TY - JOUR
T1 - The MDM2 antagonist idasanutlin in patients with polycythemia vera
T2 - results from a single-arm phase 2 study
AU - Mascarenhas, John
AU - Passamonti, Francesco
AU - Burbury, Kate
AU - El-Galaly, Tarec Christoffer
AU - Gerds, Aaron
AU - Gupta, Vikas
AU - Higgins, Brian
AU - Wonde, Kathrin
AU - Jamois, Candice
AU - Kovic, Bruno
AU - Huw, Ling Yuh
AU - Katakam, Sudhakar
AU - Maffioli, Margherita
AU - Mesa, Ruben
AU - Palmer, Jeanne
AU - Bellini, Marta
AU - Ross, David M.
AU - Vannucchi, Alessandro M.
AU - Yacoub, Abdulraheem
N1 - Publisher Copyright:
© 2022 by The American Society of Hematology.
PY - 2022/2/22
Y1 - 2022/2/22
N2 - 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 5 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n 5 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.
AB - 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 5 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n 5 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.
UR - http://www.scopus.com/inward/record.url?scp=85125326149&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2021006043
DO - 10.1182/bloodadvances.2021006043
M3 - Article
C2 - 34933330
AN - SCOPUS:85125326149
SN - 2473-9529
VL - 6
SP - 1162
EP - 1174
JO - Blood Advances
JF - Blood Advances
IS - 4
ER -