A Phase I study using Bortezomib with Weekly Idarubicin for the Treatment of Elderly (&gt;60 YEARS) and Relapsed Patients with Acute Myeloid Leukemia (AML)
Authors: Howard Dianna , Liesveld Jane , Phillips Gordon L. , Guzman Monica L. , Jordan Craig T. 
Published: April 2020

Abstract
In preclinical experiments we have shown that human AML cells overexpress NFkB and suppression of NFkB by proteasome inhibition directly induces apoptosis in primary AML cells, with little effect on normal hematopoietic progenitors. (Guzman, 2001, Blood, 98(8); Guzman, 2002, PNAS, 99(25).) Furthermore, our data has also demonstrated that the combination of the proteasome inhibitor, bortezomib (Bor), with idarubicin (Ida) robustly induced death in primary AML cells, including the relatively quiescent leukemic stem cell. (Howard, 2003, AACR abstr. 1636) From these observations, we hypothesized that Bor in combination with Ida would mediate a tumor-specific, anti-leukemia response in patients (pts) diagnosed with AML. We report the results of a phase I study with a standard up and down design looking at 4 dose levels of Bor in combination with Ida. Eligible were newly diagnosed AML pts age ≥60, with or without myelodysplasia (MDS), or any adult with relapsed AML treated at the Univ of Ky or Univ of Rochester. A minimum of 3 and a maximum of 6 pts were entered at each dose level. Twice weekly bortezomib at 0.8, 1.0, or 1.2mg/m2 was given with weekly Idarubicin 10, or 8mg/m2 for 4 wks. Therapy was administered in the outpatient setting. Bone marrow (BM) analysis was done at entry, day+18 of treatment, and either at time of hematopoietic recovery or day+50, whichever came first. A DSMB was established to review all adverse events (AEs) semiannually. Twenty eligible and consented pts were treated; 13 newly diagnosed (ND) (med age 68 (61–83)) and 7 relapsed (Rel) (med age 58 (40–77)). 10/13 ND and 2/7 Rel pts had prior MDS; of 3 ND pts without prior MDS, 2 were FAB M6 and 1 was FAB M7. Toxicities were evaluated by CTCAE, v3.0 criteria. Two dose limiting toxicities (DLT) occurred at dose level 1(Bor 0.8mg/m2 and Ida 10mg/m2) – gr 4 CPK elevation in setting of rhabdomyolysis (resolved completely) and death due to disseminated aspergillus with aplasia in the BM (gr 5 infection). After unacceptable toxicities at the first dose level, the dose of Ida was reduced to 8mg/m2. No further DLTs were observed. 15/20 patients were admitted for 17 episodes of febrile neutropenia. Only 1 pt died from infection that was treatment related. Common AEs included: infections, constitutional symptoms, pain, and gastrointestinal symptoms (see table). No patient experienced neurotoxicity. The only grade 4 non-hematologic or non-infection toxicity was the CPK elevation. 1 pt died from renal failure unrelated to treatment. All but 2 pts demonstrated a hematologic response to treatment evidenced by decreased circulating blasts. 4 pts achieved CR – 2 at dose level 1 and 2 at dose level 4; 1 pt achieved PR (returned to CMML). The combination of Bor and Ida in this older pt group with mostly poor-risk AML was well tolerated; expected hematologic and infection-related toxicities did not result in a high rate of induction mortality. While this study was not designed to evaluate efficacy, it is noteworthy that there were 4/20 complete remissions. Our results with this combination of drugs in the treatment of poor-risk, older pts with AML are provocative. Future studies should explore alternate dosing of Ida, other potentially synergistic drugs for combination with Bor, or the use of Bor in post-remission therapy.
TOXCITIES gr1 gr2 gr3 gr4 gr5 documented infection including bacteremia 1 5 14 4 1 febrile neutropenia requiring admission 17 constitutional symptoms - sweats, myalgias, weakness, fatigue, anorexia 5 11 Pain 5 4 gastrointestinal symptoms 4 bleeding (any) 1 1 1 Anemia 1 2 1 cardiac 1 1 4 respiratory 1 5 metabolic disturbance 2 1 1 renal failure 2 1 1 1 rash 1 1