The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Abstract

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Clinical response in evaluable patients at C3D28, C5D28, week 32, and C11 day 28. (A) Patients with hematocrit (Hct) control. (B) Patients who showed response according to the ELN hematologic response criteria. (C) Patients with CHR (C) or composite response (D). CR, complete remission; PR, partial remission.

Figure 2.

Change in spleen volume by ruxolitinib exposure. (A) Percentage change in spleen volume from baseline at any time in evaluable patients. (B) Percentage change in spleen volume at week 32 in evaluable patients. (C) Percentage change in spleen volume at C3D28, C5D28, and week 32 in each patient evaluable at the assessment points. SVR, spleen volume reduction.

Figure 3.

Patient-reported outcomes per MPN-SAF TSS in evaluable patients. (A) Median change from baseline in MPN-SAF TSS at key assessment time points. (B) Median percentage change from baseline in patient-reported scores at C2D1, C3D28, C5D28, and week 32. Error bars represent IQR. (C) Patients with a ≥50% reduction from baseline MPN-SAF TSS. C2D1, C2 day 1; C11D28, C11 day 28; C12D28, C12 day 28; C14D28, C14 day 28; C17D28, C17 day 28; C20D28, C20 day 28.

Figure 4.

JAK2 allele burden in evaluable patients. (A) JAK2 allele burden at baseline in patients with or without splenomegaly. (B) Percentage change from baseline in JAK2 allele burden in patients with (responders) or without CHR (nonresponders) at C3D28, C5D28, and week 32. (C) Comparison of reduction in JAK2 allele burden between patients with hematocrit control (responders) or without hematocrit control (nonresponders). (D) Comparison of reduction in JAK2 allele burden between patients with CHR (responders) or without CHR (nonresponders). Black stars represent the mean.

Figure 4.

JAK2 allele burden in evaluable patients. (A) JAK2 allele burden at baseline in patients with or without splenomegaly. (B) Percentage change from baseline in JAK2 allele burden in patients with (responders) or without CHR (nonresponders) at C3D28, C5D28, and week 32. (C) Comparison of reduction in JAK2 allele burden between patients with hematocrit control (responders) or without hematocrit control (nonresponders). (D) Comparison of reduction in JAK2 allele burden between patients with CHR (responders) or without CHR (nonresponders). Black stars represent the mean.