Hi, I'm Dr Pashna Munshi and I'm a hematologist and oncologist from MedStar Georgetown University Hospital.

Today, I’d like to discuss how I manage my transplant recipients diagnosed with steroid-refractory acute GVHD and cytopenias.

Regardless of my patients’ baseline blood counts, my top treatment goals for patients with steroid-refractory acute GVHD are getting a complete response and tapering them off steroids.

I don't let cytopenias deter my use of Jakafi in appropriate patients because the disease can progress rapidly and threaten patient outcomes posttransplant, whereas cytopenias during Jakafi therapy may be managed via close monitoring and dose adjustments.

In my practice, I’m comfortable initiating Jakafi in appropriate steroid-refractory acute GVHD patients when platelet counts are at or above 20,000 and as long as patients are not transfusion dependent.

For patients with an initial diagnosis of acute GVHD, I start them on a high dose of 2 mg/kg/day of prednisone and I check that there is no disease progression in 3 to 5 days. Within a week, I expect to see acute GVHD symptoms getting better. If I don’t see a response or if acute GVHD begins to flare when I start tapering steroids, I then have to act quickly by adding a second-line drug because I know that half of the acute GVHD patients will not achieve an adequate response to steroids. And there is no point in waiting when I don’t see response to steroids in 3 days, as the disease can progress to maximum grade in a matter of days.

This is when I turn to Jakafi at the first signs of steroid-refractory acute GVHD in appropriate patients.

Jakafi was approved based on the positive results of the REACH1 trial. REACH1 was a phase 2, single-arm, open-label, multicenter study of Jakafi for the treatment of patients with steroid-refractory acute GVHD.

In REACH 1, majority of patients treated with Jakafi achieved day 28 responses.

Safety results for Jakafi in REACH1 are shown here. The most common hematologic adverse reactions were anemia, thrombocytopenia, and neutropenia. The most common nonhematologic adverse reactions were infections and edema.

It was also studied in REACH2, a randomized, open-label, multicenter, phase 3 study comparing the efficacy and safety of Jakafi with control therapy in patients with steroid-refractory acute GVHD.

Jakafi demonstrated superior overall response at day 28 with a 62.3% overall response rate compared to 39.4% in the control therapy arm. 55% of the day 28 responders achieved a complete response with Jakafi.

Improvement was observed across all grades, with highest overall response and complete response seen in Grade II patients at 75.5% and 50.9%, respectively.

This is regardless of organs involved.

Additionally, 21% of patients in the Jakafi arm were able to discontinue steroids by day 56, compared with 14% in the control therapy arm.

To me, these data clearly support the benefit of intervention with Jakafi at first sign of steroid-refractory acute GVHD to address my treatment goals.

The way I manage Jakafi therapy with cytopenia in mind is by monitoring CBCs closely. After initiation, if platelet counts and ANCs are stable for at least 3 days, I may increase the Jakafi dose to 10 mg twice daily to maximize that therapeutic effect. I then continue to monitor CBCs twice a week.

I want to highlight that with Jakafi we have the flexibility of reducing the dose to allow patient blood labs to recover, while still potentially maintaining control of GVHD symptoms, instead of prematurely withholding the dose or discontinuing Jakafi altogether.

If patients exhibit a downward trend in their blood counts or other signs of cytopenias, I first make sure there are no other confounding factors. I then modify the dose of Jakafi–for patients receiving 10 mg twice daily, I drop that to 5 mg twice daily. For patients on 5 mg twice daily, I reduce it to 5 mg once daily.

Based on the label recommendation, if patients become neutropenic with ANC less than 1, I withhold the dose of Jakafi for up to 2 weeks and resume dosing when counts recover.

Not only does my own experience support this management approach, the clinical data from the REACH trials also supports my confidence in managing cytopenias during Jakafi therapy.

As shown here, in the REACH2 trial, the most common hematological adverse events up to day 28 were thrombocytopenia and anemia.

In addition, clinically meaningful differences in platelet and neutrophil counts were not observed over time between the group taking Jakafi and the control group in REACH2.

Based on these data, I counsel my patients with acute GVHD about cytopenias, letting them know that blood counts may decrease, but we will monitor that closely. By adjusting the Jakafi dose appropriately when necessary, we may be able to manage cytopenias associated with Jakafi.

As mentioned earlier, I prefer to maintain a therapeutic dose of Jakafi in appropriate patients with cytopenias through dose adjustment rather than discontinuing Jakafi use.

Here again, the REACH2 clinical data guide my practice. Adverse events led to treatment discontinuation in 11% of patients on Jakafi and in 5% of patients on control therapies. The percentages of patients who discontinued Jakafi due to each adverse event were 2% for thrombocytopenia, 2% for anemia, 1.3% for pancytopenia, 0.7% for leukopenia, and 0.7% for reduced neutrophil counts.

In summary, I intervene with Jakafi at the first signs of steroid-refractoriness among my patients with acute GVHD. For me, the benefit of treating acute GVHD with Jakafi balances the concerns of cytopenias when following recommended patient management approaches.

Thank you for listening. Let’s take the opportunity to review the safety information for Jakafi.

INDICATIONS AND USAGE

• Jakafi^® (ruxolitinib) is indicated for treatment of acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older.

IMPORTANT SAFETY INFORMATION

• Treatment with Jakafi 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 view Full Prescribing Information for Jakafi.