Community Oncologist

65M w/ MDS/MPN-unspecified (5-10% blasts on marrow, normal karyotype but 7 tier 1 molecular lesions - JAK2, KIT (smaller VAF at 6%, rest at 40%), ASXL1, EZH2, RUNX1, STAG2, TET2, CEBPA, NF1, SRSF2). Not a transplant candidate. He has a very proliferative phenotype (WBC >250k mature neutrophils, splenomegaly, fevers). Symptoms have improved with hydrea and then 2 rounds of decitabine but he has become transfusion dependent (1-2 pRBCs/week), WBC remains >80k, and repeat marrow is unchanged with >95% cellularity and 8% blasts. We are considering treating with ven/aza if we can't find an appropriate trial for him. Do you think ven/aza is appropriate here and do you think it's reasonable to target a lower dose with the first cycle or would you go all the way with ramp up to ven 400 for 28d? This may be too complex of a question for this forum but wanted to give it a try.

MPN Specialist

Wow. This is a tough one. First off, I'd say that truthfully the only hope for prolonged survival in this case is an allogeneic stem cell transplant so, while you mention that he is not a transplant candidate, I would make sure that really is the case. Assuming that he is truly not a transplant candidate, you have to consider what your goal of therapy is. Given no response to Dacogen after 2 cycles, it is reasonable to add Venetoclax and, in cases like these, I often switch HMA (Dacogen to Venetoclax) as you suggested. This is likely going to be quite myelosuppressive and will result in increased transfusion requirements in the short term. HMA/venetoclax in MPN and MDS/MPN has not had the impact that we've seen in high-risk MDS and AML. If you do get a response, it is likely to be short lived and may not impact his survival. If you do choose venetoclax, I may opt for a 14 or 21 day course as opposed to 28-days given that you are not targeting transplant and goal is to improve QOL. Alternatively, you could consider a less-is-more approach. Regardless of what you do, I doubt you're going to get a significance response given the molecular complexity of his disease and you may choose to minimize toxicity. In that case, I would favor adding a JAK inhibitor to see if this helps his splenomegaly and fevers. Could combine this with a shorter course of decitabine (3-day) or Vidaza (5-day) to control WBC and blasts to some extent. Lastly, you could consider avapritinib as a KIT inhibitor as he appears to have a KIT mutation and systemic mastocytosis often occurs within the context of MDS/MPN. The low VAF may make this less impactful, but this would represent an additional targeted agent. To confirm mastocytosis, I would ask the pathologists to review the marrow and stain for tryptase, CD117, CD2, CD25 and check peripheral blood tryptase as well. Super complex case and unfortunately, not a lot of good options. Always recommend talking to the patient and establishing what you are trying to accomplish - especially in cases like this where no option is likely to be super helpful.