Phase II Study of Targeted Subcutaneous (SC) Bortezomib for Patients with Low- or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) with Evidence of NF-κB Activation
Authors: Randhawa Jasleen K. , Jabbar Kausar Jabeen , Kadia Tapan , Borthakur Gautam , Pemmaraju Naveen , Daver Naval , Kantarjian Hagop M. , Cortes Jorge E. , Hearn Katherine , Bueso-Ramos Carlos E. , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Introduction:
Alterations of innate immunity signaling and activation of NF-κB are known to occur in low/int-1-risk MDS (Braun, 2006, Wei, 2013). These suggest that modulation of NF-κB could be a therapeutic target in this group of patients. Bortezomib is a proteosome inhibitor with potential inhibitory activity against NF-κB. To determine whether bortezomib has therapeutic activity in lower-risk MDS patients, we designed a phase II trial of SC bortezomib in patients with lower-risk MDS and evidence of NF-κB activation.
Methods:
This was a single-arm phase II study of bortezomib in low/int-1-risk MDS patients. Bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21 day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were then prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrows. This was performed in bone marrow aspirate smears stained for immunofluorescence using an antibody against a phosphorylated form of NF-κB p65 (phospho-Ser276). This assay was performed in the Department of Hematopathology following CLIA regulations. Pp65 was considered positive if at least 5% of all the nucleated marrow cells were positive for pp65 staining. Subsequently, pp65 levels were assessed on day 21 of cycles 1 and 2 and then in subsequent marrows as clinically indicated. Responses were assessed according to IWG06. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR.
Results:
Since 9/2013, we have enrolled 12 patients with a median age of 72 years (range 56 - 87). Median marrow blast percentage was 1.5% (range 1 – 5%). Nine patients had diploid cytogenetics, 2 had del 20q, and 1 had trisomy 8. All patients had low (2 patients) or int-1 (10 patients) disease. All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets and 5 only PRBCs). Ten (83%) of the 12 had received prior hypomethylating agent (HMA) therapy. Thus far, patients have received a median of 3.5 cycles (range 1-12). Baseline median pp65 was 26.5% (range 7 – 70%). Five patients were taken off the study, 2 for disease progression and 3 for no response after a median of 3 cycles. Seven remain on study. No grade 3/4 toxicity and minimal grade 1/2 toxicity have been observed. No peripheral neuropathy has been observed. The median overall survival has not been reached. At a median follow up of 17 weeks, the overall response rate is 33% (3 HI-EP and 1 HI-N). Six patients have stable disease, and 2 had progression. One patient achieved red cell transfusion independence, going from PRBCs every 2 weeks to no transfusions after 2 cycles. All responders had been previously treated with an HMA. At day 21, the median pp65 level was 23% (0-70) and subsequently 22% (5-50) (all NS). Pp65 decreased by at least 50% in 5 patients, but it fell below 5% in only 2 patients. Two of the 5 patients with decreased levels of pp65 had a response to therapy. Of interest, the patient that achieved transfusion independence had a substantial decrease in pp65 (to less than 5%) that was lost (up to 56% pp65) when the patient lost hematological response. We also screened patients with a 28-gene mutation panel and found a MET, JAK2, or TET2 mutation in each of the 3 patients achieving a hematological improvement, a RUNX1 or CEBPA in each of the two patients with progressive disease, and an APC or ASXL1 mutation in each of the patients with stable disease.
Conclusions:
Bortezomib is well tolerated and results in hematological improvement in pretreated patients with lower-risk MDS. It is feasible to assess pp65 in serial bone marrow samples in this group of patients. Pp65 decreases in 40% of patients, and substantial decreases may be associated with response. This study suggests that it is possible to target patients for therapeutic intent using the NF-κB pathway as a biomarker.

Disclosures
No relevant conflicts of interest to declare.