Promising Safety and Efficacy Data for Peginterferon Alfa-2a (PEG-IFN) and Bictegravir/Emtricitabine/Tenofovir Alafenamide (Biktarvy) in a North American Adult T-Cell Leukemia Lymphoma (NA-ATLL) Cohort of Patients

Background:

North American Adult T-cell leukemia/lymphoma (NA-ATLL) is a rare and aggressive malignancy of CD4+ T-cells associated with HTLV-I infection. Despite varied treatment approaches, acute ATLL has an overall survival of less than one year. Zidovudine (AZT) with Interferon-alpha has been the backbone of acute ATLL treatment for the past three decades. While AZT-monotherapy was the first treatment to show benefit for HIV infection, combination therapy, such as the fixed-dose combination tablet Bictegravir-Emtricitabine-Tenofovir alafenamide (Biktarvy) has superior outcomes and has become standard of care for HIV treatment. There is preclinical evidence that these agents have activity against HTLV-I and it was proposed to deploy them in ATLL. Thus, for the first time to our knowledge, we sought to determine safety and efficacy of PEG-IFN alpha and Biktarvy in our ATLL cohort.

Methods:

Seven patients with a range of aggressive Shimoyama phenotypes were treated: one acute, six lymphomatous (two relapsed) and one chronic unfavorable. The regimen consisted of weekly subcutaneous Peginterferon alpha-2a 180 mcg and Biktarvy daily. This backbone was combined with Venetoclax in one patient and mogamulizumab in another. We measured overall response rate via imaging, virologic response, adverse events, and mutational profile. Virologic response was evaluated by measuring HTLV-I viral load (copies/ml) before and during treatment.

Results:

Overall response rate was 100% with confirmed imaging resolution in six subjects. One patient lacked imaging confirmation but had dramatic resolution of skin lesions and lymphadenopathy. All patients remain alive, with median survival of 279 days (range 95-396 days) versus 33 days (range 3-92 days) in historic controls. This survival benefit is significant with a p-value <0.00011 via log rank test. We observed a sustained decrease in mean viral load of 91.17% (range 68% to 100%) with a one-sided p-value of 0.007813 via paired-Wilcoxon test. The circulating component of ATLL cells was eliminated in 6 out of 7 patients, 3 prior to transplant and 3 post transplant. The observed adverse effects included: grade 1-2 fatigue and cytopenias in five out of seven patients (71.4%), G4 neutropenia in one patient (14.3%) and G4 febrile neutropenia with sepsis in one patient (14.3%). Five patients continued therapy with no interruptions, one stopped due to relapse, and another due to severe cytopenia/sepsis.

Conclusions:

All cases in this study achieved a sustained complete remission, significantly superior to prior historical controls. Most observed toxicities were tolerable. There was one grade 4 adverse effect with severe pancytopenia and sepsis attributed to Venetoclax. We conclude that PEG-IFN and Biktarvy are safe and effective in patients with ATLL, particularly showing positive outcomes in multiply relapsed patients, a group previously with limited options and extremely poor outcomes. We propose integrating Biktarvy and PEG-IFN as part of induction or maintenance strategies in ATLL, possibly in combination with other agents. A prospective clinical trial is being designed to evaluate the effect of PEG-IFN and Biktarvy in a larger standardized patient cohort.