CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 12, 2022
Expiration: April 11, 2023
Prithviraj Bose, MD:
My colleagues Ilene A. Galinsky, NP, and Caitlin R. Rausch, PharmD, will now lead our discussion on supportive care and toxicity management.
Ilene A. Galinsky, NP:
Supportive care provided to individuals with SM includes patient education on the signs and symptoms of mast cell activation, avoiding known triggers, and the need to carry epinephrine pens to manage anaphylaxis.7,27 Specialist care and support should be provided to patients who are pregnant or undergoing surgery, and treatment provided to target the symptoms of mast cell mediator release.
Ilene A. Galinsky, NP:
In patients with advanced SM, symptoms can be caused by mast cell infiltration into tissues as well as activated mast cells releasing proinflammatory mediators.30 Antimediator drugs can help with management of the symptoms related to mast cell mediator release.
Antimediator drugs are introduced according to the affected organ system, and stepwise options are outlined in this table.27 Many symptoms can be managed with an H1- or H2-antagonist, although osteoporosis may require bone-modifying agents such as bisphosphonate.
We will turn now to our second case study before continuing to our discussion of administration and safety issues with targeted agents.
Ilene A. Galinsky, NP:
Our second case study is a complicated patient. She experienced skin pigmentation changes as a child and was diagnosed with urticaria pigmentosa. This condition, and the pruritis that went with it, got worse when she was exposed to the sun. As she got older, she experienced flushing when drinking alcohol as well as flushing and abdominal discomfort if she took aspirin. At the age of 40 years, pruritis was affecting her quality of life. She had also developed chronic diarrhea and abdominal bloating and cervical lymphadenopathy, although she fortunately did not have any pain. Biopsies of the neck nodes were positive for a KIT D816V mutation and her tryptase was 517 ng/mL; consequently, she was diagnosed with a mast cell disorder.
This was before the clinical trials for midostaurin, so she was started on supportive medications (ie, H1 and H2 histamine blockade) for the GI symptoms. She then started to develop mild pancytopenia, and BM revealed systemic mast cell disease. At that time, she was placed on hydroxyurea and imatinib. Unsurprisingly, imatinib was not effective for her, given that her disease was positive for KIT D816V.
The patient’s disease progressed to the point that she could not eat and required a central line for total parenteral nutrition. She was about to be admitted to hospice when we saw her at the age of 46 years. By this time, her tryptase level was 774 ng/mL and her histamine level was 4777 pg/mL. A CT scan showed ascites and hepatosplenomegaly, and esophagogastroduodenoscopy showed esophageal varices, gastric erythema, and duodenal nodules. Colonoscopy showed pancolonic edema, liver biopsy showed an elevated hepatic pressure gradient, and BM showed >30% cellularity of her mast cells.
The patient was started on midostaurin in a clinical trial at that time and remained on the trial for 12 years. After 3 months of therapy on midostaurin, she was weaned off parenteral nutrition and her GI symptoms resolved. After 12 years, her disease progressed on midostaurin, and she was started on avapritinib at 200 mg/day—the starting dose approved by the FDA. She achieved a PR but reported “brain fog” symptoms, including difficulty with memory recall, indicative of grade 2 cognitive dysfunction.
Please take a moment to answer the following question before continuing with the activity.
Caitlin R. Rausch, PharmD:
In patients with advanced SM, midostaurin is dosed at 100 mg orally twice daily with food.14,28 It is worth noting that the dose used in advanced SM is double that used in patients with AML. Because midostaurin can cause GI symptoms (eg, nausea, vomiting, diarrhea), the patient should take a prophylactic antiemetic before dosing. If a dose is missed or vomited, the patient should not make up that dose. Instead, the patient should take the next dose at the scheduled time.
Midostaurin is metabolized by hepatic CYP3A4. Thus, coadministering midostaurin with strong CYP3A inhibitors may increase midostaurin concentration and the risk of toxicity. It is recommended to consider alternative therapies without strong CYP3A inhibitory activity or, if unavoidable, to monitor for toxicity. Strong CYP3A inducers may decrease midostaurin concentration and efficacy, and coadministration should be avoided.
