Graft Versus Host Disease - Episode 4

Initial Therapy in GVHD

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Experts in hematology-oncology share insights on approaching initial treatment and the treatment goals for acute and chronic GVHD.

Haris Ali, MD: The goals of acute GVHD [graft-vs-host disease] treatment are rapid resolution of symptoms and abnormalities, especially the laboratory test abnormalities, and bringing it down to either very mild acute GVHD or complete remission or resolution of the GVHD.

You want resolution of the symptoms, a decrease in the complications, to decrease the use of the steroid, and resumption of organ function. The approaches and the goals are pretty much the same for both types of GVHD.

There are some patients who we may not start off with a systemic steroid, especially early grade skin acute GVHD. Most of them will resolve with a topical agent or the topical steroids. In each patient, we look at how many risk factors they have and how severe the risk factors are for the GVHD. If someone doesn’t have very high-risk factors for GVHD and they only come in with, for example, a skin rash, a topical steroid for a limited skin rash may be sufficient.

The standard of care for any patient who has high-grade, grade 2 or above, acute GVHD is treatment with systemic steroids. There are studies underway looking at alternative agents to control the GVHD, but the current standard of care is to control the GVHD with systemic steroids in these patients.

Corey S. Cutler, MD, MPH, FRCPC: The main regimen that we use to treat acute graft-vs-host disease is corticosteroids, generally at a dose of 2 mg/kg when there is gastrointestinal [GI] or hepatic involvement, but sometimes lower doses when there is only cutaneous involvement, as low as 1 mg/kg. There are 2 different pathways that are being studied in acute GVHD initial therapy. For patients deemed to have the lowest risk of GVHD bad outcomes, we’re working on ways of de-escalating therapy.

The CTN [Clinical Trials Network] recently published a study where patients had Minnesota standard-risk acute GVHD and biomarker-based lower-risk acute GVHD, according to the MAGIC [Mount Sinai Acute GVHD International Consortium], or Ann Arbor biomarkers. In this trial, patients were randomized to either receive corticosteroids or sirolimus. At 6 months, there was no difference in outcome in the patients who were randomized to receive sirolimus, suggesting that not all patients require corticosteroids as initial therapy for acute GVHD.

On the other hand, with higher-risk GVHD, we’re trying to understand how we can improve upon steroids alone for them. We have not yet been successful in improving outcomes with steroids alone. We’ve tried with several randomized trials. The 2 that are most important to mention are the randomized trials conducted by the Blood and Marrow Transplant Clinical Trials Network, where we looked at steroids vs steroids plus mycophenolate. Unfortunately, the arm that was randomized to receive additional mycophenolate to corticosteroids did slightly worse than the steroid-alone arm. Another very important trial was recently halted. It looked at steroids with or without itacitinib, but unfortunately it did not meet its primary end point, although there was a very nice signal in improvement in outcomes. That trial was halted early, and we do not yet have the final results from that study.

Chronic GVHD, very similar to acute GVHD, is initially treated with corticosteroids; although here we often add agents such as tacrolimus, or more recently sirolimus based on the CTN’s 0801 study, to initial therapy.

Yi-Bin Chen, MD: The accepted initial therapy for a patient with acute graft-vs-host disease would be systemic steroids, usually at a dose between 1 and 2 mg/kg per day of prednisone or its equivalent. The patients with lower GI involvement will often need to receive IV [intravenous] dosing due to fears of absorption of the drugs. It’s usually that dose that has become the accepted standard. There have been trials in the past that have tried to escalate to higher doses, but they showed no benefit. There have been some retrospective studies suggesting that a lower dose of 1 mg/kg was not that different from 2 mg/kg. In our practice, if patients have visceral involvement, be it the liver or the GI tract, we tend to steer more toward 2 mg/kg. If it’s just skin involvement, we tend to give 1 mg/kg. It’s difficult to know how the dose of steroids impacts outcomes. Acute graft-vs-host disease is so biologically heterogeneous that it’s tough for me to conclude that the dose of steroids between 1 and 2 mg/kg definitively matters.

Other factors that impact the overall outcome for the patient include the severity of acute graft-vs-host disease. We know that matters in terms of organ severity. There is some evidence that there may be some acute graft-vs-host disease biomarkers that will be more mature in the years to come that better judge the biological severity than what we see clinically. We do know that patients’ other comorbidities matter because they dictate their resilience and if they’re able to make it through the various obstacles that they have to steer through to recover from graft-vs-host disease. Older patients certainly do worse, along with patients who have chronic comorbidities and organ dysfunction or preexisting infections. All of those things contribute to a patient’s resilience and the ability to eventually achieve a full recovery if we can put the acute graft-vs-host disease into remission.

Transcript Edited for Clarity