How I Treat: A Patient With Myelodysplastic Syndrome With Isolated Deletion of 5q

Benjamin Tomlinson, MD, University Hospital Seidman Cancer Center, Cleveland, Ohio, discusses the course of treatment he chose for a younger patient with a common presentation of myelodysplastic syndrome (MDS) with isolated deletion of 5q. 

Transcript:

Hello, my name is Benjamin Tomlinson. I'm an assistant professor of medicine and a myeloid malignancy physician at the University Hospital Seidman Cancer Center in Cleveland, Ohio. Today, we're going to be talking about a fairly common presentation of myelodysplastic syndrome in a younger patient. 

The example today is [of] a 49-year-old woman who originally presented to her primary care physician. The patient described a sensation of severe palpitations after minimal exertion. She described [activities such as] carrying a basket of laundry up 2 flights of stairs, and then her heart would not stop pounding. The primary care physician did a basic workup and identified a substantial macrocytic anemia with a hemoglobin of 6.9. She immediately referred the patient to the emergency department where the patient felt better after 2 units of packed red blood cell transfusion. 

Subsequently, the patient was evaluated by hematology. They noted that the patient had a normal folate, B12, and iron studies, and there was no history or sign symptoms of any acute blood loss, and so a bone marrow biopsy was recommended. The bone marrow biopsy returned with the diagnosis of myelodysplastic syndrome with isolated deletion of 5q.

However, the bone marrow aspirate had 3% blasts. It was noted to be hypercellular with megakaryocyte atypia. Additionally, genetic studies in the bone marrow biopsy with both the standard karyotype and [fluorescence in situ hybridization] (FISH) revealed 5q as the sole abnormality in 17 out of 20 cells with the other 3 cells having a normal female karyotype. But a broad molecular panel that included all genes on the modern [International Prognostic Scoring System–Molecular] (IPSSM) panel identified an ASXL1 mutation and an [isocitrate dehydrogenase 1] (IDH1) mutation at the R132 residue with a variable frequency of 31%. 

The hematologist in the setting, recognizing isolated deletion 5q-as being highly responsive to lenalidomide, recommended this therapy for the patient. Within 6 weeks, the patient had a complete hematologic response and was tolerating the therapy well.

At this point the patient came in for an interval visit and the hematologist had some decisions to make. Once we have a patient with 5q MDS who is very young, the question is, what is the next most appropriate step in management or how would we manage these patients in the long run?

I think the textbook answer here is to continue the lenalidomide until there is some form of disease progression. But I think it's important we take the entire patient case into account. Modern risk stratification tools, including IPSSM if we take the patient's hemoglobin [at] presentation, blast percentage and other findings would find that this patient has a positive score or in the moderate high-risk category. By [Revised International Prognostic Scoring System] (IPSS-R), this patient is [at] intermediate risk as well, and it's probably not appropriate to continue this patient [with this treatment] without considering the potential long-term outcomes.

Now, most patients with isolated deletion 5q will have durable responses to lenalidomide, but not all patients. In the original phase 3 clinical trial from 2008, we see that the median duration of response was not reached. But large retrospective data sets have suggested that the median duration response is probably about 2.5 years for most patients. But there's a handful of patients [whose] responses last only 6 to 12 months, and you still have about 10% to 20% of patients that don't respond at all. Now, obviously, that doesn't apply to this patient, but the other piece of this is when we look at the long-term outcomes for intermediate-risk by IPSS-R and moderate-high-risk, we see a median overall survival of only 2.5 to 3 years. Now admittedly, some of that is skewed because MDS tends to be diagnosed in older patients, but in a very young patient like this, even with an excellent response to lenalidomide, the long-term prognosis into her 60s and 70s is still going to be guarded.

Since we don't have tools to predict exactly how long her response to lenalidomide is, the most appropriate step, even at this early stage, is to refer her for evaluation for stem cell transplant. Older decision modeling shows us that most patients with lower-risk myelodysplastic syndrome have the best life expectancy when transplant is delayed until progression on their initial therapy. 

But we also know that sometimes myelodysplastic syndrome patients, when they progress, the mechanism resistance can include high-risk mutations such as [runt-related transcription factor] (RUNX1) or [tumor protein p53] (TP53). In a patient under the age of 50, this could put the long-term outcome of an allogeneic stem cell transplant at risk. I do think most physicians would recommend delay in any transplant, but it's important that we be prepared for the unknown. 

The most appropriate next step is to have this patient evaluate a transplant center and have a long-term risk-benefit conversation about optimal timing and observation in order to proceed to transplant at the appropriate time for this particular patient. In other words, it would not be recommended to wait to refer to a transplant center until such time that the patient has progressed.

It's also worth talking about this patient's IDH1 mutation, which is at a residue where we would expect she would have a good response to ivosidenib. At this time, however, the ivosidenib for MDS is only approved in the second line, or relapsed/refractory setting, and we don't have the same long-term data and outcomes that we have for lenalidomide. It's also the case that we can't count on that mutation necessarily being there in the future. 

Mutational profiles and MDS can change over time, and so it does not change the fact that a patient [in] this age group, even in first initial response, should have a long-term discussion with an allogeneic stem cell transplant physician about timing, risks, and benefits.

Learn More About This Case Here:

How I Treat: Myelodysplastic Syndromes