Resistance to Hydroxyurea Spurs Investigators to Seek Further Treatments in PV

Abdulraheem Yacoub, MD

Hydroxyurea has been the primary treatment for polycythemia vera (PV) for decades and it works for the majority of patients, said Abdulraheem Yacoub, MD. However, there is a subset of patients who develop resistance or intolerance to hydroxyurea, and investigators are working to find a solution for those patients.

Speaking at the 2018 SOHO Annual Meeting, Yacoub, associate professor of Hematology at the University of Kansas Cancer Center, walked his audience through the current modalities for the 30% of patients who develop resistance or intolerance, and touched on some investigational agents that may fulfill this unmet need in the future.

“Those patients have poor outcomes and significant morbidity,” he said. “It would be great to live in a world where we can offer them better options.”

PV, a classical BCR-ABL negative myeloproliferative neoplasm, is associated with clonal myeloid proliferation with erythrocytosis, extramedullary hematopoiesis, and sometimes thrombocytosis and leukocytosis. Hydroxyurea, along with therapeutic phlebotomy, is indicated for first-line treatment of PV, with the goal of achieving a sustained hematocrit of >45%.

Resistance to hydroxyurea can result in failure to reduce splenomegaly by 50% or failure to completely resolve splenomegaly-related symptoms, while intolerance can lead to hematologic toxicity with the minimal dose of hydroxyurea necessary for clinical response and unacceptable non-hematologic toxicity with any dose. Yacoub added that many patients develop both resistance and intolerance.

“Patients with hydroxyurea resistance do have an adverse outcome,” he said. “They manifest a higher risk of transformation to acute leukemia, and a higher risk of mortality altogether.”

Ruxolitinib (Jakafi), approved by the FDA in 2014, and interferons like PEGylated interferon alfa-2a (Pegasys) are the only agents currently approved to treat PV in the second-line setting. PV is associated with an acquired JAK2 mutation leading to activated JAK-STAT pathway and ruxolitinib, a JAK 1 and 2 inhibitor, has demonstrated efficacy in treating PV in results from a pair of phase III clinical trials.

In data from the RESPONSE trial published in 2015 by Vannucchi et al, phlebotomy-dependent patients with splenomegaly were assigned to a starting dose of 10 mg of twice-daily ruxolitinib (n = 110 patients) or physician’s choice of best available therapy (n = 112). Physician’s choice included hydroxyurea (58.9%), interferon (11.6%), anagrelide (7.1%), immunomodulators (4.5%), and pipobroman (1.8%). Six patients received more than 1 standard therapy.¹

The composite primary endpoint was ≥35% reduction in spleen volume at week 32 as assessed by means of imaging and hematocrit control through week 32.

Twenty-one percent of the patients in the ruxolitinib group achieved the primary endpoint versus 1% in the standard-therapy group (P<.001). Both hematocrit control (60% vs 20%) and percentage of patients who had &ge;35% reduction in spleen volume (38% vs 1%) were superior in the ruxolitinib group.

Twenty-four percent of patients in the ruxolitinib arm had a complete hematologic remission compared with 9% of those assigned to physician&rsquo;s choice (P= .003). In the ruxolitinib arm, 49% had &ge;50% reduction in the total symptom score at week 32 versus 5% in the physician&rsquo;s choice arm.

In the follow-up RESPONSE-2 trial, 74 patients were randomly assigned to ruxolitinib and 75 to best available therapy including hydroxyurea (49%), no treatment (28%), interferon or PEGylated interferon (13%), pipobroman (7%), lenalidomide (1%), or other (1%). Hematocrit control by week 28 was the primary endpoint.²

Sixty-two percent of patients in the ruxolitinib arm achieved the primary endpoint versus 19% in the best available therapy group (odds ratio [OR], 7.28; 95% CI 3.43-15.45;P<.0001).

Twenty-three percent of patients in the ruxolitinib arm achieved the key secondary endpoint of complete hematological remission compared with 5% in the best available therapy group (OR, 5.58; 95% CI; 1.73-17.99;P= .0019).

&ldquo;Ruxolitinib was associated with other benefits, including splenic reduction, splenic symptom improvement, improvement in general symptoms and quality of life, as well as more favorable iron metabolism to avoid iron deficiency associated with phlebotomy,&rdquo; he said.

However, responses were durable but short. Furthermore, treatment with ruxolitinib did not prevent transformation to myelofibrosis (MF) and acute myeloid leukemia (AML).

&ldquo;This therapy does not necessarily change the outcome of the disease,&rdquo; said Yacoub. &ldquo;You still have patients who will go through the natural evolution and transform to high-risk disease.&rdquo;

Physicians have used interferons to treat myeloproliferative neoplasms for more than 50 years. Yacoub said that these agents have shown promise as a first-line option, especially for young patients who will live with treatment longer and who may want to avoid some of the long-term adverse effects associated with hydroxyurea and/or want to preserve fertility. PEGylated interferons, in particular, have demonstrated the ability to induce clinical and molecular responses in patients with PV, both following hydroxyurea therapy and in first-line.

In results from the MPD-RC 111 study presented by Yacoub at the 2017 ASH Annual Meeting, 60% of patients treated with PV achieved objective responses to PEGylated interferon alfa-2a at 12 months, including a complete response rate of 22%.³

Patients with PV in the study (n = 50) were intolerant to hydroxyurea or had developed resistance. The study included patients with any disease duration and with high-risk features, such as older age, history of thrombosis, erythromelalgia/migraine, significant or symptomatic splenomegaly, elevated platelet count, and diabetes or hypertension.

Yacoub noted that there was a high rate of grade 3 adverse events (34.2%), but the discontinuation rate of 13.9% suggests that those events can be managed.

If ruxolitinib and PEGylated interferon represent the current modality of MPN treatment, Yacoub said MDM2 may represent the future.

&ldquo;There is a lot of research going in PV to raise the bar higher and achieve better results, including harvesting what we know about PV physiology,&rdquo; he said. &ldquo;Among the more promising molecules are the MDM2 inhibitors, which are drugs that suppress the MDM2 binding to p53. This results in activation of p53, leading to rapid apoptosis in PV.

Yacoub said that the MDM2 protein regulates p53, a pro-apoptotic protein and a powerful inhibitor of proliferation, through a negative feedback loop. In patients with PV, JAK2 activation results in upregulation of MDM2. Idasanutlin, an investigational Nutlin-family MDM2 antagonist, is currently under investigation in phase II studies.

References:

1. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera.N Engl J Med. 2015; 372(5):426-435. doi: 10.1056/NEJMoa1409002.
2. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study.Lancet Oncol. 2017;18(1):88-99. doi: 10.1016/S1470-2045(16)30558-7.
3. Yacoub A, Mascarenhas J, Kosiorek HE, et al. Single-arm salvage therapy with pegylated interferon alfa-2a for patients with high-risk polycythemia vera or high-risk essential thrombocythemia who are either hydroxyurea-resistant or intolerant: final results of the myeloproliferative disorders-research consortium (MPD-RC) protocol 111 global phase II trial. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 321.

&ldquo;The clinical experience has been that these drugs are very effective and if we can tweak the dosing correctly, we can shift the paradigm in terms of PV treatment,&rdquo; Yacoub added. &ldquo;We&rsquo;re all looking forward to the results of those studies once they&rsquo;re made available because we have high expectations for this molecule.&rdquo;