When counseling patients starting midostaurin, I always tell them to let us know if they are starting a new medication prescribed by a different HCP, simply so we can double-check that there are no drug–drug interactions. This also applies to over-the-counter medications and herbal supplements. I also caution them to avoid grapefruit and grapefruit juice because these are strong CYP3A inhibitors.
Caitlin R. Rausch, PharmD:
Patients receiving midostaurin should be monitored for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and then monthly.14 Dose modifications are recommended for patients experiencing common midostaurin toxicities such as high-grade neutropenia, thrombocytopenia, or anemia; midostaurin should be discontinued if these AEs persist for >21 days and are suspected to be treatment related. Patients who experience grade 3/4 nausea or vomiting despite receiving an antiemetic should interrupt treatment for 3 days, then resume at 50 mg twice daily, increasing to 100 mg twice daily if tolerated.
Caitlin R. Rausch, PharmD:
Avapritinib is dosed 200 mg/day orally.19 Unlike midostaurin, avapritinib should be taken on an empty stomach. If a dose is missed, the patient should not make up the dose if within 8 hours of the next scheduled dose. If the dose was vomited, the patient should not repeat the dose but just take the next scheduled dose.
Both avapritinib and midostaurin are associated with cytopenias.14,19 Of these, thrombocytopenia is the major concern. Patients who are starting avapritinib should be counseled about the need to monitor their platelet count. We also counsel them about the risk of edema, as well as nausea, vomiting, and diarrhea. Providing patients with antiemetics is helpful when they are starting therapy, so that they have something they can take at home. Avapritinib should be taken on an empty stomach and that can sometimes be more difficult in terms of causing nausea. Eating smaller meals throughout the day rather than larger meals can help patients with nausea. As with midostaurin, patients may take a scheduled medication such as ondansetron before avapritinib if they are experiencing significant nausea.
Avapritinib is associated with broad cognitive effects, including cognitive dysfunction characterized by “brain fog” and memory problems. It may be difficult for patients to describe exactly what they are feeling, but they should be counseled to report any sort of confusion or memory changes to their healthcare team.
Avapritinib is predominantly metabolized by CYP3A4 and CYP3A5, presenting the potential for drug–drug interactions when taken alongside CYP3A inhibitors or inducers. Patients receiving avapritinib should avoid grapefruit or grapefruit juice while receiving their medication and should be reminded to inform the team if they start a new medication prescribed by a different provider or a new over-the-counter medication or herbal supplement.
Prithviraj Bose, MD:
It was always my perception that the nausea, vomiting, and diarrhea is a bigger issue with midostaurin than avapritinib. Would you agree?
Ilene A. Galinsky, NP:
I agree, in my experience.
Caitlin R. Rausch, PharmD:
Overall, I think midostaurin is more difficult to tolerate. I know that many patients say that it can be hard to take any medication on an empty stomach. But certainly, comparing the two, midostaurin dose tend to cause more nausea.
Caitlin R. Rausch, PharmD:
Patients receiving avapritinib should be monitored closely for intracranial hemorrhage and treatment should be permanently discontinued for any intracranial bleeding, regardless of severity.19 For grade 1 cognitive effects, dosing may be reduced or held until resolution or improvement. Patients experiencing grade 2/3 cognitive effects should have avapritinib held until resolution and then resume at the same or reduced dose. Avapritinib must be discontinued permanently for grade 4 cognitive effects.
Patients who develop thrombocytopenia (platelet count <50 x 109/L) should interrupt treatment until platelets return ≥50 x 109/L, and then resume at a reduced dose. If the platelet count does not recover above this level, platelet support can be considered.
Ilene A. Galinsky, NP:
Patients on avapritinib should have their platelet counts monitored regularly. Platelets should be monitored before initiating avapritinib and then every 2 weeks for the first 8 weeks of treatment; monitoring frequency then depends on the patient’s platelet level.19 We have used romiplostim in some patients with low platelet counts.
It is important to tell patients to let their healthcare team know if they notice any bruising or bleeding, because avapritinib does reduce their platelet count and it can happen at any time on therapy. I had a patient whose platelet count dropped to 59 x 109/L after 6 months on therapy, so it is clearly something to be mindful of.
