Synthetic lethality in ATL

In this issue of Blood, Izutsu et al report the results of the phase 2 trial of valemetostat, a dual inhibitor of enhancer of zeste homolog 1 (EZH1) and EZH2, in relapsed or refractory adult T-cell leukemia/lymphoma (ATL).¹ Heavily pretreated patients with a median of 3 prior lines (range, 1-8) of treatments were enrolled and received 200-mg daily doses of valemetostat until progression or intolerance. The authors reported encouraging activity with an overall response rate (ORR) of 48% with no differences in ORR by disease status (relapse vs refractory) or previous exposure to mogamulizumab and lenalidomide.

Notably, 5 patients achieved complete response with the duration of response being more than 1 year. Hematologic toxicities, particularly thrombocytopenia (grade ≥3: 32%, 3 patients with grade 4) were common but valemetostat was reasonably well tolerated with minor grade ≥3 non-hematologic toxicity. Based on the trial, valemetostat is approved for relapsed or refractory ATL in Japan. Many patients with ATL are not candidates for aggressive treatment, including allogeneic transplants with curative potential. Thus, this trial provides hope for patients with a great unmet need.

Multiple groups engaged in understanding the molecular biology of ATL provided the framework needed for the development of this drug. Yamagishi et al found an abnormal accumulation of histone H3 Lys27 trimethylation (H3K27me3) in ATL cells.^2,3 This accumulation of H3K27me3 causes epigenetic silencing in various transcription factors, epigenetic modifiers, developmental genes, and loss of microRNA including miR-31 which activates the NF-κB pathway by MAP3K14 expression.³ The accumulation is seen not only in acute or lymphoma subtype of ATL but also in smoldering/chronic ATL or even in human T-lymphotropic virus type 1 (HTLV-1) infected T cells from patients with asymptomatic HTLV-1. This suggests that abnormal gene downregulation occurs early in disease progression. EZH1/2-containing polycomb repressive complex 2 catalyzes H3K27me3 (ie, accumulation is EZH1/2 dependent), and EZH2 is overexpressed in HTLV-1–infected ATL cells.⁴ EZH1 is also highly expressed in peripheral T cells, compensates the EZH2 functions, and contributes to the accumulation of H3K27me3. Simultaneous depletion of both EZH1 and EZH2 causes synthetic lethality, significantly decreases cellular H3K27me3 level and dramatically inhibits ATL cell growth compared with single depletion.⁵ These findings laid the molecular groundwork for developing the dual EZH1/2 inhibitor, valemetostat.

Although the scientific background of the trial and reported activity are exciting, we need to be careful when applying it to typical patients with relapsed or refractory ATL. The median time since the last treatment was 60 days (and up to 1400 days), the median lines of previous treatment were 3 (range, 1-8), and only 2 patients (8%) had Eastern Cooperative Oncology Group performance status (PS) of 2. The typical course or presentation of symptomatic and often the treatment of patients with refractory ATL may differ from participants in the trial who could wait for the treatment without declining PS. A similar challenge of selecting patients with ATL for clinical trials was seen in mogamulizumab development. Initial phase 2 trial in Japan of patients treated with mogamulizumab with the relapsed (not refractory) disease, the majority of whom had good PS in second-line treatment, showed encouraging ORR of 50%.⁶ However, a global randomized phase 2 study of mogamulizumab vs investigator choice conducted in the United States, Europe, the Caribbean, and South America showed a lower best ORR of 28% and only 11% of patients showed persistent response for more than 8 weeks in the mogamulizumab arm likely because of enrolling more high-risk patients on the trial (40% PS = 2, 40% progressive disease to prior line). In fact, patients with refractory disease had difficulty completing the first cycle and thus the protocol was amended to exclude patients who had received >2 lines of treatment and had not achieved a response or stable disease ≥12 weeks for the immediate prior therapy. Owing to this “negative” study, mogamulizumab is not approved for the treatment of ATL outside Japan. This trial is one of many that taught us that agents require a well-thought-out trial to evaluate the appropriate target population and full potential of the activity. The global study, VALENTINEPTCL01 using valemetostat, targeting both peripheral T-cell lymphoma (PTCL) and ATL is ongoing (NCT04703192). We hope to see confirmation of activity in ATL and would be delighted to see activity in other PTCLs.

Where do we go from here? ATL remains one of the most fatal lymphoid malignancies with 5-year overall survival of less than 20%.⁷ Although we now have 3 active agents for ATL, which are mogamulizumab, lenalidomide,⁸ and valemetostat, much more is clearly needed. A combination treatment such as lenalidomide and valemetostat may work synergistically, and trials evaluating these combinations with well-designed correlative studies are warranted. Another epigenetic modulatory agent, romidepsin, a histone deacetylase inhibitor in combination with lenalidomide was evaluated in the phase 1 trial showing ORR of 53% in PTCL including ATL⁹; however, the treatment was relatively toxic and 63% of patients required dose reduction. The safety profile of valemetostat may help facilitate combination trials. ATL is an endemic disease and thus clinical investigations to explore new agents have been very challenging in areas where it is not endemic, such as Europe and in the United States, where most new drug developments are usually undertaken. Global collaboration will be a key to facilitating clinical investigation.

It is estimated that there are at least 10 to 20 million people worldwide with HTLV-1 infection. HTLV-1 is present throughout the world with clusters of areas of high endemicity in developing countries, such as the Caribbean, Central and South America, and tropical Africa, where patients have no way to access cutting-edge clinical research and expensive, new targeted agents. In addition to continuing clinical investigation in developed countries, it is imperative to support research, treatment, and drug access in developing countries where the majority of patients reside. Because of long latency and low lifetime risk of developing ATL (<5%), the accurate prevalence of HTLV-1 carriers is extremely challenging to capture but the incidence of ATL is rising in areas of nonendemicity, including the United States, most likely owing to migration.¹⁰ We should continue exploring the effective prevention strategy by appropriate screening process considering the nature of extremely fatal HTLV-1–driven disease.

Conflict-of-interest disclosure: The author declares no competing financial interests.