Combination reduces spleen length in intermediate-, high-risk myelofibrosis
Click Here to Manage Email Alerts
The combination of ruxolitinib and pegylated interferon alpha-2a exhibited encouraging activity among patients with myelofibrosis who had not previously received either drug, according to study results presented at ASH Annual Meeting and Exposition.
“We observed high rates of profound decreases not only in spleen length but also in JAK2 V617F alle burden that we have never seen before in patients with overt myelofibrosis,” Jean-Jacques Kiladjian, MD, PhD, consultant hematologist and head of the clinical investigation center at Saint Louis Hospital in Paris, said during a presentation.
Background
Myelofibrosis is characterized by splenomegaly, anemia and bone marrow fibrosis. Patients often experience debilitating symptoms.
Ruxolitinib (Jakafi, Incyte) — an oral Janus kinase (JAK) inhibitor — is standard treatment for myelofibrosis.
The agent has demonstrated efficacy for splenomegaly and alleviating symptom burden. However, it has had little impact on the malignant clone and bone marrow fibrosis, according to study background.
Interferon alpha can reduce fibrosis and mutant allele burden; however, it is poorly tolerated by highly symptomatic patients, researchers wrote.
Methodology
Kiladjian and colleagues conducted the phase 1/phase 2 Ruxopeg trial to evaluate the efficacy and safety of ruxolitinib plus pegylated interferon alpha-2a among patients with myelofibrosis who had not received prior treatment with either agent.
Key inclusion criteria included intermediate- or high-risk disease by International Prognostic Scoring System (IPSS) criteria, need for active therapy and presence of a driver mutation. Researchers excluded patients eligible for stem cell transplantation; those with inadequate liver, cardiac or renal function; those with autoimmune disease; and those with history of depression.
Phase 1 of the multicenter, adaptive randomized trial assessed combinations with various doses of ruxolitinib (10 mg, 15 mg or 20 mg twice daily) and interferon alpha-2a (45 mcg, 90 mcg or 135 mcg per week). Researchers established six cohorts, each with three patients.
Dose-limiting toxicities within 45 days served as the primary tolerance criterion in phase 1.
In phase 2, researchers randomly assigned patients to the two best dose combinations selected from phase 1.
In this phase of the trial, reduction of spleen length by more than 50% by palpation within 24 weeks served as the primary efficacy outcome. Secondary outcomes included OS, EFS, molecular response, quality of life and symptom evolution, and reduction of bone marrow fibrosis.
Researchers completed phase 1 enrollment in November 2018 and phase 2 enrollment in November 2020.
Kiladjian reported data collected after November 2021, when the last patient enrolled had been on the study for 12 months.
The analysis included 37 patients (phase 1, n = 18; phase 2, n = 19; median age, 63.5 years; range, 37-71) treated at six centers. Of those in phase 2, nine received 15 mg ruxolitinib plus 135 mcg pegylated interferon alpha-2a, and 10 received 20 mg ruxolitinib plus 135 mcg pegylated interferon alpha 2-a.
Twenty had intermediate risk-1 disease per IPSS criteria, and 17 had intermediate risk-2 or high-risk disease.
Twenty-one (56.7%) study participants had primary myelofibrosis, and 16 (43.2%) developed myelofibrosis after essential thrombocythemia or polycythemia vera.
At baseline, researchers reported median spleen length of 9 cm (range, 0-20) by palpation and 19.5 cm (range, 10.6-30) by imaging; mean hemoglobin of 12.2 g/dL (range, 7.8-16.2), mean white blood cell count of 12.2 G/L (range, 3.5-36.1) and mean platelet count of 372 G/L (range, 150-1,304).
Patients harbored a mean 3.4 mutations; 21 patients had JAK2V617F mutations, 11 had CALR mutations and four had MPL mutations.
Next-generation sequencing identified 90 additional mutations in 17 genes among 33 patients. These included mutations in high-risk genes such as ASXL1 (n = 21), EZH2 (n = 5), TP53 (n = 5), SRSF2 (n = 2) and IDH1 (n = 1).
Safety outcomes
After 24 weeks, 363 adverse events occurred (grade 1, 59%; grade 2, 33%; grade 3, 7.5%; grade 4, 0.5%). These included six serious adverse events — two skin cancers, two cases of anemia, one urinary infection and one case of Raynaud’s phenomenon. Only 2.5% resulted in treatment interruption, according to investigators.
The most frequent adverse events included anemia (18.7%), thrombocytopenia (13.7%), gastrointestinal events (7%), musculoskeletal events (6.8%) and asthenia (6.6%).
One patient died of acute myeloid leukemia transformation after 10.4 months on study.
Efficacy outcomes
Overall, 70% (95% CI, 53-84) of trial participants achieved the primary efficacy endpoint of at least 50% reduction in spleen length within 24 weeks. Two-thirds (67%) of patients in phase 1 and three-quarters (74%) in phase 2 achieved this efficacy outcome.
The majority (75%; 95% CI, 59-88) of patients achieved this outcome at 12 months, including 67% (95% CI, 41-87) of phase 1 participants and 84% (95% CI, 60-97) of phase 2 participants.
Researchers reported a median 3.5 cm (range, 0-12) decrease in spleen length by palpation at week 24, and this was maintained at 12 months (median, 3 cm; range, 0-12), with 38% of patients exhibiting complete resolution of palpable splenomegaly.
Bone marrow biopsy showed improved cellularity in 57% of evaluable patients, improved megakaryocyte morphology in 25% of evaluable patients and improved fibrosis grade in 5% of evaluable patients.
Investigators observed an 83% response rate among patients assigned 135 mcg/week interferon alpha-2a plus ruxolitinib 15 mg twice daily. In this group, JAK2V617F allele burden declined from a median of 84% at baseline to 65% after 6 months and 56% after 12 months.
Presence of additional mutations in ASXL1 — but not in TET2 or DNMT3A — reduced JAK2 V617F molecular response, Kiladjian said.
Collapse
Kiladjian J-J, et al. Abstract 235. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
Read more about
Click Here to Manage Email Alerts