Ponce Discusses Use of Steroids and Next-Line Treatment for Chronic GVHD

Publication
Article
Peers & Perspectives in OncologyJuly II 2023
Volume 1
Issue 3
Pages: 44

During a Targeted Oncology™ Case-Based Roundtable™ event, Doris M. Ponce, MD, and participants discussed treatment goals and management of graft-vs-host disease.

Ponce, Doris

Doris M. Ponce, MD, MS (MODERATOR)

Associate Attending Physician

Director, GVHD Program (Adult BMT)

Memorial Sloan Kettering Cancer Center

New York, NY

PARTICIPANT LIST

Jean Yared, MD

Adrienne Phillips, MD, MPH

Mari Dallas, MD

Parastoo Dahi, MD, MS

Molly Gallogly, MD, PhD

EVENT REGION: New York

CASE SUMMARY

A man aged 48 years had a hematopoietic cell transplant with myeloablative conditioning from a matched unrelated donor for acute myelocytic leukemia (AML) with tacrolimus plus methotrexate as graft-vs-host disease (GVHD) prophylaxis. The donor was a cytomegalovirus (CMV) seropositive woman aged 50 years with 3 children. At day 22 after transplant, acute GVHD of the skin emerged and was successfully treated with slow steroid taper. Bone marrow biopsies performed at 6 and 12 months post transplant show AML in complete remission.

One and a half years post transplant, the patient had new onset skin changes with hyperpigmentation, lichen planus, and superficial sclerotic features (able to pinch the skin) on his lower trunk and lower extremities; 15% body surface area (BSA) was involved.

DISCUSSION QUESTIONS

  • What are the treatment goals for a patient such as this?
  • How often do you prescribe calcineurin inhibition for patients with steroid-sensitive
    chronic GVHD (cGVHD)?

PONCE: When it’s mild cGVHD, consider supportive treatments according to the organ involved, such as topical steroids, eye drops, etc. But if it’s moderate or severe, systemic treatment with steroids is recommended. Moderate is if you have any organs with a score of 2, any lung involvement, 3 or more organs involved, and obviously if you have an organ with a score of 3, which is severe.1 Another option is to add your original immunosuppression, especially if it happened over a taper. Then wait for a response. Let’s say you tapered off tacrolimus, then you get skin involvement. Would you consider resuming tacrolimus?

YARED: Physicians do things differently. Now that we have several available treatments for cGVHD, if the patient has moderate skin involvement I would probably try 0.5 mg/kg of prednisone or methylprednisolone and taper it slowly as a single agent, and, while waiting, see [whether] this will resolve or this will progress, potentially looking at a gentler way to treat GVHD.

We all know tacrolimus and cyclosporine need to be monitored for adverse effects [AEs]. For somebody with moderate skin involvement, such as this patient, it is inconvenient to bring him back every few days to check the tacrolimus level. I would probably go with steroids alone. But this is not a universal practice. I know some of my colleagues restart calcineurin inhibitors.


PONCE: This is always the same debate. If it’s not established, some physicians do resume calcineurin inhibitors. Others don’t, especially if it happened in the setting of a taper. The argument is that a calcineurin inhibitor does decrease all the T-cell populations, including regulatory T cells, so ultimately you might not achieve tolerance if you keep a calcineurin inhibitor on board. It is variable in terms of practice.

What we all agree on is that the patient does require treatment. If you’re in the setting of tapering, you should stop the taper. I have heard some say it is very mild, so we’ll just keep going with the taper and see what happens. Typically, your patient’s [condition] will become more severe, and then the problem will magnify. On that, at least, we all agree. Whether to put them back on a therapeutic dose is very debatable.

If your patient can benefit from supportive care, like PT [physical therapy], OT [occupational therapy], or prophylaxis, especially if you’re starting steroids, those are things to consider as well. Something that we do in our practice is bone health. We try to keep patients with capsule vitamin D3 [cholecalciferol], especially if they’re on steroids, and do weight-bearing exercises because we don’t want the AEs of steroids to catch up to them.


YARED: Deep sclerosis and fibrosis are relatively difficult to reverse. In this case, he has a relatively limited involvement of his skin, and he’s not complaining about it a lot. I would be happy if I stopped treatment here, knowing that full reversal of any sclerotic or fibrotic manifestation is limited.

I would explain to the patient that this is a chronic disease. The fibrosis will not likely disappear. Our goal is to make it go away as much as we can and prevent it from progressing in the same organ or to other organs.


PONCE: That’s very important. Also, for clinical trial overall response rates, when they show the numbers, they include patients who had complete response and partial response. So if your patient improves, we’ll say they’re a success, and many of our patients don’t have complete reversibility but improvement.

If they improve, then they achieved the goal. The goal is first to not progress or get worse, and then the next goal should be for symptoms to get better. But they will not necessarily be completely reversible, particularly if you start treatment when your patient has very advanced cGVHD. It will be difficult for your patient to have complete reversibility, and that’s also part of the conversation when you’re treating that patient.


DISCUSSION QUESTIONS

  • Would you offer this patient topical steroids?
  • What counseling/supportive care would you offer this patient?


PONCE: [Topical steroid use] is something that we can do to enhance a response. Let’s say they have oral GVHD, and you add steroid rinses to their mouth. It could enhance or make that response a bit sooner, on top of the systemic steroids, if your patient has an indication for systemic treatment.

Do your patients go to other specialists, such as a rehabilitative physician [or] endocrinologist, or do you refer them at this time?


PHILLIPS: We tell them to stay out of the sun and keep their skin moist. Many wear gloves with [petrolatum ointment].


