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Adrienne A. Phillips et al.
Introduction
Adult T-cell leukemia/lymphoma (ATL) is an aggressive, rare, peripheral T-cell lymphoma (PTCL) caused by human T-cell lymphotropic virus type I (HTLV-1).1-5 Approximately 2-7% of people infected with HTLV-1 develop ATL, often after decades of infection.6 HTLV-1 is endemic in Southern Japan, the Caribbean, Central and South America, Central and South Africa, parts of the Middle East and Melanesia, and aboriginal regions of Australia.7 In non-endemic areas such as North America and Europe, HTLV-1 infection and ATL have been linked to immigration from endemic areas.8-10 It is estimated that ATL accounts for 0.2% of lymphomas in the US but as many as 37% in Kyushu, Japan.11 Compared to other sub- types of PTCL, ATL has the worst prognosis with 5-year overall survival (OS) of 14%.5
Adult T-cell leukemia/lymphoma is classified as smol- dering, chronic, lymphoma, and acute subtypes.12 In Japan, aggressive subtypes of ATL (acute and lymphoma) have a poor prognosis with median OS of around 12 months, even with intensive chemotherapy regimens.13 A long-term retrospective study has shown that even the indolent subtypes of ATL (smoldering, chronic) have a poorer than expected prognosis with median survival of only 4.1 years.14
skin, peripheral blood, or bone marrow. Patients were required to be Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with adequate hematologic, hepatic, and renal function. Patients were excluded if they had a history of allo-SCT, active concurrent cancers, or central nervous system (CNS) involvement. Patients randomized to the investigator’s choice arm could not receive a regimen that they had previously received or to which they had a contraindication.
Because the disease is aggressive, refractory patients enrolled early in the study had difficulty completing the first treatment cycle. To enroll a population able to receive adequate drug expo- sure and more likely to be able to benefit from treatment, the pro- tocol was amended to exclude patients with acute or lymphoma subtypes who had received >2 prior systemic therapy regimens and had not achieved a response or maintained stable disease ≥12 weeks on immediate prior therapy.
The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization consoli- dated good clinical practice guideline, and any applicable national and local laws and regulations. The protocol was reviewed and approved by institutional review boards or independent ethics committees at each site. All patients provided written informed consent.
Study design
This was an international, multicenter, open-label, randomized study conducted at 22 centers (see Online Supplementary Appendix) in Belgium, Brazil, France, Martinique, Peru, the UK, and the US; 18 centers screened and 17 randomized patients. A Steering Committee selected investigator’s choice regimens: pralatrexate, GemOx (gemcitabine and oxaliplatin), or DHAP (dexamethasone, cisplatin, and cytarabine) which were appropriate for a relapsed/refractory population. Eligible patients were randomized 2:1 to mogamulizumab or investigator’s choice arms with stratifi- cation by ATL subtype (acute, chronic, or lymphoma). Patients who progressed in the investigator’s choice arm were permitted to cross over to mogamulizumab.
The primary objective of the study was to determine the ORR of mogamulizumab that persisted and was confirmed at a subse- quent response evaluation, 8 weeks after initial response (con- firmed ORR, cORR). Secondary objectives were to compare cORR, progression-free survival (PFS), OS, time to response, and duration of response (DoR) between the treatment arms and to assess safety.
Drug administration
Mogamulizumab 1.0 mg/kg was administered by intravenous (IV) infusion over ≥1 hour (h) once weekly during the first cycle (days 1, 8, 15 and 22 of the first 28-day cycle) and on days 1 and 15 of subsequent cycles without dose modification. Pralatrexate 30 mg/m2 was administered IV over 3-5 minutes (min) once week- ly for 3 weeks followed by 1 week without.24 GemOx comprised IV gemcitabine 1000 mg/m2 over 30 min followed by IV oxali- platin 100 mg/m2 over 2 h every 2 weeks. DHAP comprised IV dexamethasone 40 mg over 5-15 min on days 1 to 4 and IV cis- platin 100 mg/m2 over 24 h on day 1 followed by IV cytarabine 2000 mg/m2 over 3 h immediately after cisplatin and again 12 h later on day 2 every 4 weeks. For investigator’s choice regimens, dose modifications were permitted and applicable treatment rec- ommendations followed according to local prescribing informa- tion. Treatment continued until progressive disease (PD), unac- ceptable toxicity, or withdrawal of consent.
Assessments
Efficacy was determined by an independent, blinded review
Outside Japan, there is no approved treatment for ATL. In a retrospective series of 89 ATL patients at three New York City medical centers, median OS across subtypes was approximately 6 months.15 Allogeneic stem cell trans- plantation (allo-SCT) can significantly prolong survival, but there are few appropriate candidates because of age, availability of a stem cell source, lack of adequate response to primary therapy, and/or absence of effective agents in the relapsed/refractory setting.16-18
Almost all patients (≥90%) with ATL over-express C-C chemokine receptor 4 (CCR4) on tumor cells.19,20 Mogamulizumab is a first-in-class defucosylated human- ized IgG1 kappa monoclonal antibody that selectively binds to CCR4 and has enhanced antibody-dependent cel- lular cytotoxicity (ADCC) activity.21 Mogamulizumab is approved in Japan for the treatment of relapsed/refractory CCR4+ ATL on the basis of a phase II trial showing a 50% overall response rate (ORR) in a relapsed population.22 It was subsequently approved for chemotherapy-naïve CCR4+ ATL on the basis of a randomized phase II trial in combination with the mLSG15 regimen.23
In order to study mogamulizumab outside Japan, we conducted a phase II randomized trial of mogamulizumab monotherapy compared to investigator’s choice of chemotherapy in patients with relapsed/refractory ATL and, herein, report the results.
Methods
Patients
Patients ≥18 years of age with a confirmed diagnosis of ATL (HTLV-1 antibody positive) who met criteria for the acute, lym- phoma, or chronic ATL subtypes12 and who were refractory or relapsed after at least one prior systemic therapy were eligible to enroll [chronic patients were retrospectively designated favorable or unfavorable based on serum BUN, lactate dehydrogenase (LDH) and albumin levels]. Disease had to be evident in at least one compartment: lymph nodes, extranodal masses, spleen, liver,
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haematologica | 2019; 104(5)