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FAQs: aGVHD and cGVHD
Pharmacists’ FAQs on the Novel Approaches in the Management of Acute and Chronic GVHD

Released: February 01, 2022

Expiration: January 31, 2023

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In this commentary, Eno-Abasi Inyang, PharmD, BCPS, BCOP, and Marissa Olson, PharmD, BCOP, answer questions on the management of acute and chronic graft-vs-host disease (GVHD) using current guidelines and recent approvals that were submitted by an audience of healthcare professionals during a recent live ProCE webinar.

Regarding CYP3A4 and other drug–drug-interactions (DDIs) with some of the novel prophylactic medications for acute GVHD, what can be done to mitigate potential toxicities?

Eno-Abasi Inyang, PharmD, BCPS, BCOP:
This is an important question, and unfortunately, we did not get to cover different prophylactic options during the webinar. Certainly, understanding of CYP3A4 enzymes and their role in drug metabolism and drug interaction is key when considering the use of prophylactic medication for acute GVHD. Thus, it is important to increase monitoring when you have identified agents with DDIs, particularly when prophylactic agents are to be started or discontinued. For example, in our practice, we monitor tacrolimus or sirolimus levels more often. There are also evidence-based drug information databases that provide guidance on preemptive dose reductions for DDIs of some immune suppression agents that are used for prevention of acute GVHD. For example, concomitant use of abatacept with a tumor necrosis factor (TNF) antagonist has been associated with an increased risk of serious infections and is not recommended.

Is it recommended to obtain biomarkers of potential acute GVHD for all patients getting a transplant since they have been shown to be predictive?

Eno-Abasi Inyang, PharmD, BCPS, BCOP:
Obtaining biomarkers for all patients undergoing hematopoietic stem cell transplant (HSCT) as a predictive function is not widely recommended at this time. Questions remain regarding whether therapeutic intervention based on predictive biomarkers can change the outcomes for patients with GVHD and who is the most appropriate patient to undergo biomarker testing and how to manage them afterward.

At this time, the use of biomarkers for GVHD risk remains an area of active research with ongoing clinical trials (NCT04284904, NCT03918343, NCT02067832). There are data on the use of biomarkers as a measure of response to acute GVHD treatment. Most recently, the Mount Sinai Acute GVHD International Consortium algorithm probability has been validated to predict mortality in all GVHD grades after treatment (with the use of serum biomarkers). It will be interesting to see if this algorithm will be incorporated into future trials of GVHD treatment.

At what point should α1-antitrypsin be considered in comparison to TNF-α inhibitors like infliximab?

Eno-Abasi Inyang, PharmD, BCPS, BCOP:
Sometimes it comes down to the adverse event profiles of the medications being considered. At my institution, we go through adverse event profiles of these agents to determine which one should be started, and we look at the clinical data in terms of what was seen for response rates and what type of GVHD the patients had and how they responded.

In a patient receiving belumosudil who has nausea and the inability to swallow, can belumosudil be suspended in water and administered via a nasogastric (NG) tube? Does the example of suspending ruxolitinib in approximately 40 mL of water and administering via NG tube also apply to ibrutinib and belumosudil?

Marissa Olson, PharmD, BCOP:
The 40 mL example only applies to ruxolitinib. This question arises quite often with patients receiving belumosudil, whether it’s because they are intubated in the intensive care unit or are having difficulty swallowing pills because of significant nausea as an adverse event with this drug. We have contacted the drug manufacturer and have done a literature search, but there is no evidence to suggest crushing and suspending belumosudil in water, as is done with ruxolitinib, would be appropriate or safe. For this reason, we have not done it, but there is certainly a need to answer this question in clinical studies. When this scenario occurs, we typically hold the medication and watch for a flare of GVHD. In patients who have active GVHD or are at a high risk for a flare, we may empirically increase their steroid dose until we can resume belumosudil. If we expect the problem to persist, particularly if it’s due to nausea related to the medication, we will switch them to an alternative agent for their chronic GVHD (eg, ruxolitinib).   

