Although proactive care is at the forefront of every practice, it could not be more important than in the treatment of patients with chronic graft-versus-host disease (GVHD). When those patients become refractory to steroids, it is critical to consider second-line treatment early. “It is important to consider these agents sooner rather than later to treat steroid-refractory chronic GVHD,” said Betty Ky Hamilton, M.D., associate director, blood and marrow transplant program, Cleveland Clinic. “Early action can help address further disease progression, which may be harder to treat over time, or in some cases, become irreversible.”
Patients with certain types of cancers, such as acute or chronic leukemia, may need an allogeneic bone marrow transplant, and GVHD can be a common complication. In severe GVHD cases it can be a life-threatening complication. GVHD occurs when donor immune cells attack the recipient's organs and tissues after an allogeneic stem cell transplantation.1,2 GVHD occurring within the first 100 days following transplantation is typically considered acute. Chronic GVHD typically occurs 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 nonrelapse mortality in recipients of allogeneic hematopoietic stem cell transplantation.3 The risk of developing GVHD is often mitigated by ensuring correct human leukocyte antigen matching between the host and donor, although various factors including the use of peripheral blood stem cells, donor age, recipient age and pregnancy may increase the likelihood of the onset of GVHD. GVHD and its treatment may result in several complications including 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 testing of liver function and pulmonary function, or by biopsy of affected organ.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 crucial, because this chronic disease may continue to result in disease progression, further tissue damage or risk of comorbidities.5 “The most optimal outcomes for chronic GVHD typically come with early identification of symptoms and swift intervention with a personalized treatment plan. Those at greater risk for complications, including people who don’t tolerate steroids well and those with more severe forms of GVHD, may benefit more from earlier introduction to second-line treatment,” said Dr. Hamilton.
First-line treatment for chronic GVHD often includes systemic therapies such as oral immunosuppression with corticosteroids, most commonly prednisone.1 If this is unsuccessful, there are other, more advanced options available. “Approximately 50% of people who develop chronic GVHD become refractory, or nonresponsive, to traditional steroid therapy. Determining steroid-refractoriness may be made as early as one to two weeks following corticosteroid first-line therapy, if the disease continues to progress.3 The potentially progressive nature of this disease and the supporting safety and efficacy data underscore the importance of early intervention with a second-line solution,” said Dr. Hamilton.
Jakafi for Adult and Pediatric Patients 12 Years and Older with Chronic GVHD
Jakafi® (ruxolitinib) tablets (5mg, 10mg, 15mg, 20mg, 25mg) 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 randomized, open-label, multicenter, phase 3 study of Jakafi versus best available therapy (BAT)I, in patients with steroid-refractory chronic GVHD (N=329) after allogenic stem cell transplantation. The starting dose for Jakafi was 10 mg BID. Crossover from BAT to Jakafi was permitted on or after week 24 if patients progressed, had a mixed or unchanged response, developed toxicity to BAT, or experienced a cGVHD flare.7 The primary endpoint of overall response rate (ORR) at Week 24 (i.e., Cycle 7 Day 1) was 49.7% (82/165) for Jakafi compared to 25.6% (42/164) 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 (OR, 2.99 [95% CI: 1.86, 4.80]; P<0.0001). Furthermore, the ORR through Cycle 7 Day 1 was 70% (116/175) for Jakafi compared to 57% (94/164) for BAT.8
The most common adverse events of grade 3 or higher were thrombocytopenia (in 15.2% of patients who received ruxolitinib and 10.1% of patients who received control therapy), anemia (in 12.7% and 7.6%), neutropenia (in 8.5% and 3.8%), and pneumonia (in 8.5% and 9.5%). Serious adverse events up to week 24 occurred in 55 patients (33.3%) who received ruxolitinib and in 58 patients (36.7%) who received control therapy. Viral infections were the most common (33.9% and 29.1% in the ruxolitinib and control groups, respectively), followed by bacterial (27.9% and 25.9%) and fungal infections (11.5% and 5.7%); infections of unknown type occurred in 21.2% of patients who received ruxolitinib and in 20.3% of patients who received control therapy. Cytomegalovirus infection and reactivation were similar in the two groups (5.5% and 8.2%). Adverse events led to treatment discontinuation in 27 patients (16.4%) who received ruxolitinib and in 11 (7.0%) who received control therapy.7
It’s important to intervene at the earliest signs of systemic therapy failure, which commonly manifests with increased severity and occurrence 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 stageII (59.5%) (47/79) versus the severe stageIII (40.7%) (35/86), and response rates were consistently higher with Jakafi versus BAT at (32.5%; 26/80) versus (19.0%; 16/84), respectively.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. Hamilton.
