The Importance of Early Recognition and Intervention of Chronic GVHD

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While proactive patient care is at the forefront of every practice, it could not be more important in the treatment of chronic graft-versus-host disease (GVHD). When a patient becomes steroid-refractory, a critical window to initiate second-line treatment begins to close. “You have one good shot at treating steroid-refractory GVHD,” said Navneet Majhail, MD, MS, FASTCT Deputy Physician-in-Chief of Blood Cancers, Sarah Cannon and Director of Sarah Cannon Transplant and Cellular Therapy Program at Centennial Medical Center, Nashville, TN. “Once the disease has developed in a patient, it becomes harder to combat the symptoms.”

GVHD is a life-threatening condition that occurs when donor immune cells attack the recipient's organs and tissues after an allogeneic stem cell transplantation.1 GVHD is particularly a concern for people with cancer who may need to receive stem cell or allogeneic bone marrow transplantation, such as those with acute or chronic leukemia and multiple myeloma.2 GVHD occurring within the first 100 days following transplantation is considered acute, while delayed onset months after transplantation is considered chronic, typically diagnosed after presentation of symptoms 100 or more days after transplantation, although a syndrome of late acute GVHD is also recognized.1

Chronic GVHD is the primary cause of late non-relapse mortality in recipients of allogeneic hematopoietic stem cell transplantation.3 The risk of developing GVHD is often mitigated by ensuring correct human leukocyte antigen (HLA) matching between the host and donor, although various factors including donor age, recipient age and pregnancy may increase the likelihood of the onset of GVHD. GVHD may result in complications for ongoing cancer treatment in addition to damage to tissues such as the skin, eyes, oral cavity, lungs, liver, muscle, or connective tissue.2

Diagnosis and Treatment of Chronic GVHD

Chronic GVHD can be diagnosed through clinical evaluation of symptoms, which are distinct from the acute disease but often requires confirmation by testing liver function, immunoglobulin levels, pulmonary function or by performing a complete blood count with differential.4 Chronic GVHD often presents with vision changes, dry eyes, skin changes such as rash, lichen planus or sclerodermatous changes, muscle weakness, fatigue, difficulty swallowing, dry mouth or shortness of breath. New signs and symptoms seen in the year following transplantation should be evaluated as potential chronic GVHD.5

Early identification of chronic GVHD is critical, as it is possible this chronic disease is an extension of acute GVHD and may continue to result in rapid disease progression, further tissue damage or risk of comorbidities.5 “The most optimal outcomes for chronic GVHD typically come with early treatment prescribed to patients, monitoring overall progress and making the decision to switch to second line therapies when needed as early as possible,” stated Dr. Majhail.

First-line treatment for chronic GVHD often includes systemic thearpies such as oral immunosuppression with corticosteroids, most commonly prednisone.1 If this is unsuccessful, there are other, more advanced options available. Dr. Majhail stated, “Approximately 50% of people who develop chronic GVHD become refractory, or non-responsive, to traditional steroid therapy. This call can be made as early as one week following first line treatment, as the disease will continue to progress.3 The fast-paced nature of this disease ultimately underscores the importance of having a second-line solution in the treatment toolkit.”

Jakafi for Adult and Pediatric Patients 12 Years and Older with Chronic GVHD

Jakafi® (ruxolitinib) is an effective treatment for chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.6 Jakafi is a janus kinase (JAK) inhibitor that blocks JAK1 and JAK2. JAKs regulate signaling that drives immune responses and increases production of blood cells in the bone marrow. By disrupting this signaling cascade, Jakafi can downregulate the immune response mobilized against the patient’s transplantation or graft.6

Jakafi was approved by the U.S. Food and Drug Administration (FDA) in 2021 to treat chronic GVHD based on data from the REACH3 study, a Phase 3, randomized, open-label, multicenter study of Jakafi in comparison to best available therapy (BAT) for the treatment of steroid-refractory chronic GVHD after allogeneic stem cell transplantation.7 The primary endpoint of overall response rate (ORR) at Week 24 (i.e., Cycle 7 Day 1) was 49.7% for Jakafi compared to 25.6% for BAT (P<0.0001). Patients treated with Jakafi were three times more likely to achieve an overall response at Week 24 compared with those treated with BAT (ORR, 2.99). Furthermore, the ORR through Cycle 7 Day 1 was 70% for Jakafi compared to 57% for BAT.7 The most common hematologic adverse reactions (incidence >35%) were anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥20%) were infections (pathogen not specified) and viral infection.7

It’s important to intervene at the earliest signs of systemic therapy failure, which commonly manifests with increased severity and occurance of symptoms with no signs of improvement, within weeks of administration of systemic therapy. In a subgroup analysis of the REACH3 data, patients were more likely to respond to Jakafi when intervention was initiated at the moderate stage (59.5%) versus the severe stage (40.7%), and response rates were consistently higher with Jakafi versus BAT.7

“Jakafi is a valuable tool for physicians to have in their chronic GVHD toolkit, as many patients are steroid-refractory and face significantly higher mortality rates than those who respond to steroid therapy,” said Dr. Majhail. “By definition, chronic GVHD is a long race—while starting treatment early gives you a leg up, the ability to adapt to each hurdle, and keep up the fight, makes all the difference.”

