Phase III Study of Immunotherapy with Recombinant Interleukin-2 (IL-2) Versus No Further Therapy in Acute Myeloid Leukemia (AML) Patients ≥ 60 Years in First Complete Remission (CALGB 9720).
Authors: Baer Maria R. , George Stephen L. , Caligiuri Michael A. , Sanford Ben L. , O’Loughlin Kieran L. , Mrozek Krysztof , Kolitz Jonathan E. , Powell Bayard L. , Moore Joseph O. , Stone Richard M. , Bloomfield Clara D. , Larson Richard A. 
Published: April 2020

Abstract
Older AML patients have short disease-free survival (DFS) and overall survival (OS) with current therapies; new approaches are needed. CALGB 9720 was a phase III trial evaluating multidrug resistance (MDR) modulation by PSC-833 (valspodar) in induction and consolidation therapy and subcutaneous IL-2 maintenance therapy. The PSC-833-containing arm was closed because of excessive toxicity after randomization of 120 patients, as reported previously (Blood100:1224, 2002), and all subsequent patients received ADE induction (cytarabine 100 mg/m2 daily x 7 days by continuous intravenous infusion, with daunorubicin 60 mg/m2 and etoposide 100 mg/m2 each daily x 3 days) and one consolidation course (same drugs and doses x 5, 2 and 2 days, respectively) without PSC-833. Following recovery of neutrophils ≥0.75 x 109/L and platelets ≥50 x 109/L after consolidation therapy and documentation of lack of marrow AML recurrence, patients were randomized to receive IL-2 maintenance or no further therapy. The IL-2 regimen consisted of a 14-day low-dose regimen aimed at expanding natural killer cell populations, followed by a 3-day higher-dose regimen aimed at activating the cytotoxicity of this expanded effector population to produce lysis of residual AML cells. IL-2 was administered as 0.9 x 106 IU/m2/day on days 1–14, 19–28, 33–42, 47–56, 61–70 and 75–90, followed by 12 x 106 IU/m2/day on days 15–17, 29–31, 43–45, 57–59 and 71–73, with rests on days 18, 32, 46, 60 and 74. A total of 669 AML patients ≥ 60 years old (median age 71) with (n=183) and without (n=481) antecedent myelodysplastic syndromes (MDS) were enrolled on CALGB 9720 between March 1998 and April 2002. 311 patients (46%) achieved CR, 253 (38%) received consolidation therapy and 157 of these 253 patients (62%) were randomized to IL-2 immunotherapy (n=79) or to no further therapy (n=78). Reasons for lack of randomization of 96 (38%) patients after consolidation therapy included primarily patient refusal (n=43) and relapse (n=24). The 157 randomized patients included 37 (24%) with prior MDS and only 14% with complex karyotypes (≥3 abnormalities) or rare cytogenetic aberrations (Blood 108:63, 2006) but the multidrug resistance proteins ABCB1, ABCC1 and ABCG2 were expressed in 31%, 36% and 56% of studied cases, and drug efflux mediated by these proteins was present in 62%, 43% and 48%, respectively. Grade 4 toxicities during IL-2 therapy included thrombocytopenia in 66%, neutropenia in 63% and malaise/fatigue and dyspnea in 4% of patients each; grade 3 toxicities included anemia (36%), infection (27%) and malaise/fatigue (13%). 42 (53%) of the 79 patients randomized to IL-2 completed the full 90-day course of immunotherapy. To date, 146 of the randomized patients (93%) have had an event (relapse or death), and 142 patients (90%) have died. Patients randomized to IL-2 or no maintenance therapy had similar distributions of both DFS (overall median 9 mos; p=0.68) and OS (overall median 19 mos; p=0.23). We conclude that low-dose IL-2 immunotherapy is not a successful strategy for prolonging DFS or OS in older AML patients. Another CALGB study (19808) is testing this approach in younger AML patients, in whom immunotherapy might be more successful because of greater chemosensitivity and the likelihood of lower levels of residual disease following more intensive post-remission therapy.