More Hematologic Responses Seen With Interferon-Alpha Than Hydroxyurea in MPN Comparison

April 16, 2019
Audrey Sternberg

In an analysis comparing real-life outcomes, interferon-a demonstrated more profound hematologic responses compared with hydroxyurea in select patients with myeloproliferative neoplasms. Additionally, molecular responses to therapy were limited to those patients who received IFN-a.

In an analysis comparing real-life outcomes, interferon (IFN)-a demonstrated more profound hematologic responses compared with hydroxyurea (HU) in select patients with myeloproliferative neoplasms (MPNs). Additionally, molecular responses to therapy were limited to those patients who received IFN-a.

“Unlike HU, IFN-a was able to induce molecular responses,” said study investigators led by Patrizia Mondello, MD, PhD, MSc, a research associate in the Department of Medicine at Weill Cornell Medicine in New York, New York. “The observation that IFN-a therapy leads to durable molecular remission in a reproducible manner across various studies indicates that IFN-a might be a disease-modifying drug,” they wrote in their report.

Both HU and IFN-a are used in the treatment of patients with Philadelphia chromosome—negative (Ph-) MPNs, including polycythemia vera (PV) and essential thrombocytosis (ET); however, HU is the standard-of-care cytoreductive drug. The penchant for clinicians to treat most patients with HU stems from a lack of comparative trials for the 2 drugs and a higher frequency of adverse events (AEs) observed with IFN-a.

Although HU is usually well tolerated, data suggest that it could favor the transformation into acute leukemic disease.2 In IFN-a, past studies showing positive efficacy were single-arm trials without a comparator.3,4

Investigators on the study compared the available therapies in patients with PV (n = 28), of which 15 (54%) were treated with IFN-a versus 13 with HU (46%), or ET (n = 35), with 20 patients (57%) and 15 patients (43%) getting IFN-a and HU, respectively.

IFN-a was administered at 3 MU subcutaneously 3 times a week. Induction therapy with HU was given at 15 to 20 mg/kg daily until complete hematologic remission was achieved or the development of AEs and was followed by maintenance therapy at 10 to 15 mg/kg daily.

Efficacy was assessed by hematologic response, molecular response by the JAK2 V617F allele burden, overall survival (OS), progression-free survival (PFS), and safety.

The JAK2 V617F mutation was present in 26 of the patients with PV (93%) and 18 of the patients with ET (51%). The 2 remaining patients with PV harbored a JAK2 exon 12 mutation and 2 patients with ET (6%) had MPL mutations. Patients with BCR/ABL translocations were excluded from the cohort.

At the median follow-up of 121 months, 97% of patients in the IFN-a arm achieved a hematologic response with 60% having a complete hematologic response (CHR), compared with 78% and 56% of patients taking HU, respectively (P <.01). A CHR was defined as hematocrit lower than 45%, platelet counts below 400 × 109 L, and a normalization of spleen volume from baseline at week 32.

A partial hematologic response (PHR) occurred in patients who saw a reduction in the number of phlebotomies by ≥50% or ≥35% in spleen size. PHR was seen in 37% of patients on IFN-a and in 20% of those taking HU.

The median time to CHR with IFN-a was 20 weeks (range, 12-60); initial control of hematocrit and platelet count occurred within 12 weeks with HU.

The overall molecular response rate with IFN-a was 60% in both patients with PV and ET. The JAK2 V617F mutation was undetectable after treatment in 3 patients (20%) with PV and 2 (10%) with ET; this was consistent with achievement of a complete molecular response (CMR). No patient with a CMR was observed to have hematologic or molecular relapse after a median follow-up of 92 months.

Adding to that, 33% and 20% of patients with PV and ET achieved a partial molecular response (PMR), respectively, or ≥50% reduction in JAK2 V617F allele burden for patients with ≥20% allele burden at baseline. Among these patients with PV, 2 each (22%) either remained in PMR or displayed minor molecular remission and 5 (56%) lost their response.

Conventional cytogenetics were also assessed at baseline. Patients with cytogenetic abnormalities were followed for response or clonal evolution every 6 months and those patients with normal cytogenetics were re-evaluated for cytogenetic evolution once per year. In the IFN-a arm, 1 out of 6 patients had resolution of cytogenetic abnormalities during the study and no patients with normal baseline cytogenetics were observed to have new abnormalities. With HU, none of the 4 patients with baseline abnormalities had resolution of their abnormalities and 2 more patients developed them over the course of treatment. These findings suggest HU is unable to prevent leukemogenesis, according to the study investigators.

Survival data also favored IFN-a with a median OS of 7.8 years versus 5.8 years with HU (P = .006). The median PFS was 5.0 versus 3.1 years in the IFN-a and HU groups, respectively (P <.001). Mondello et al hypothesized the superiority in survival with IFN-a may be attributed to a decrease in tumor burden and achievement of molecular remission.

There were no grade 3/4 toxicities experienced with IFN-a in the study cohort and no treatment interruptions were necessary. Grade 1/2 AEs with IFN-a consisted of neutropenia in 11% and infection, diarrhea, depression, and elevated liver function in 3% each.

Conversely, HU resulted in severe thrombocytopenia in 4 patients during induction, which was resolved after dose interruption. Two cases of acute leukemia and 1 myelodysplastic syndrome arose in patients treated with HU. However, Mondello et al said the rate of leukemia could also be attributed to the natural progression of the disease and not the HU itself since long-term study data have not confirmed an increased rate of leukemic transformation with the drug.

No secondary malignancies were observed in patients randomized to IFN-a. Mondello et al said the data suggest IFN-a reduces the risk of disease evolution by inducing molecular remission but future studies are needed to clarify this hypothesis.

Vascular complications were higher with HU treatment, with 8 patients (29%) developing nonfatal serious vascular thrombotic events compared with 3 patients (9%) in the IFN-a arm (P = .002).

Notably, study investigators pointed out that JAK2 inhibitors, such as ruxolitinib (Jakafi), were unavailable at the time of trial design and all patients with PV and ET received 1 of the 2 therapies that were compared in the trial.

References:

  1. Mondello P, Di Mirto D, Cuzzocrea S, Arrigo C, Mian M, Pitini MV. Interferon alpha has strong anti-tumor effect in Philadelphia-negative myeloproliferative neoplasms [published online April 1, 2019].Clin Lymphoma Myeloma Leuk. doi: 10.1016/j.clml.2019.03.027.
  2. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea threapy in polycythemia vera and allied disorders: prospective study of efficacy and leukemogenicity with therapeutic implications.Eur J Haematol. 1994;52(3):134-139. doi: 10.1111/j.1600-0609.1994.tb01303.x.
  3. Kiladjian J-J, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera.Blood.2008;112(8):3065-3072. doi: 10.1182/blood-2008-03-143537.
  4. Quint&aacute;s-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.J Clin Oncol.2009;27(32):5418-542 doi: 10.1200/JCO.2009.23.6075.