To learn more about Jakafi, visit https://hcp.jakafi.com/chronic-graft-versus-host-disease.


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

About Jakafi® (ruxolitinib)

Jakafi is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

Jakafi is also indicated for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea, intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults, and for treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older.2

Jakafi is marketed by Incyte in the U.S. and by Novartis as Jakavi® (ruxolitinib) outside the U.S. Jakafi is a registered trademark of Incyte. Jakavi is a registered trademark of Novartis AG in countries outside the U.S.

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Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi® (ruxolitinib) may cause low platelet, red blood cell, and white blood cell counts. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will do a blood test to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Cancer: Some people have had certain types of non-melanoma skin cancers during treatment with Jakafi. Your healthcare provider will regularly check your skin during your treatment with Jakafi. Tell your healthcare provider if you develop any new or changing skin lesions during treatment with Jakafi.

Increases in cholesterol: You may have changes in your blood cholesterol levels during treatment with Jakafi. Your healthcare provider will do blood tests to check your cholesterol levels about every 8 to 12 weeks after you start taking Jakafi, and as needed.

Increased risk of major cardiovascular events such as heart attack, stroke or death in people who have cardiovascular risk factors and who are current or past smokers while using another JAK inhibitor to treat rheumatoid arthritis: Get emergency help right away if you have any symptoms of a heart attack or stroke while taking Jakafi, including: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back, severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw, pain or discomfort in your arms, back, neck, jaw, or stomach, shortness of breath with or without chest discomfort, breaking out in a cold sweat, nausea or vomiting, feeling lightheaded, weakness in one part or on one side of your body, slurred speech.

Increased risk of blood clots: Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, (PE) have happened in people taking another JAK inhibitor for rheumatoid arthritis and may be life-threatening. Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with Jakafi, including: swelling, pain, or tenderness in one or both legs, sudden, unexplained chest or upper back pain, shortness of breath or difficulty breathing.

Possible increased risk of new (secondary) cancers: People who take another JAK inhibitor for rheumatoid arthritis have an increased risk of new (secondary) cancers, including lymphoma and other cancers. People who smoke or who smoked in the past have an added risk of new cancers.

The most common side effects of Jakafi include: for certain types of MF and PV – low platelet or red blood cell counts, bruising, dizziness, headache, and diarrhea; for acute GVHD – low platelet counts, low red or white blood cell counts, infections, and swelling; and for chronic GVHD – low red blood cell or platelet counts and infections including viral infections.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Call your doctor for medical advice about side effects.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had low white or red blood cell counts, have or had tuberculosis (TB) or have been in close contact with someone who has TB, had shingles (herpes zoster), have or had hepatitis B, have or had liver or kidney problems, are on dialysis, have high cholesterol or triglycerides, had cancer, are a current or past smoker, had a blood clot, heart attack, other heart problems or stroke, or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change your dose or stop taking Jakafi without first talking to your healthcare provider.

Women should not take Jakafi while pregnant or planning to become pregnant. Do not breastfeed during treatment with Jakafi and for 2 weeks after the final dose.

Please see the Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

You may also report side effects to Incyte Medical Information at 1-855-463-3463.

Incyte and the Incyte logo are registered trademarks of Incyte.

© 2022, Incyte. MAT-Jak-04051 08/22

References

  1. Graft versus host disease (GVHD): What it is, symptoms, treatment. Cleveland Clinic. (n.d.). Retrieved June 7, 2022, from https://my.clevelandclinic.org/health/diseases/10255-graft-vs-host-disease-an-overview-in-bone-marrow-transplant
  2. Flowers, M. E., Inamoto, Y., Carpenter, P. A., Lee, S. J., Kiem, H. P., Petersdorf, E. W., Pereira, S. E., Nash, R. A., Mielcarek, M., Fero, M. L., Warren, E. H., Sanders, J. E., Storb, R. F., Appelbaum, F. R., Storer, B. E., & Martin, P. J. (2011). Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood117(11), 3214–3219. https://doi.org/10.1182/blood-2010-08-302109
  3. MacDonald KPA, Betts BC, Couriel D. Emerging therapeutics for the control of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(1):19-26.
  4. Lee S. J. (2017). Classification systems for chronic graft-versus-host disease. Blood129(1), 30–37. https://doi.org/10.1182/blood-2016-07-686642
  5. Incyte Corporation. (n.d.). Potential for Rapid Disease Progression Makes Early Identification Critical. Retrieved June 7, 2022, from https://hcp.jakafi.com/graft-versus-host-disease/steroid-refractory-gvhd-patient-id
  6. Martini, D. J., Chen, Y. B., & DeFilipp, Z. (2022). Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease. The oncologist, oyac076. Advance online publication. https://doi.org/10.1093/oncolo/oyac076
  7. Zeiser, R., Polverelli, N., Ram, R., Hashmi, S. K., Chakraverty, R., Middeke, J. M., Musso, M., Giebel, S., Uzay, A., Langmuir, P., Hollaender, N., Gowda, M., Stefanelli, T., Lee, S. J., Teshima, T., Locatelli, F., & REACH3 Investigators (2021). Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med385(3), 228–238. https://doi.org/10.1056/NEJMoa2033122