Case 2: AML With Myelodysplasia-Related Changes

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Naval G. Daver, MD:Moving to our next case, we’re going to discuss a patient with AML [acute myeloid leukemia] with myelodysplasia-related changes, also called MRC. Dr Rizzieri, could you please do the discussion?

David Alan Rizzieri, MD:Great. Thank you very much. I’m really excited you chose this case because this diagnosis is still somewhat confusing to me, so I’ll be really interested in our pathologist’s contribution here.

As you see in case 2, this is a 70-year-old gentleman with MDS [myelodysplastic syndrome] diagnosed approximately a year and half before presenting to our center with a very good performance status. The patient previously received decitabine for 6 cycles, and responded, but did not achieve complete transfusion independence. The patient did experience mild depression and fatigue with therapy, but no other serious complications and no infections were noted.

Past medical history was fairly noncontributory and only notable for hypercholesterolemia that was well controlled with lovastatin. White counts at presentation to us were notable for a white count of 1.9 with an ANC [absolute neutrophil count] of .9, so mildly decreased, a hemoglobin of 9.2 with hematocrit of 31. Platelets were markedly decreased at 42,000 with peripheral blasts at 16%. A bone marrow aspirate and biopsy were performed, and as we see, the blast percentage was 65%. Cytogenetics were returned, indicating del [deletion] 5q and a del 7q. Molecular analysis was performed, indicating thatFLT3was not mutated, and a 75-gene panel was still pending at the time of evaluation. A diagnosis was made of AML with myelodysplastic-related changes, or AML-MRC.

Naval G. Daver, MD:Thank you very much. Dr Weinberg, we’ll start with this patient now, getting the samples to you. What would be the traditional work-up in a patient who you did not know, who, for example, has MRC and this new AML. What FISH [fluorescence in situ hybridization] probes would you use, and what are the other nuances of the diagnosis?

Olga K. Weinberg, MD:In all cases, we would look at the bone marrow aspirate, and we’ll also look for dysplasia in the background. Taking aside the blasts, we would look at neutrophils, erythroid cells, and megakaryocytes and see if they’re abnormal.

In a setting of MDS, we would only need 10% of cells to be dysplastic to call it MDS. In the setting of AML, we recognize that the body may be under stress and there might be a lot more dysplasia around, so we would require over 50% of the cells to be dysplastic. If we see more than 50% of cells in each lineage, and we need 2 lineages to be effective, then we would say this case has morphological dysplasia. This is therefore, AML with myelodysplasia-related changes.

This is kind of a confusing entity because you can’t see a lot of dysplasia in other types of AML like therapy-related AML. Even AML with recurrent genetic abnormalities can sometimes have that kind of dysplasia, especially things like 6;9 translocation.

Aversion of chromosome 3 or 3q can have a lot of dysplasia in the background. If you see morphological dysplasia, that would lead us to AML MRC. If cytogenetics come back and instead of a normal karyotype, we have abnormalities of chromosome 5 or 7, or we have at least 3 or more unrelated cytogenetic abnormalities, which we often refer to as complex karyotype, that’s what we could consider as AML-MRC.

A third way to get into this category is to have a history of a previous myeloid neoplasm like MDS or a mixed MDS/MPN [myeloproliferative neoplasm]. That would also qualify somebody as having AML with myelodysplasia-related changes.

Of course, that could be a little confusing because you could say, why is this not therapy-related AML, if they had therapy? Some of these nuances are just hard, clinically, to sort out, but we would do the same thing that we would usually do. We’d do a cytogenetic analysis, in which you grow the cells and you look to see any abnormalities. The problem with FISH probes is that you have limited probes. Most [laboratories] will do probes to chromosome 5, 7, or 20q, and maybe chromosome 11. In cytogenetic analysis, you really want to see the entire range of abnormalities that may be present.

The problem with cytogenetic analysis is that it may not grow. Especially if it’s being sent out to a reference laboratory, it may fail, for maybe other sorts of the reasons. That’s where FISH can still be really helpful.

Then there’s been some reports where some abnormalities that we see on a mutational panel may indicate an underlying MDS. If we see things likeP53mutations or we seeSRSF2orSF3B1mutations, that may indicate that even if there’s no history of MDS, there may be an underlying MDS that was recognized because maybe the patient didn’t present for a long time to a clinician, or maybe transferred hospitals and we didn’t have a good story of what happened.   

Naval G. Daver, MD:I think this is something that’s emerging, especially in the hematopathology publications. Are there any mutations that clearly rule you in or out from MRC? You mentioned theSF3B1could be suggestive, and then there are some data withNPM1. Let’s say somebody has not enough dysplasia to meet the 50% and then you see some of these mutations. Which ones can really say, “This person should be MRC,” or not?

Olga K. Weinberg, MD:I think that remains a subject of the study. I don’t know that it’s very definitive. There’s been a publication out of Dana-Farber [Cancer Institute] by Coleman Lindsley [,MD, PhD,] that addressed it. I don’t know of any other publications that looked at it, but in that study, they found that things likeNPM1mutations were more likely to be associated with de novo AML. We’ve all seen in clinical practiceNPM1-mutated AML that arises after MDS, or core binding factor leukemias may have that. Outside of that, there are certain mutations that may underlie secondary MDS, likeSRSF2, but none of these are very specific or definitive.

I would say the most definitive things are morphologic dysplasia and cytogenetic abnormality, especially complex karyotype or abnormalities of chromosome 5 or 7.

Naval G. Daver, MD:That’s useful. At this time, I think the 3 groups we could think of are people who have known secondary AML, known chemoradiation, and then known cytogenetics. The molecular [testing] is still in process; we’re not sure if we can use that to differentiate people.

Transcript edited for clarity.