To learn more about Jakafi, visit hcp.Jakafi.com.
Please see Important Safety Information below and click here for Full Prescribing Information for Jakafi.
About Jakafi® (ruxolitinib)
Indications and Usage
Jakafi is indicated for treatment of chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.
Jakafi is indicated for treatment of steroid-refractory acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older.
Jakafi is indicated for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.
Jakafi is indicated for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults.
The recommended starting dose is 10 mg twice a day. Evaluate blood parameters before and during treatment with Jakafi. Dose reductions should be considered based on platelet counts, absolute neutrophil counts or bilirubin elevations, or other adverse reactions as described in the Full Prescribing Information. Doses may be modified based on safety and efficacy. Dose reductions may be used to manage side effects: 10 mg twice daily may be reduced to 5 mg twice daily; 5 mg twice daily may be reduced to 5 mg once daily. Patients who are unable to tolerate Jakafi at 5 mg once daily should have treatment interrupted until their clinical and/or laboratory parameters recover. Tapering may be considered after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper Jakafi by 1 dose level approximately every 8 weeks (10 mg BID to 5 mg BID to 5 mg QD). If GVHD signs or symptoms recur during or after the taper of Jakafi, consider retreatment.
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.
I BAT was chosen by the investigator prior to randomization, options included: ibrutinib, extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, rituximab, everolimus, sirolimus, imatinib, infliximab, or pentostatin
II Moderate cGVHD was defined as ≥1 organ (not lung) with a score of 2, ≥3 organs with a score of 1 in each organ, or lung score of 1.
III Severe cGVHD was defined as ≥1 organ with a score of 3 or lung score of 2 or 3.
Important Safety Information
Treatment with Jakafi® (ruxolitinib) can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.
Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary.
Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi.
Severe neutropenia (ANC <0.5 × 109/L) was generally reversible by withholding Jakafi until recovery.
Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.
Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination.
Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate.
Herpes zoster infection has been reported in patients receiving Jakafi. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment. Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving Jakafi. Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with Jakafi; patients should be promptly treated and monitored according to clinical guidelines.
Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines.
When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation.
Non-melanoma skin cancers (NMSC) including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations.
Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.
Another JAK-inhibitor has increased the risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (compared to those treated with tumor TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.
Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. In patients with myelofibrosis (MF) and polycythemia vera (PV) treated with Jakafi in clinical trials, the rates of thromboembolic events were similar in Jakafi and control treated patients. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.
In myelofibrosis and polycythemia vera, the most common nonhematologic adverse reactions (incidence ≥15%) were bruising, dizziness, headache, and diarrhea. In acute graft-versus-host disease, the most common nonhematologic adverse reactions (incidence >50%) were infections (pathogen not specified) and edema. In chronic graft-versus-host disease, the most common nonhematologic adverse reactions (incidence >20%) were infections (pathogen not specified) and viral infections.
Avoid concomitant use with fluconazole doses greater than 200 mg. Dose modifications may be required when administering Jakafi with fluconazole doses of 200 mg or less, or with strong CYP3A4 inhibitors, or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy.
Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breastfeed during treatment 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.
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