Introduction: Cancer patients (pts) with chronic anemia require long-term blood transfusions causing tissue iron (Fe) overload in the heart, liver, endocrine organs leading to morbidity and shortened life expectancy. Fe overload is usually treated with Fe chelation therapy, which have significant safety concerns (renal and hepatic failure, GI hemorrhage, bone marrow suppression) and require monthly monitoring of blood, renal and hepatic function imposing cost and inconvenience. Our natural defense mechanism to prevent Fe overload is plasma haptoglobin (Hp), which removes Fe-containing free hemoglobin (Hb) released during hemolysis from blood transfusions. Hp is rapidly depleted during elevated hemolysis. In the Phase (Ph) 2 trial BPI-2358-106 (NCT03294577) with the small molecule immune modulator Plinabulin (Plin) for the prevention of chemotherapy-induced neutropenia (CIN), we unexpectedly observed an increase in plasma Hp levels with Plin. The positive CIN data this trial was reported previously (Blayney, St Gallen 2019). Plin is also evaluated as an anticancer treatment in a Ph 3 NSCLC trial (Mohanlal, IASLC 2019; ESMO 2019). Plin has been administered to-date to more than 500 cancer patients through Ph 1,2 and 3 trials, displaying a favorable safety profile. Methods: Breast Cancer pts received TAC (taxotere, doxorubicin, cyclophosphamide), followed by a single dose of Plin 10 (n=15), 20 (n=15) or 30 (n=12) mg/m2, given 60 min after the last chemo as a 60 min IV infusion in the Ph 2 CIN trial 106. Blood draws for Hp in the hematology panel were taken as prospectively defined at predose, and post-dose Plin on Day (D) 2,3,6,7,8,9, 10,11,12,13,15, 22 in cycle 1. Results: Plin at 30 mg/m2 was the most effective dose for increasing plasma Hp levels (p<0.01): baseline mean (SD) predose Hp was 1.32 (0.45) g/L and increased to 2.93 (1.27) g/L, a more than two-fold increase on D8 post-Plin dose (p<0.0005). Hp increase occurred within 2 days (P<0.03) and lasted for several weeks following a single Plin 30 mg/m2 dose (see below). Hp normal range is 0.3 to 2 g/L. Conclusion: A single dose of Plin 30 mg/m2 produces a rapid (within 2 days) and sustained (for >3 weeks) increase in Hp, to levels double of baseline. Co-administration of Plin with blood transfusions, holds the promise of a new, safe and convenient treatment paradigm for Fe-overload with primary prevention potential. Confirmatory trials will be undertaken.