PONCE: That is very critical, right? Because they could have flares with sun exposure.


DALLAS: I work…on the pediatric side. We have specialists to whom we refer patients for their symptoms, [including] ophthalmologists. They are good about prescribing drops and making sure [patients’] eyes are healthy. I think dental care is critical. We sometimes forget about that. Gynecological referrals are helpful because some of the genitourinary symptoms are often not addressed. Usually for younger women and adolescents, we refer to…a gynecologist, just for exams.

They’re embarrassed to talk about it with an oncologist, but the gynecologists would send us a note saying, “We see some atrophy.” They also help with management of certain topical steroids, which is helpful. We have a great social support for adolescents and young adults, but nothing in our institution for cGVHD. We do have patients who had severe cGVHD, and they have a support group. If there are any respiratory issues, I always get the pulmonary team involved earlier rather than later, and for gastrointestinal issues as well [we get gastroenterologists] involved.

PONCE: There are not a lot of good support systems, at least on my end, that I know of. I know some patients engage in GVHD Facebook groups. The Leukemia & Lymphoma Society has some groups such as the BMT InfoNet [Blood & Marrow Transplant Information Network]. But some patients don’t identify with those groups, and they do need the social support as well. Also, the caregiver who gets the weight of all the multiple specialists and the multiple visits and seeing their loved one sick [is] another issue that we don’t necessarily pay attention to.


CASE UPDATE

Prednisone was initiated at a dose of 0.5 mg/kg per day, then a 4-week taper. After 7 days of prednisone, there was initial improvement in BSA involvement. The patient received taper; however, increase in BSA involvement from 15% to 20% occurred during the prednisone taper. Two months later, a subsequent taper was attempted unsuccessfully. His symptoms remained stable thereafter on 0.5 mg/kg every other day.

poll

DISCUSSION QUESTION

  • What therapy would you choose for this patient, and why?


DAHI: Ruxolitinib [Jakafi]. It is FDA approved and category 1 on the NCCN [National Comprehensive Cancer Network] guidelines.2


PONCE: One hundred percent of you would choose ruxolitinib. Ibrutinib [Imbruvica] is also an option for second-line treatment. Is there any reason why none of you would consider it?


GALLOGLY: In addition to the published data not being as strong, based on our institutional experience we haven’t seen as much success with ibrutinib compared with ruxolitinib. The AE profile in general tends to be less favorable. With ruxolitinib, we’re mostly concerned about cytopenia and CMV reactivation, and for ibrutinib there are more extensive possibilities. That’s our institutional preference.


YARED: As a disclosure, I am on the ibrutinib paper [for the iNTEGRATE study; NCT02959944] as a coauthor. The data that led to the approval of ibrutinib [are] based on 42 patients. It was a phase 2 study [NCT02195869]. So it has all the caveats that one can imagine. It’s a small population of patients and this was a phase 2 trial compared with the REACH3 trial [NCT03112603], which is a gold standard phase 3 randomized study [of ruxolitinib], with much stronger data that included several hundred patients. It’s not fair, as a scientist or as a clinician, to compare the 2 drugs.

I participated in the clinical trial of combining ibrutinib with corticosteroids, and although this will not be shown clearly in the papers that we just published in the Journal of Clinical Oncology, the combination of ibrutinib and corticosteroids increases the risk of infections, at least in my eyes.3

This was not an easy combination. Last, but not least, you cannot count on one hand the contraindications for ibrutinib, including atrial fibrillation, hypertension, bleeding, etc. For ruxolitinib, other than cytopenia, it’s a relatively well-tolerated drug, if you keep an eye on the CMV reactivation and some of the infections, for which you could put your patient on prophylaxis [From the Data4]. Usually, they cruise without any issues. This is my opinion.


data: REACH3

PONCE: Thank you so much. The toxicity profile plays a role in why we are not using ibrutinib as we did at the very beginning. But now we have more options. Also, the real-world analysis data by…Corey Cutler, MD, MPH, are showing different results from the phase 2 trial,5 and we’re seeing that many of the patients drop off treatment at some point, so the duration of therapy by patients doesn’t seem to be that great, which shows that probably some toxicities are playing a role in why the patients don’t stay on treatment.


DISCUSSION QUESTIONS

  • What are the key factors that drive your decision-making?
  • What if this patient was steroid refractory or intolerant, instead of steroid dependent?
  • What if this patient had mild to moderate cGVHD with multiple organs involved?


PONCE: The ruxolitinib approval was based on a phase 3 randomized, placebo-controlled trial with a larger patient population.4 If the patient was steroid refractory or intolerant, instead of steroid dependent, we would still consider second-line treatment.

If the patient had mild to moderate cGVHD with multiple organs involved, you could add a topical treatment on top of your systemic therapy. Let’s say they had oral GVHD; you can use steroid rinses to improve their oral symptoms that are bothersome. If they had an active skin rash, you could also add a topical steroid to your systemic [therapy] to try to improve their symptoms initially.


REFERENCES

1. Sullivan KM, Witherspoon RP, Storb R, et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood. 1988;72(2):555-561.

2. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation (HCT), version 1.2023. Accessed May 31, 2023. https://bit.ly/3m0dGPh

3. Miklos DB, Abu Zaid M, Cooney JP, et al. Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study. J Clin Oncol. 2023;41(10):1876-1887. doi:10.1200/JCO.22.00509

4. Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122

5. Chin KK, Kim HT, Inyang EA, et al. Ibrutinib in steroid-refractory chronic graft-versus-host disease, a single-center experience. Transplant Cell Ther. 2021;27(12):990.e1-990.e7. doi:10.1016/j.jtct.2021.08.017

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