There is also a case report suggesting that ibrutinib capsules can be opened and given via a NG tube and “flushed” with water. Although I have not encountered this situation, I would feel comfortable using this strategy if needed based on this report.

Dr. Inyang, do you have any experience with this at your institution?

Eno-Abasi Inyang, PharmD, BCPS, BCOP:
This is a question that comes up with patients treated at our institution as well. I have also heard that several other institutions have been wondering about this, particularly when it comes to patients in the intensive care unit. And, unfortunately, we also have no answer to this question. Currently, we don’t recommend it since there isn’t any high-level clinical data to support it, but risks and benefits should be weighed and each patient case should be individually examined when making a treatment decision.

Would you recommend transitioning a patient off ruxolitinib to belumosudil? Would you overlap therapies for a certain amount of time?

Marissa Olson, PharmD, BCOP:
Ruxolitinib is indicated for steroid-refractory acute GVHD or chronic GVHD after failure of at least 1 previous systemic therapy. Belumosudil is indicated for patients with chronic GVHD after failure of at least 2 previous lines of systemic therapy. Transitioning a patient with chronic GVHD off ruxolitinib to belumosudil depends on whether the patient is having a poor response with ruxolitinib and whether you are constantly having to hold the medication due to cytopenias. In either scenario, I would consider trying belumosudil. Although there is no guidance on how to transition patients from ruxolitinib to belumosudil, we generally initiate belumosudil and taper the ruxolitinib by 50% every 1-2 weeks until the dose is down to 5 mg/day, then stop it altogether. In some patients and in an effort to limit the use of steroids, we may choose to continue both ruxolitinib (at a reduced dose) and belumosudil since they have distinct mechanisms of action and toxicities.

What about use of mesenchymal stromal cells for GVHD?

Eno-Abasi Inyang, PharmD, BCPS, BCOP:Mesenchymal stromal cells have been shown to possess immunomodulatory properties, which can have clinical implications in GVHD. There are published data on the use of mesenchymal stromal cells for GVHD, but its therapeutic efficacy varies depending on the study and the patient. When considering its use, I would recommend analyzing studies and patient characteristics.

Key Takeaways

Eno-Abasi Inyang, PharmD, BCPS, BCOP:
GVHD is a serious complication of HSCT and remains a major cause of morbidity and mortality following HSCT. Corticosteroids remain the first-line therapy for both acute and chronic GVHD. Supportive care management is key in preventing and optimizing treatment of GVHD. A better understanding of GVHD pathophysiology in the past decade has led to the development and incorporation of novel targeted agents such as ibrutinib, belumosudil, and ruxolitinib for chronic GVHD and ruxolitinib for acute GVHD.

Marissa Olson, PharmD, BCOP:
The take-home message is that ruxolitinib is the agent of choice for steroid-refractory acute GVHD. In patients being treated for chronic GVHD, we must take the following into consideration: Ibrutinib was the first agent approved for chronic GVHD. Its use can be limited by its toxicities but may be useful in patients with renal impairment or those who have difficulty eating or swallowing pills. Ruxolitinib has the highest-quality controlled data and may be particularly useful in patients with nausea or an inability to swallow pills. Belumosudil has shown highly encouraging response rates in patients with steroid-refractory chronic GVHD including those with previous failure to ibrutinib and ruxolitinib, and it is especially useful in patients with poor graft function or renal impairment.

Your Thoughts?
What are your thoughts and questions on pharmacist management of patients with acute or chronic GVHD using novel targeted therapies? Please answer the polling question and join the conversation by posting a comment in the discussion section below.

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Which of the following agents was recently approved in combination with a calcineurin inhibitor and methotrexate for the prevention of acute GVHD in adults and pediatric patients 2 years of age or older undergoing HSCT?
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