he has just had a myocardial infarction and is facing a diagnosis of acute myeloid leukemia. And unlike many times, he actually has a leukocytosis at presentation, which is a challenge because when the white blood cell count in AML approaches 100,000, you can have signs or symptoms of leukostasis that can be devastating if not fatal, such as intracranial hemorrhage or pulmonary decompensation from pulmonary infiltration. And so, all of this makes the case very emergent. So, I’m glad he was transferred expeditiously to a hematologist for management.
What’s interesting about his whole story is that it has probably been going on for several months. That doesn’t necessarily mean he has had a history of myelodysplastic syndrome, but it kind of suggests the possibility that it has been smoldering for several months with these recurrent infections.
What’s the challenge here is his presentation of a high white blood cell count, and what’s surprising is we actually have some cytogenetic data back already on this patient. Now if that cytogenetic data were by normal karyotypic analysis, classical karyotype, that could take at least a week, if not 2 or 3 weeks at some institutions. What I do to get that information, which is important for treatment, is do a FISH analysis, or florescence in situ hybridization, and look for the recurring cytogenetic changes that are common in AMLthe core binding factor leukemias, trisomy 8,MLLgene rearrangements, and, as in this case, deletions of all or part of chromosome 5 or chromosome 7. And that FISH data can give you very important information about the patient in terms of how likely they are to respond to conventional chemotherapy. The fact that he has deletion 5q in his karyotype is what makes the diagnosis of AML with myelodysplasia-related changes.
According to the World Health Organization classification of AML, it’s a higher archaical classification. The first broad category of AML is acute myeloid leukemia with recurrent genetic changes. These include the core binding factor translocations like the t(8;21) or inv(16). It includes the 15;17 translocation of acute promyelocytic leukemia. It also includes some that are less common, specificMLgene rearrangements, the 6;9 translocation inversion 3, to name just some of them. And then most recently, what has been added are the genetic subtypes of nucleophosmin-mutated and biallelicCEBP alpha-mutated AML.
If you don’t see any of those genetic changes, then the next classification is AML with myelodysplasia-related changes, which I’m going to come back to. After that, if it doesn’t fall into that category, it’s AML due to therapy, and then finally AML not otherwise specified. So, let’s come back to what he has: AML with myelodysplasia-related changes.
You still have to have over 20% blast in blood or the bone marrow, as in this patient, but then you have to have 1 of 3 things. One, a documented history of myelodysplastic syndrome or, specifically, an overlap of myelodysplastic syndrome and myeloproliferative neoplasm, the MDS/MPN overlap. Chronic myelomonocytic leukemia in an adult is probably the most common, but there are others like atypical chronic myeloid leukemia and others that are in that classification.
The second way of classifying as myelodysplasia-related changes is if you have what is apparently a de novo AML, as in this patient but with myelodysplasia-related cytogenetic changes. And there’s a long list of them. The most common of them are complex cytogenetic changes where you have more numeric and/or structural changes in the chromosomeor monosomic 5, deletion 5q, as in this patient; monosomic 7, or deletion 7q. And then a number of other cytogenetic changes, which quite frankly I have to look and can’t remember off the top of my head.
The third classification of myelodysplasia-related changes is if the pathologist notes morphologic dysplasia in at least 2 lineages in over 50% of the cells in that lineage. This is a bit more of a challenge for a number of reasons. First of all, in a patient like this whose marrow is probably packed with leukemia with a white count of 85,000, there may be very few hematopoietic cells left behind to judge dysplasia.
The second problem is that there is some subjectivity to that and pathologists don’t always agree on what makes a cell appear dysplastic or not. But the third most important issue in that subtype of myelodysplasia-related changes is that studies have shown that patients who have AML with myelodysplasia-related changes, solely based on morphologic dysplasia, actually have the same outcome in terms of survival as AML not otherwise specified when given intensive chemotherapy. The patients with myelodysplasia-related changes with a history of MDS or de novo AML with cytogenetic changes of MDS, those are the patients who have a worse outcome compared to AML not otherwise specified with intensive chemotherapy.
Further analysis of that subset of patients sheds some light on why that might be. You can actually have morphologic dysplasia in patients who have a nucleophosmin mutation and aCEBP-alphamutation. So now in the WHO 2016, to make a diagnosis of myelodysplasia-related changes based on morphologic dysplasia alone, multilineage morphologic dysplasia, you have to first exclude having a nucleophosmin mutation or a biallelicCEBP alphamutation. So, that can take some time before you make that diagnosis. But that’s how we make the diagnosis of myelodysplasia-related changes.
Transcript edited for clarity.
Case: A 68-Year-Old Man With Newly-diagnosed AML
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