Report of the Relapsed/Refractory Cohort of SWOG S0919: A Phase 2 Study of Idarubicin and Cytarabine in Combination with Pravastatin for Acute Myelogenous Leukemia
Authors: Advani Anjali S. , Li Hongli , Michaelis Laura C. , Medeiros Bruno C. , Liedtke Michaela , List Alan F. , O'Dwyer Kristen , Othus Megan , Erba Harry P. , Appelbaum Frederick R 
Published: October 2019

Abstract
Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)] in relapsed AML (British Journal of Haematology 2014; 167: 233-7). However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥ 3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi < 6 months following their last induction regimen or with refractory disease. Here, we report the results in this poor risk group.
Methods: Pts were treated at SWOG institutions from April 2013 through November 2014. The protocol was approved by each institution's review board. Pravastatin was supplied by Bristol-Meyers Squibb. Eligibility: age ≥ 18 yrs, relapsed/refractory AML, cardiac ejection fraction ≥ 45%, CR/CRi following most recent chemotherapy < 6 months, no prior hematopoietic transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2 IV Days 4-6, and cytarabine 1.5 g/m2/day continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by International Working Group criteria. Thirty-seven pts were to be accrued. If ≥ 12 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level=5% if the true CR rate is 20% and power of 87% if the true CR rate is 40%).
Results: Forty-one pts with a median age of 54 yrs (range 23-75) were enrolled. Nineteen pts (46%) were male and the median WBC was 3000/ uL (range 200-450,000). The median time from initial diagnosis to registration was 4.1 months (range 0.7-49.5). Disease status: primary refractory (63%), relapsed (37%). Cytogenetic risk defined by NCCN criteria: 41% poor, 54% intermediate, 5% missing. The response rate was 34% CR/CRi (95% CI: 20.1%, 50.6%). The p-value comparing 34% to 20% (the null response rate) is 0.024 at a one-sided alpha level of 0.05. The estimated median overall survival is 3.6 months and the median relapse-free survival is 2.6 months. No clinical factors (age, WBC, cytogenetic risk, disease status, time from diagnosis, AML onset) were associated with response. Nine pts proceeded to allogeneic hematopoietic stem cell transplant (AHSCT) and the median overall survival for these patients has not been reached with a median follow-up of 10 months.
Conclusions: The CR/CRi rate in this poor risk relapsed/refractory population is encouraging and suggests that targeting the cholesterol pathway may have therapeutic impact. However, these pts still have rapidly relapsing disease. Pts who were able to proceed quickly to AHSCT achieved prolonged survival.

Disclosures
Off Label Use: pravastatin in the treatment of AML. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Erba:Millennium/Takeda: Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celator: Research Funding; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Amgen: Consultancy, Research Funding; Astellas: Research Funding; Millennium/Takeda: Research Funding; Sunesis: Consultancy; Celator: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding; Ariad: Consultancy; Sunesis: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Pfizer: Consultancy; Jannsen (J&J): Other: Data Safety and Monitoring Committees.