Preventive and Early Intervention Strategies Among Next Steps in cGVHD Management

Haris Ali, MD

As the armamentarium continues expanding for the treatment of patients with chronic graft-vs-host disease (cGVHD), research is ongoing to determine whether earlier integration of novel therapies, such as ruxolitinib (Jakafi), could yield better response rates for patients, said hematologist/oncologist Haris Ali, MD. He added that, ultimately, preventive strategies for cGVHD will be the next frontier.

“Early treatment rather than waiting too long [to intervene] is the key to success [with ruxolitinib] to get better responses,” said Ali, an associate professor in the Division of Leukemia of the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. “[However], it’s a dynamic field and things are changing. Down the road, we will probably be looking less at treating GVHD and more at prevention.”

In an interview with OncLive®, Ali discussed the importance of assessing patients post-transplant for signs of cGVHD, frontline treatment considerations based on disease severity and organ involvement, and the next steps the field should take with ruxolitinib in the management of this disease.

OncLive^®: How do you follow patients to assess for signs of cGVHD?

Ali: Usually in the post-transplant follow-up, we evaluate patients proactively for any cGVHD. We ask them questions directed toward the symptoms of cGVHD and do a thorough physical examination. It’s very simple. We ask questions about whether they have dry mouth, dry eyes, or joint stiffness. The [physical evaluation consists of] a skin examination, mouth and eye [examinations], and [testing] range of motion. The diagnosis is basically [made from] proactively checking on patients so we can catch them earlier rather than later.

Are there certain types of patients who are at an increased risk of developing cGVHD?

It used to be that patients who [underwent] myeloablative conditioning and [had] an unrelated donor for transplant would be at a higher risk for developing GVHD. Other factors [include] patients getting a transplant from female donors who had undergone multiple pregnancies and patients with aplastic anemia. There are multiple risk factors.

[We’ve seen] a slight change in cGVHD because of more use of post-transplant cyclophosphamide. We tend to see [cGVHD] a bit less than before based on comparative studies.

How do frontline treatment considerations for cGVHD change based on severity and organ involvement?

When a person presents with cGVHD, [frontline treatment] typically depends on the extent of involvement. If someone presents with oral GVHD with dry mouth, we will typically use topical steroids to stimulate saliva production. If someone presents with dry eyes and GVHD that is limited to the eyes, we will use more artificial tears. If those patients progress, we refer them to our cGVHD-specific ophthalmologists who can screen patients for trials using agents such as cyclosporine [Restasis] or, in very advanced cases, scleral lenses for treatment.

For patients with more extensive GVHD, such as someone with multiple organ involvement, the initial treatment is systemic steroids.

What second-line options are available to patients?

Most patients who [need] steroids will have an incomplete or suboptimal response and require some sort of additional therapy to help their current GVHD. Currently, we have 2 approved medications [in the second-line setting]: ibrutinib [Imbruvica] and ruxolitinib. Another treatment that is often used is extracorporeal photopheresis [ECP].

Ruxolitinib was approved [in September 2021], but in the transplant community, it was used quite frequently [before that] because of the data that were available from a German paper. Generally, [second-line] treatment could be ibrutinib or ruxolitinib, but more data are available with ruxolitinib, and we have a randomized trial supporting its use. [Ruxolitinib is] usually the go-to treatment at this point. If someone mainly has GVHD with skin involvement, we can use ECP, which is a very good option for patients who are more at risk for immunosuppression and potential infections. ECP doesn’t make patients immunocompromised.

What did the data from the phase 3 REACH2 trial (NCT02913261) show in terms of responses with ruxolitinib by grade? How are you interpreting these data?

Patients who had [low-grade GVHD], such as grade 2 disease, had higher responses compared with patients with grade 3 and 4 disease. Patients who had only skin involvement also had higher responses [compared with patients with additional organ involvement].

These data suggest that we should use [ruxolitinib] early rather than late because late-stage disease responded less [than early-stage disease].

What were some of the key conclusions that can be drawn from the results of the phase 3 REACH3 trial (NCT03112603)?

The key takeaway was that more patients had complete or partial responses [with ruxolitinib vs best available therapy], so the overall response rate was much higher.

We don’t get a 100% response rate though; responses [occur] in about one-third of patients. In the transplant community, [we would like to see] development of combination trials [with ruxolitinib] or [trials evaluating] a higher dose of ruxolitinib in patients who can tolerate it to see if these responses can be improved upon. Ruxolitinib is approved at 10 mg twice daily, but we have good science behind using a potentially higher dose that may give us better and more responses.

Where is belumosudil (Rezurock) currently being used in the management of cGVHD?

The trial [of belumosudil] was open at our site and we enrolled several patients to it. We saw a good number of responses in patients who got belumosudil. It is definitely [an option] for patients who have progressed on ruxolitinib and ibrutinib. These patients have much more advanced and refractory disease, so being able to give an option to them to improve their cGVHD is good.

What advances do you foresee regarding the management of cGVHD in the coming years?

Preventive strategies for cGVHD are evolving. We know that the use of anti-thymocyte globulin is decreasing in cGVHD. We are seeing more frequent use of post-transplant cyclophosphamide, which seems to be decreasing the incidence of cGVHD.

So, in addition to looking more toward treating cGVHD, we are moving ahead to look at preventing cGVHD. Data are available showing that peri-transplant use of various medications that are currently being used for the treatment [of patients with cGVHD], such as JAK inhibitors, can help with downstream acute and cGVHD.