In general, ~ 40 to 45% of younger and 10 to 20% of older adults with AML can be cured with current standard chemotherapy(2). Most patients with AML experience relapse or primary drug resistance and are then considered as having R/R-AML. At present, R/R-AML is the biggest challenge for hematologists worldwide. For decades, there has been no revolutionary improvement in the efficacy of treatments for AML, and experts have been looking for ways to conquer R/R-AML. Currently, there are many new drugs and new chemotherapy combinations. However, patients with poor physical condition and economic burden can only be given, at best, symptomatic treatment and supportive care. Therefore, we tried to improve the quality of life of these patients with R/R-AML by application of a new combination of affordable old drugs. The present study determined that this new ITI regime can provide a new, affordable treatment option for patients with R/R-AML, and efficiently drives MRD negativity. In addition, the ITI regimen was associated with improved quality of life and longer survival of patients with AML with CR.
Our results suggest that the CR/CRi rate was only 13.4%, when the ITI regimen with a combination of rhIFNα-1b, rhIL-2 and thalidomide was used for the salvage therapy of R/R-AML. This does not hold an advantage over some intensive chemotherapy regimens such as CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor), in terms of remission rate(16, 17). However, chemotherapy proved ineffective for the patients in the present trial, or patients were unable to receive chemotherapy due to physical or economic reasons. The guidelines of the National Comprehensive Cancer Network (NCCN) recommend only best supportive care for patients with R/R-AML. However, if patients are unable to avoid blood transfusion and require long-term hospitalization, this always degrades their quality of life. In the present study, these patients received the ITI regimen and 12 (20%) were freed from blood transfusions and received subcutaneous injection and oral medication only as outpatients. The survival time and quality of life for these patients was significantly improved.
Many new drugs have been used in the treatment of R/R-AML with specific targets, and the curative effect has been remarkable in some cases. Yet, multi-drug combinations are urgently needed for R/R-AML with no specific targets. Current combinations of new drugs always cause severe bone marrow suppression(17, 18).
In the present study, some of the patients showed a decrease in blood routine counts during the stage of malignant cell elimination when undergoing the ITI regime, and these patients required transfusion of blood components. However, the patients who achieved CR did not need transfusion of blood components, or they needed only a small amount of blood transfusion, due to the acceptable limit of cell number decline caused by interferon.
The persistence of positive MRD is an independent prognostic factor for long-term survival of patients with AML(19). The earlier the MRD of these patients turns negative, the better chance they have of long-term survival. Patients with persistent positive MRD during the course of treatments, or MRD that turns from negative to positive, are more likely to experience morphological recurrence, and allo-HSCT may be the best option to improve the survival of these patients.
The ITI regimen described herein may be the best choice for those who are not able to undergo allo-HSCT due to financial burden or poor physical condition. Also notable, the ITI regimen efficiently drives MRD negativity, which benefits the patient’s fitness for allo-HSCT and betters the chance of long-term survival. After receiving the ITI regime, 9 of the 18 MRD-positive patients (66.7%) became MRD-negative, while in 4 patients the MRD decreased significantly. This suggests that the ITI program can be an alternative economic option that can substantially improve the long-term survival rate of patients who are unable to undergo allo-HSCT.
Currently in AML, the maintenance treatment of patients after allo-HSCT(20, 21) is given more research attention compared with patients after the first CR. In the present study, rhIFNα-1b, rhIL-2, and thalidomide were combined toward maintenance therapy for patients with initial CR. The cumulative recurrence rate was relatively low (3 years, 17.7%) compared with other reports(22–26), and the ITI regimen can be implemented in a much simpler manner.
In vitro cytological experiments have shown that interferon exerts its antitumor effect mainly by directly acting on immune cells, and indirectly through immunomodulatory effects(6). Interferon can potently stimulate immune responses in dendritic cells, T cells, and NK cells, which are key to promoting anti-tumor immune responses that enhance the killing of leukemic cells(6). The immune responsiveness of patients may be severely damaged by immune dysfunction in these cells, while the ability of type I interferon in restoring their defective immune functions further underscores its biological basis for treating leukemia. In addition, interferon can promote IL-2-mediated T cell proliferation and survival, thus enhancing the cytotoxic effect of T cells on hematological malignancies. IL-2 is considered the most important regulatory factor in the immune network, as it has a major role in the growth and proliferation of many immune cells, including NK and T cells(27). In addition to inhibiting tumor angiogenesis, thalidomide has a strong immunomodulatory effect. On the one hand, thalidomide, as a costimulator, increases the stimulating effect of T cells on T cell receptor-mediated antigen stimulation, and promotes the proliferation of T cells to produce more IL-2, IL-10, and interferon(28). On the other hand, thalidomide reduces the production of inflammatory cytokines, such as IL-5, IL-6, IL-8, and IL-12.
The results of the present study suggest that the ITI regimen, comprising thalidomide, rhIFNα-1b, and rhIL-2, raised the ratio of CD4+ to CD8+ T cells and the percentage of NK cells in peripheral blood. Moreover, the ITI regimen was associated with increased levels of perforin and granzyme-B in NK cells, increased plasma concentrations of IFN-γ and TNF-α, and decreased plasma concentrations of VEGF and inflammatory IL-6. This implies the enhancement of antitumor ability in these patients. These factors further support the rationale for applying the combination of these 3 drugs in the treatment of AML.
The current investigation has several strengths and limitations. To the best of our knowledge, this is the first report of the combined application of thalidomide, rhIFNα-1b, and rhIL-2 in Chinese patients with AML. The major limitation of the current study is the relatively small sample size, in which referral bias is possible.
In summary, the ITI regimen can provide a new, affordable treatment option for patients with R/R-AML, and those with AML who cannot tolerate conventional chemotherapy. In patients with CR status but MRD positivity, the ITI regimen can cause MRD to turn negative and improve patients’ short-term survival. As a maintenance treatment option, it can also benefit the survival of patients with AML after initial CR.