Because avapritinib is associated with both thrombocytopenia and the risk of intracranial hemorrhage, I am always concerned to check that a patient presenting with “brain fog” may actually be experiencing a bleed. It is important to consider a neurologic examination if a patient presents with cognitive symptoms.
Prithviraj Bose, MD:
I agree. Avapritinib does cross the blood–brain barrier and it does impair platelet function. In the PATHFINDER and EXPLORER trials, there were some instances of intracranial bleeding, but these generally occurred in patients with a baseline platelet count <50 x 109/L.16,17 That is why avapritinib is not recommended in patients with advanced SM and a platelet count <50 x 109/L.
I have also used romiplostim in a patient with low platelets on avapritinib. Dose reduction is also quite common because of cytopenias.
Ilene A. Galinsky, NP:
Yes, most of my patients receiving avapritinib have had their dose reduced to 100 or 50 mg/day and are doing quite well at the lower dosing level, with a little better tolerability.
Caitlin R. Rausch, PharmD:
In the registrational trials, 68% and 72% of patients receiving avapritinib had to reduce their dose.16,17
Prithviraj Bose, MD:
That was quite a substantial percentage. In the PIONEER trial of avapritinib in indolent SM, the dose going forward into phase II evaluation is 25 mg/day.24 This is a very active drug with a wide dose range associated with efficacy.
Prithviraj Bose, MD:
Switching therapy from midostaurin to avapritinib may be considered for some patients with advanced SM, given that avapritinib appears to be a more potent drug. As we have seen, the EXPLORER and PATHFINDER trials included patients with prior treatment experience, including some who had taken midostaurin, although the numbers are relatively small. The ORR in those with prior midostaurin ranged from 59% to 82% in these trials of avapritinib.16,17
Ilene A. Galinsky, NP:
The clinical trials evaluating avapritinib included a washout period. Is that needed when switching patients between these agents in clinical practice?
Caitlin R. Rausch, PharmD:
I would not include a washout unless the medication is being held for an overlapping toxicity, such as thrombocytopenia. For example, in the event of thrombocytopenia leading to midostaurin discontinuation, we would want to allow the platelet count to recover before initiating avapritinib. But if the patient is switching for a tolerability issue that may not be a toxicity common to both agents—or because they are not responding to midostaurin—I would not include a washout period. I would stop the first agent on one day and start the new medication the next day, especially if the patient is experiencing SM symptoms.
In the trials of avapritinib, the median time to response was 8 weeks, but the half‑life of avapritinib is 20-39 hours vs 19 hours for midostaurin.14,19 I do not see a need to taper one drug before starting the other one.
Please take a moment to answer the following repeated question before continuing with the activity.
Ilene A. Galinsky, NP:
Recall that our second case featured a woman who, at the age of 46 years, was about to enter hospice due to severe complications from advanced SM. She had KIT D816V–positive disease that had progressed on hydroxyurea and imatinib. However, before entering hospice, she was enrolled on a clinical trial for midostaurin, then achieved a response and resolution of her GI symptoms. After 12 years, her disease progressed on midostaurin, and she was started on avapritinib at 200 mg/day. She had a PR but experienced “brain fog” symptoms, including difficulty with memory recall, indicative of grade 2 cognitive dysfunction.
“Brain fog”—cognitive dysfunction—is a common AE that we see with patients on avapritinib. We first attempted to manage this patient’s cognitive dysfunction by decreasing her dose of avapritinib from 200 mg/day to 100 mg/day. Unfortunately, she had a recurrence of cognitive dysfunction, and we had to further decrease her dose to 50 mg/day, which ameliorated her “brain fog” symptoms. A year later, we tried to increase her dose, but her cognitive symptoms returned, albeit with reduced severity. Thus, she continues on the 50 mg/day dose with no further cognitive decline.
At her visit last month to begin cycle 40 on therapy, she had a normal blood count, a slight tryptase increase on her BM, but otherwise is doing fantastically well. She remains in PR after 20 months of therapy.
Prithviraj Bose, MD:
That is an exceptionally gratifying case.
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