FROM THE LANCET HAEMATOLOGY

Pegylated interferon alfa-2a can induce durable hematologic and molecular responses in patients with advanced essential thrombocythemia and polycythemia vera, according to a post hoc analysis of data from a prospective, open-label, phase II trial.

Of 83 patients treated with pegylated interferon alfa-2a, 66 (80%) experienced hematological response, and of 55 of the 83 who were positive for the JAK2 Val617 mutation and who were evaluable for a molecular response, 35 (64%) experienced molecular response. The median response durations were 66 months and 53 months, respectively, wrote Lucia Masarova, MD, and her colleagues at MD Anderson Cancer Center, Houston.

Of the 66 hematological responders, 26 (39%) maintained some response during a median follow-up of 83 months. Among the 40 who lost their response, 19 had dose reductions or had the drug withheld because of intolerance or toxicity, 1 developed concurrent diffuse large B-cell lymphoma, and 20 progressed despite treatment with the highest tolerable dose of pegylated interferon alfa-2a. Of note, 7 (28%) of 25 patients who were treated for at least 46 months (median of 77 months) sustained their hematologic response for a median of 6 months after discontinuation of therapy, the investigators said ( Lancet Haematol. 2017 Apr;4:e165-75 ).

Of the 35 molecular responders, 25 (71%) maintained some response during follow-up. Of the nine evaluable patients who did not maintain response (the 10th patient was taken off the study because of concurrent non-Hodgkin lymphoma) four lost response at a median of 2 years after the drug was withheld, and five lost response while on therapy. Three maintained their complete molecular remission – for 18, 55, and 79 months – after discontinuation of therapy.

“Only one patient who achieved a complete molecular remission has relapsed after stopping therapy for 16 months (complete molecular remission duration, 66 months). The other 9 of 10 patients had durable remissions (median duration 69 months),” the investigators wrote, noting that among the 20 patients with a partial molecular remission, 5 (25%) sustained best partial remission, 7 (28%) are in minor molecular remission, 8 (32%) lost their response, and 3 of 5 (60%) with minor molecular remission sustained that remission.

The study comprised adults over age 18 years who were diagnosed with essential thrombocythemia (40 patients) or polycythemia vera (43) and were enrolled during May 2005 to October 2009. Of the 83 patients, 52 (63%) had received some form of therapy prior to enrollment, including 14 who were treated with standard interferon alfa-2a and 1 who was treated with pegylated interferon alfa-2a. The initial starting dose of pegylated interferon alfa-2a used in the study was 450 mcg delivered subcutaneously once each week, but the dose was decreased in a stepwise manner to a final starting dose of 90 mcg per week due to toxicity; starting doses include 450 mcg in 3 patients, 360 mcg in 3 patients, 270 mcg in 19 patients, 180 mcg in 26 patients, and 90 mcg in 32 patients). Treatment continued as long as clinical benefit continued, and hematological responses were assessed every 3-6 months.

Treatment-related toxicities decreased over time, but five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy; overall 18 patients (22%) discontinued treatment due to toxicity.

The therapeutic approach to essential thrombocythemia and polycythemia vera has mainly focused on control of blood counts and reduction of the risk of thrombosis. Those at high risk for thrombosis generally undergo cytoreductive therapy with hydroxyurea. Recombinant interferon alfa is an alternative to hydroxyurea “given its biological, anti-proliferative, immunomodulating, and anticlonal effects,” the investigators explained.

“However, the widespread use of this biological drug has been limited by high rates of discontinuation due to side effects. Pegylated forms of interferon have a better pharmacological profile than short-acting interferons: they require less frequent injection, lower immunogenicity, and possibly fewer toxic effects,” they said.

Although pegylated interferon-alfa 2a has shown promise in several trials, most had short follow-up. The nearly 7 years of follow-up in the current trial is almost twice as long as in those prior studies.

During the current study, including follow-up, eight major vascular thromboembolic events occurred. One was associated with heart catheterization, one with elective chest surgery, and one with an angiogram. The remaining five occurred with no discernible cause after a median of 38 months of therapy for an incidence of 1.22 unprovoked vascular thromboembolic events per 100 person-years, and three of those were in patients with complete hematologic response. Two of the five patients were under age 60 years and had no history of thrombosis. Another patient had a serious unprovoked cerebrovascular hemorrhage after 3 years on therapy and while in complete hematological response.

In addition, 7 of the 83 patients in the study had disease progression on therapy; 6 progressed to myelofibrosis, and 1 developed acute myeloid leukemia. The median time to transformation in these patients was 40 months.

At the time of publication, 32 patient remained in the study and 24 were receiving treatment. Nineteen were in hematologic response at last follow-up, and most (75%) were on a dose of 90 mcg or less per week.

In addition to showing that some patients achieve durable responses on pegylated interferon alfa-2a, this study provided five important observations, the investigators said: 1) Patients might continue to derive clinical benefit from pegylated interferon alfa-2a even after losing response. 2) Only complete molecular remissions are durable, and some cases can be sustained after therapy discontinuation. 3) Clinical activity of pegylated interferon alfa-2a is not correlated with JAK2 mutation status. 4) Toxic effects unrelated to dose may develop and can be treatment-limiting, even after a long exposure to the drug. 5) Disease-related vascular complications or progression to myelofibrosis can still occur in patients on therapy.

“Our findings suggest that pegylated interferon alfa-2a is a viable treatment option, especially for young patients who want to avoid prolonged cytotoxic therapy. Lower doses minimize side effects while retaining efficacy,” they wrote, suggesting – based on these and other results – a starting dose of 45 mcg weekly to limit adverse events and maximize response.

They also noted that treated patients with a history of autoimmune disease and those with mood disorder should be monitored closely for side effects.

Future studies on pegylated interferon afla-2a alone or in combination with novel immunomodulatory drugs are needed to identify patients who would benefit most from treatment, and additional objective response criteria, such as measurement of spleen size, bone marrow histology, and quality of life should be used to better assess clinical benefit, they said.

The National Cancer Institute funded the study. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

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