Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis

In this study, we present the latest findings on the utilization of the AZT/IFN regimen for treating ATLL patients. Our analysis included fifteen studies, primarily retrospective cohorts, encompassing a total of 1101 ATLL patients. The majority of the available treatment data focused on patients with the aggressive forms of the disease, namely the acute and lymphomatous subtypes.

Our quantitative analysis of the AZT/IFN regimen’s response rate revealed an OR of 67%. Among individuals who received this regimen at any point during their treatment, a complete response (CR) rate of 33% and a partial response (PR) rate of 31% were observed. Subgroup analyses demonstrated that patients receiving front-line and combined AZT/IFN therapy exhibited higher response rates compared to those receiving AZT/IFN alone. Notably, patients with indolent subtypes showed significantly higher response rates compared to those with aggressive diseases.

While these findings suggest the potential benefits of initiating AZT/IFN-containing regimens early in the disease course, it is important to note that more research with an adequate sample size of indolent patients is needed to precisely investigate the effect of the AZT/IFN regimen in the early stages of ATLL.

The combination of AZT (azidothymidine) and IFN-α (alpha-interferon) was initially proposed by Gill et al.[27] and Hermine et al. [28] and is currently recognized as one of the most effective therapies for ATLL [7]. his combination is believed to suppress ATLL cells by activating the immune response against HTLV-1-infected cells and interfering with HTLV-1 replication [29]. Zidovudine, an anti-HIV drug, can also inhibit HTLV-1 transmission, and when combined with alpha-interferon, a naturally produced cytokine that responds to viral infections, it has shown positive effects in ATLL treatment. Additionally, the presence of wild-type p53 has been associated with a better response to AZT treatment [27]. Arsenic trioxide is another antiviral that impedes the growth of HTLV-1 and induces apoptosis [30]. Current data cannot evaluate the synergic effect of the chemotherapy and AZT plus IFN-α plus Arsenic effect. However, more research is needed to demonstrate that these regimens are attributed to better clinical response and longer medial survival time (MST) than chemotherapy. The pathophysiology of these regimens is described in Table 3.

HTLV-1 genome includes several genes such as tax and HBZ. Tax stimulates the proliferation of T-lymphocytes and inhibits their apoptosis by activating pathways including the NF-kappa B signaling pathway, Basal transcription factors, actin cytoskeleton, P53 pathway, and PI3K-Akt signaling pathway[31, 32]. Although Tax proliferation is vital for the expansion of the infected CD4 + T cells, it provokes the immune system and may decline the number of these cells. Genetic and epigenetic alternations, mostly unknown, accumulate during the latent period and result in the development of these cells to ATLL [33]. These alternations lead to different types of ATLL ranging from smoldering ATLL, which is usually asymptomatic or presents with skin rashes, to chronic type, characterized by lymphocytosis and is stable for months or even years, and acute and lymphoma type, which manifests systemic symptoms and progress quickly [34].

Bazarbachi et al. [7] conducted a meta-analysis in 2010 that aimed to review AZT/IFN effects on ATLL treatment in trials. Their study, similar to our systematic review, concluded that first-line AZT/IFN therapy leads to a better survival rate than chemotherapy alone. Since 2010, some studies extended our knowledge of clinical outcomes of the combination of AZT/IFN; for example, Datta et al. study demonstrated that this combination has a significant effect on patients with wild type p53 however it is not helpful in the treatment of patients with mutated inactive p53 [35]. Furthermore, Oliveira et al. showed that the MST was longer in patients with the chronic type who received AZT and IFN on their first-line therapy (44 months). At the same time, MST of patients with acute form was conversely longer in the group of patients who got first-line chemotherapy than the group which got both chemotherapy and AZT/IFN-α. Among all types, the smoldering form has the longest MST. Moreover, lymphoma and acute type have shorter MST than chronic types, despite the method of treatment[17]. Kchour et al. study added Arsenic (As) to the combination of AZT and IFN. Their triple regimen that consists of As/IFN/AZT is attributed to an impressive response in ATLL patients, especially in chronic type. That is to say, the complete response rate is lower in patients who get AZT and IFN alone in comparison to patients who receive a triple regimen [36]. In 2017, Oliveira et al. evaluated the mean survival time (MST) for the antiviral and chemotropic regimen [17]. The highest MST was among smoldering-type patients who received skin-directed therapy and watchful waiting, whereas the participants with different ATLL subtypes treated with VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin and prednisolone; doxorubicin, ranimustine and prednisolone; vindesine, etoposide, carboplatin and prednisolone) had the lowest MST. On average, patients treated with AZT plus IFN-α lived 11.35 months longer than patients treated with VCAP-AMP-VECP.

Apart from chemotherapy, and stem cell transplantation, which approach ATLL treatment as a malignancy therapy, some therapeutic approaches toward ATLL consider the disease a complication of a viral infection with HTLV-1. For instance, Mogamulizumab, a monoclonal antibody targeting the CCR-4 receptor, causes a reduction in the number of HTLV-1 infected cells. Several studies revealed that Mogamulizumab has a great response in patients diagnosed with an acute type of ATLL [37‐39]. One of the highest complete response rates (100%) was found in Kawano et al. study, which used Mogamulizumab plus Allo-HSCT plus VCAP-AMP-VECP for treatment. Meanwhile, Mogamulizumab plus MLSG15 had a relatively lower complete response rate (37.5%). (MLSG15 regimen is a dose-intensified multidrug regimen, namely the modified LSG15 (mLSG15) regimen including VCAP‐AMP‐VECP). In addition, the combination of MLSG15 and Mogamulizumab had a higher PR rate (41%) and CRU rate (25%) than MLSG15 alone (34%). It should be noted that Mogamulizumab plus Allo-HSCT plus CHOP regimen was not effective in lymphoma Type (CR = 0%). Ishida et al. study indicated that people treated with mLSG15 plus Mogamulizumab (52%) have a higher complete remission rate than patients who received mLSG15 alone (33%). [38]. In addition, Kawano et al. showed that using Mogamulizumab before allogeneic-HSCT increases the survival time. They can be used in the refractory type of diseases, although one of the disadvantages of this treatment is the increased chance of severe GVHD (graft versus host diseases reaction). One way to solve this problem is to increase the interval between the last Mogamulizumab administration and allo-HSCT [37].

Our study faced several limitations. First, there were not so many articles that reported the clinical outcome of ATLL patients who received the AZT/IFN regimen. Second, there was a paucity of data because several studies included in our meta-analysis were conference abstracts. Third, the conclusions were made based on a limited number of observational studies, which lowers the certainty of evidence because of their retrospective nature. Finally, the possible variation in the outcome criterion among the studies could be contributed to the heterogeneity seen in the results of our meta-analysis. One of the major concerns regarding AZT/IFN-based regimens is the discontinuation of the production of intravenous and subcutaneous interferon alfa-2b. As of September 2021, Merck & Co. has discontinued the production of both intravenous and subcutaneous formulations of interferon alfa-2b. The reasons for this decision have not been publicly disclosed. But there has been news regarding a business decision [40].

In conclusion, this study showed that prescribing AZT/IFN regimen is attributed to a favorable clinical response rate in ATLL patients. These findings indicate that, as a clinician, choosing an AZT/IFN therapy not merely depends on the patient’s circumstances, such as their malignancy type but also hangs on the treatments that patients have received. AZT/IFN combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate. Future studies with vigourous foucus on the survival rate of the patients receiving these treatment is highly suggested to inform the clinicians regarding the efficacy of these regimens.