Differentiation syndrome is a fairly non-specific term. It was first described in acute promyelocytic leukemia treated with differentiating agents, such as ATRA, all-trans retinoic acid, or arsenic. These patients who were treated with these agents have had a therapeutic impact, but initially the differentiation of myeloid cells, which was part of that therapeutic impact was quite robust, leading to a cytokine-mediated inflammatory process that manifested in weight gain, pleural effusions, shortness of breath, hypoxia, dyspnea, unexplained fevers, oftentimes requiring the initiation of steroid therapy...
Differentiation syndrome is a fairly non-specific term. It was first described in acute promyelocytic leukemia treated with differentiating agents, such as ATRA, all-trans retinoic acid, or arsenic. These patients who were treated with these agents have had a therapeutic impact, but initially the differentiation of myeloid cells, which was part of that therapeutic impact was quite robust, leading to a cytokine-mediated inflammatory process that manifested in weight gain, pleural effusions, shortness of breath, hypoxia, dyspnea, unexplained fevers, oftentimes requiring the initiation of steroid therapy.
Well, with some of the newer targeted therapies that are emerging, such as IDH inhibitors and probably to a lesser extent, FLT3 inhibitors, and maybe some of the newer targeted agents, you can also get differentiation as the myeloid cells release their block on differentiation. The malignant cells become more mature and, quote unquote, “normally mature.” That process too, can be associated with an inflammatory cytokine-mediated differentiation process that can be similar to what we had seen with APL and is also called differentiation syndrome.
Typically, with targeted therapies, the differentiation syndrome can occur later, as opposed to 5, 7, 10 days after initiation of therapy for APL, I would say that individuals who are exposed, let’s say to IDH inhibitors tend to develop IDH differentiation syndrome around two weeks to six weeks, sometimes as far out as four to six months following initiation of therapy. And again, the presentation is quite pleomorphic and nonspecific, unexplained fevers, weight gain, pleural effusions, pericardial effusions, adenopathy, rash.
So, a lot of these symptoms can also be seen with leukemia itself and can be seen with infectious complications of leukemia and it’s treatment or cardiac complications. So, you can’t be sure if it’s differentiation syndrome, but if you suspect it and the timing makes sense, and there is some suggestion of differentiation and you worry about it even a little bit, my recommendation is to treat the other causes, the infectious cardiac potential causes, you can treat those, but also treat the potential differentiation syndrome because if left untreated, differentiation syndrome can progress quite rapidly and can be lethal. And the treatment we recommend, is steroids, dexamethasone 10 milligrams twice daily. And if it is differentiation syndrome, patients should respond relatively quickly with resolution of symptoms in a matter of days to a week. And that gradual improvement will continue over time and then the steroids can be tapered off.
Stopping the drug itself usually is not sufficient, and I caution against it because a lot of these drugs, including IDH inhibitors specifically, have a long half-life. So, just stopping the drug and not giving steroids may not allow you to salvage the situation because the drug is hanging around despite you stopping it. So, we recommend steroids. Now, differentiation syndrome can also be accompanied by leukocytosis, a high white blood cell count, in which case we recommend the use of cytoreductive measures, such as Hydrea. It could be accompanied by tumor lysis or DIC, in which case we recommend the appropriate management for those types of syndromes.