Interferon-α Therapy Bests Donor Lymphocyte Infusion in AML Comparison Study

Interferon-α (IFN-α) therapy produced greater response in 104 patients with acute myeloid leukemia (AML) following return of minimal residual disease (MRD)-positive status after allogeneic hematopoietic stem cell transplantation (allo-HSCT) compared with donor lymphocyte infusion (DLI). MRD recurrence was evaluated using RUNX1-RUNX1T1 transcript levels.

These findings were published recently in Frontiers in Oncology, and MRD levels were stratified by the following (all vs pretreatment baseline measures):

• High-level MRDs: < 2.5-log reductions in RUNX1-RUNX1T1 transcripts
• Intermediate-level MRDs: 2.5 to 3.5-log reductions in RUNX1-RUNX1T1 transcripts
• Low-level MRDs: 3.5 to 4.5-log reductions in RUNX1-RUNX1T1 transcripts

Patients were enrolled from October 1, 2013, through February 28, 2021, and their choice of preemptive treatment strategy was influenced by donor availability and physician and patient intent.

“Regular monitoring of MRD after allo-HSCT can identify patients with a higher risk of relapse,” the study authors wrote. “However, no studies have compared the efficacy of preemptive DLI and IFN-α therapy at different levels of RUNX1-RUNX1T1 transcript and the selection of appropriate preemptive interventions according to RUNX1-RUNX1T1 transcript levels remains unknown.”

Significant differences were seen in achievement of MRD-negative status for the IFN-α treatment group vs the DLI treatment group.

Those with low-level RUNX1-RUNX1T1 who received IFN-α had the most patients achieve MRD negativity (87.5%), followed by patients with an intermediate-level RUNX1-RUNX1T1 measure (58.1%) and a high-level RUNX1-RUNX1T1 measure (22.2%). In addition, patients who received DLI and achieved an intermediate-level RUNX1-RUNX1T1 measure had 50.0% of patients reach MRD negativity once again compared with 14.3% with a high-level RUNX1-RUNX1T1 measure.

A significant difference was seen in overall survival at 2 years between the IFN-α and DLI groups for patients with low- and intermediate-level RUNX1-RUNX1T1: 87.6% (95% CI, 80.3%-95.6%) vs 55.6% (95% CI, 31.0%-99.7%; P = .003). And although a wide gap was still seen for patients with high-level RUNX1-RUNX1T1 (53.3% [95% CI, 28.2%-100.0%] vs 83.3% [95% CI, 58.3%-100.0%; P = .780], respectively), these results were deemed comparable.

Subcutaneous IFN-α-2b treatment was administered twice weekly every 4 weeks, and IFN-α was scheduled for 6 cycles or RUNX1-RUNX1T1 transcripts came back with MRD-negative results 2 consecutive times. To be included in their analysis, all participants had to be 65 years or younger and show loss of MRD-negative status after allo-HSCT. For this study, the investigators defined MRD-positive status as “loss of a ≥ 4.5-log reduction and/or <4.5-log reduction in the RUNX1-RUNX1T1 transcripts.” Preconditioning methods contained cytosine arabinoside, busulfan, cyclophosphamide (CY), and simustine, and patients who underwent DLI, received a short-term course of immunosuppressive drugs.

MRD initially was evaluated at 6 time points after preemptive intervention—1, 2, 3, 4.5, 6, 9, and 12 months and then at 6-month intervals thereafter.

Eight-eight patients received IFN-α therapy initially, with a median 3 (range, 1-26) cycles, with 24 subsequently receiving salvage DLI. Sixteen patients started with DLI, with 6 subsequently receiving salvage IFN-α therapy.

Additional study results show the following cumulative rates at the 2-year mark after preemptive therapy in the IFN-α and DLI treatment groups, respectively:

• Relapse: 16.8% vs 19.6%(P = .810)
• Nonrelapse mortality: 3.6% vs 20.1% (P = .001)
• Leukemia-free survival: 78.2% vs 60.3% (P = .023)
• Overall survival: 84.2% vs 66.7% (P = .004)

Also at 2 years, 45.1% of patients who received only IFN-α were found to have chronic graft-versus-host disease (cGVHD) vs 57.1% who received just DLI. Among those who received both, 75.3% had cGVHD. Rates of severe cGVHD were 3.2%, 0.0%, and 10.1%, respectively.

“To our knowledge, this is the first study to compare the efficacy of preemptive IFN-α therapy and DLI in a population of patients with a specific disease,” the authors noted. “This study showed that patients with low-level and intermediate-level RUNX1-RUNX1T1 could benefit from preemptive IFN-α therapy, while the clinical outcomes of preemptive IFN-a therapy and DLI in patients with high-level RUNX1-RUNX1T1 were unsatisfactory.”

Of particular note was that patients who first received DLI without benefit went on to benefit from IFN-α salvage therapy, which the authors suggest may indicate the influence of therapeutic order. However, total patients receiving both treatments was small, so this should be investigated further, they suggested.

An additional area for future study, the authors added, should include a randomized, comparative study of outcomes from IFN-α and DLI, since the nonrandomized nature of the present study was noted as a limitation to its generalizability.

Reference

Fan S, Shen M-Z, Zhang X-H, at al. Preemptive immunotherapy for minimal residual disease in patients with t(8;21) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Front Oncol. Published online January 6, 2022. doi:10.3389/fonc.2021.773394