Effective Immunomodulation with Pomalidomide Beginning at Early Lymphocyte Recovery during Induction Timed Sequential Therapy (TST) for Acute Myeloid Leukemia (AML) and High-Risk Myelodysplasia (HR-MDS)

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.335-335
• Main Authors: Zeidner, Joshua F, Knaus, Hanna, Zeidan, Amer M., Blackford, Amanda, Montiel-Esparza, Raul, Prince, Gabrielle T., Gondek, Lukasz P., Ghiaur, Gabriel, Showel, Margaret M., DeZern, Amy E., Pratz, Keith W., Smith, B. Douglas, Levis, Mark J., Foster, Matthew C, Coombs, Catherine C., Streicher, Howard, Karp, Judith E., Luznik, Leo, Gojo, Ivana
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-114961

Introduction: Adults with AML have immune aberrations leading to immune suppression, exhaustion, evasion, and senescence. Early lymphocyte recovery (ELR) after induction TST is dominated by an expansion of oligoclonal peripherally derived regulatory T cells (Tregs). Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), leads to the selective ubiquitination of Aiolos and Ikaros by cereblon; this ubiquitination increases IL-2 production, inhibits Tregs, and inhibits angiogenesis. We hypothesize that Pom administration after induction TST may enhance anti-leukemic activity through immune modulation. Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom administration after induction TST in newly diagnosed AML and HR-MDS patients 18-65 years. Favorable-risk cytogenetics were excluded. All patients received induction TST with AcDVP16: Cytarabine 667 mg/m2/day continuous IV days 1-3, daunorubicin 45 mg/m2 IV days 1-3 (or idarubicin 8-12 mg/m2 IV days 1-3 in daunorubicin shortage), etoposide 400 mg/m2 IV days 8-10, followed by Pom administration at ELR (after day 14 and within 3 days of the total white blood cell (WBC) reaching ≥0.2x109/L above nadir, but no later than day 30). Pom dose escalation occurred in 2 cohorts: 10 days versus 21 days of administration, in a traditional 3+3 design. Results: A total of 51 patients were enrolled and 43 (AML: n=39, HR-MDS: n=4) received Pom across 3 institutions (Table 1). Eight patients did not receive Pom due to no ELR by day 30 (n=3), sepsis (n=3), noncompliance with treatment (n=1), and death prior to ELR due to acute respiratory distress syndrome (n=1). Median time for Pom initiation after AcDVP16 induction was day 21 (range: 15-30 days). Pom maximal tolerated dose (MTD) was 4 mg for 21 consecutive days at ELR. The most common non-hematologic grade ≥3 toxicities related to Pom were febrile neutropenia (30%), maculopapular rash (14%), and aminotransferase elevation (5%). Dose-limiting toxicities (DLTs) of Pom at 8 mg for 21 days were grade 3 ALT/AST elevation and grade 4 respiratory failure, respectively. Pom was discontinued early (median duration = 7 days; range: 3-20 days) in 14 (33%) patients due to disease progression (n=4), grade 3 rash (n=3), DLT (n=2), patient decision (n=2), progressive cytopenias (n=1), and grade 4 acute kidney injury (n=1). Overall, 32/43 (74%) achieved CRc (CR: n= 30, CRi: n=2). Among the 4 HR-MDS patients, 2 (50%) ach