Plinabulin Rapidly (within 24 Hours) Reverses Myelosuppression Induced By Chemotherapy
Authors: Blayney Douglas W. , Chang Mengru , Huang Lan , Mohanlal Ramon 
Published: November 2021

Abstract

Introduction
Plinabulin (Plin), a small molecule selective immune-enhancing microtubulin binding agent (SIMBA) has anti-cancer activity, and also prevents chemotherapy (Chemo) induced neutropenia (CIN). Plin has a rapid onset CIN prevention (1 st week) and G-CSF a delayed onset (2 nd week) of the cycle. Single agent Plin has non-inferior protection against CIN compared to Peg. Combining Plin with pegfilgrastim (Peg) has superior protection against CIN throughout the entire Chemo cycle (Blayney ASCO 2021). Plinabulin protected LSK cells in mice receiving myelosuppressive Chemo, which are cells equivalent to CD34+ in humans (Tonra Cancer Chemotherapy and Pharmacology. 2020). We evaluated the mechanism of Plin's rapid onset for CIN prevention in patients (pts).
Methods
Data from the CIN phase 2/3 Plin trials PROTECTIVE-1 (NCT03102606) with docetaxel 75 mg/m2 in pts with NSCLC, Breast Cancer, Prostate Cancer and PROTECTIVE-2 (NCT0329457) with docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 (TAC) in early stage Breast Cancer was analyzed for pts receiving either Plin (n=228) or Control (no Plin); n=172). Both studies 105 and 106 had patients randomized to either Plin or Pegfilgrastim, which latter was given on the next day of Chemo, on day (D)2. The safety blood draw, taken on D2 at predose Pegfilgrastim, served as a no-treatment Control on D2 in this blood cell analysis for comparison with Plin, which was given on D1. The Plin dose was 20 mg/m2 or 40 mg, and was given as a single dose per cycle, by 30 min IV infusion, 30 min after Chemo on day (D)1. The 40 mg fixed dose is equivalent to 20 mg/m2 Plin. Absolute neutrophil count (ANC), monocyte (M), eosinophil (E), basophil (B), lymphocyte (L), erythrocyte (RBC), and platelet (P) counts were obtained from peripheral blood draws and analyzed by Central Laboratory (Covance). The primary analysis was to compare cell counts between Plin and Control in blood draws taken 24 hour (hr)post-Chemo (thus D2). Separately, we also established Spearman correlation coefficients (r) of scatter plots between ANC and M,E,B,L,RBC, or P count on D2, in a broader dataset that also included Plin doses of 5,10 and 30 mg/m2 in addition to 0 and 20 mg/m2 (40 mg fixed) doses to allow for dose-response evaluation (total n=451). D2 cell counts were expressed as change from pre-dose D1, in absolute values.
Results
At predose D1 (baseline), counts of ANC, M,E,B,L,RBC, and P were similar between the Plin and Control groups (p=NS). On D2, at 24 hr post-Chemo, ANC, M,E and B ,had all significantly decreased compared to D1 in the Control group (indicating myelosuppression by Chemo), whereas significantly increased with Plin (suggesting reversal of this myelosuppression), albeit within normal range (Table below). At 24 hr post-Chemo, counts for L and RBC had significantly decreased compared to D1 with both Control and Plin, however this decrease was ~50% less with Plin compared to Control (P&lt;0.001). No difference in P counts were observed between Plin and Control at 24 hr post Chemo (p=0.69). Correlative analyses showed that at 24 hr post-Chemo (D2), ANC was positively correlated with counts of M (r=+0.42; p&lt;0.0001), E (r=+0.16; p=0.0008), B (r=+0.20; p&lt;0.0001), L (r=+0.32; p&lt;0.0001), RBC (r=+0.07; p=0.1187) and P (r=+0.18; p=0.0002). Thus, with larger increase in ANC counts on D2, the larger were the increase in the other blood cell types. The observed results were Plin dose-dependent, and consistent between pts receiving either docetaxel alone or TAC . Shown below are mean (SD) of absolute cell count on D2, expressed as change from predose D1.
Conclusion
Plin rapidly (within 24 hours) reversed myelosuppression induced by Chemo, by protecting granulocyte-monocyte-progenitor (GMP) stem cells (responsible for producing ANC, M, B and E cells) or progenitor cells further upstream in the hematopoietic lineage tree.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.