https://orcid.org/0000-0002-6844-7920
In this issue of Blood, Yoshimitsu and colleagues1 report the efficacy and the safety of mogamulizumab combined with the CHOP regimen (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) in a phase 2 study of patients experiencing adult T-cell leukemia/lymphoma (ATLL) who are not eligible for allogeneic stem cell transplantation (alloSCT).
ATLL is an aggressive mature T-cell lymphoid malignancy caused by human T-lymphotropic virus 1. ATLL belongs to the heterogeneous group of peripheral T-cell lymphomas (PTCLs). Compared with other PTCLs, the prognosis is extremely poor, especially in the aggressive subtypes (acute and lymphoma), which represent the majority of the cases at diagnosis, with a median overall survival (OS) of <1 year.2 In these subtypes, the standard of care is polychemotherapy (ie, the LSG-15 protocol in Japan, which consists of a sequential combination of chemotherapies [VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and VCEP (vindesine, etoposide, carboplatin, and prednisone)], or CHOP-like regimens elsewhere) followed by alloSCT, when feasible. Apart from alloSCT, which proved to cure some patients and improve the outcome of ATLL,3 no significant improvement in OS has been observed since the original publication of Shimoyama describing different ATLL subtypes in 1991.2 Notably, the so-called “antiviral therapy” with the combination of zidovudine–interferon alfa has not been able to improve the outcome of ATLL.4
For patients not eligible to alloSCT and especially older patients, ATLL remains an unmet clinical need, and no standard of care has been so far established. As the LSG-15 protocol has not demonstrated an advantage in the subgroup of patients aged >55 years old because of an excess rate of adverse effects, the CHOP-like regimen seems to be the most reasonable option for patients with comorbidities or those aged >60 years.5 However, even more than in other peripheral T-cell lymphomas, response rate to CHOP is low in ATLL, translating in a poor outcome.
Mogamulizumab is the first dedicated targeted therapy for ATLL. This monoclonal antibody directly targets the CC chemokines receptor CCR4 and induces cell death via antibody-dependent cellular cytotoxicity. The CC chemokines receptor CCR4 is overexpressed in ATLL via several mechanisms, including gain-of-function CCR4 mutations that occur in ≈1 of 3 of ATLL cases.6 Mogamulizumab has been approved in Japan for the treatment of ATLL. In Europe and in the United States, mogamulizumab is only approved for the treatment of mycosis fungoides and Sézary syndrome. The main adverse effects of mogamulizumab are cutaneous and immune-mediated adverse reactions.
Regarding studies of mogamulizumab for ATLL, a phase 1 study has shown promising results in relapse/refractory patients.7 However, the randomized study comparing mogamulizumab-LSG15 with the LSG15 protocol as first-line therapy failed to demonstrate an advantage in progression-free survival (PFS) and OS despite an increased overall response rate in the immune-chemotherapy arm.8 This lack of improvement was attributed to an increased risk of developing severe graft-versus-host disease (GVHD) after alloSCT when patients were previously exposed to mogamulizumab. Indeed, patients exposed to mogamulizumab before alloSCT had both an increased risk of severe acute GVHD and steroid-refractory acute GVHD.9 Indeed, mogamulizumab has a prolonged half-life, thus depleting regulatory T cells for several months. Thus, the use of mogamulizumab in first line is limited for patients eligible for alloSCT, with experts recommending to not use mogamulizumab for at least 50 days before an alloSCT.10
The present study overcomes this issue by focusing on the patient population who is not eligible for alloSCT. As reported in this issue of Blood, this multicenter study was a single-arm phase 2 study of initial therapy that included 48 patients aged ≥66 years or aged 56 to 65 years ineligible for transplantation. The patients received 6 cycles of mogamulizumab–CHOP-14, followed by 2 cycles of mogamulizumab monotherapy. The results are promising. The complete response (CR) and the overall response rate (ORR) are 64.6% (95% confidence interval [CI], 49.5%-77.8%) and 91.7% (95% CI, 80.0%-97.7%), respectively. In a phase 3 study published in 2007, CR and ORR were 25% (95% CI, 14.5%-37.3%) and 66% (95% CI, 52.3%-77.3%), respectively, in the biweekly CHOP arm.5
The key message of the article is the favorable outcome with an acceptable safety profile of this combination with a 1-year PFS of 36.2% and 1-year OS of 66.0%. The multivariable analysis revealed that 2 factors (the presence of CCR4 gene mutation and mogamulizumab-associated adverse events) were associated with a better OS. Finally, the study met its initial goal, which was aimed to show a clinically significant improvement of PFS in older patients with CCR4-positive aggressive ATLL, compared with a historical prospective study.
However, this study has several limitations that should be considered for follow-up studies. The initial strategy was to administrate CHOP every 2 weeks. However, only 20 (42.6%) received CHOP-14, among whom 12 (25.5%) completed 6 cycles, suggesting that CHOP-21 regimen seems to be more tolerable regimen. This study used response criteria published in 2009 that seem now outdated.10 Notably, this study has not included modern tools for response assessment, such as flow cytometry and/or positron emission tomography–computed tomography. Moreover, this study does not address the relevance of maintenance therapy. Indeed, despite a high response rate, the 1-year PFS was only 36.2%. Finally, as mentioned above, mogamulizumab is not registered for ATLL treatment in Europe and in the United States.
Despite these caveats, this study brings new insights regarding the management of patients experiencing aggressive ATLL and who are not eligible for alloSCT. This population will increase as the median age at onset of ATLL in Japan has risen to nearly 70 years. This article will be of interest for clinicians who treat patients with ATLL and will help in designing new clinical studies.
Conflict-of-interest disclosure: The author declares no competing financial interests.
