New Treatments for Adult T-cell Leukemia/lymphoma

Abstract

Adult T cell leukemia lymphoma (ATL) is a mature T cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). ATL is endemic in specific geographic regions of the world closely related to areas with high prevalence of HLTV-1 infection, including Southwestern Japan, the Caribbean Basin, Central Africa, South America, Northern and Central Australia. HLTV-1 is primarily transmitted through breastmilk in asymptomatic carriers with a long latency period before transformation into ATL in 3 – 5% of carriers after acquisition of multiple leukemogenic mutations. The Shimoyama classification established by the Japanese Lymphoma Study Group more than three decades ago remains clinically relevant and practical for guiding treatment. Due to the rarity of this illness, prospective, large prospective clinical are challenging to perform and treatment recommendations are based upon limited evidence. Aggressive disease subtypes have median survival ranging in months and the only curative therapy remains achieving deep remission with induction therapy followed by consolidative allogeneic transplantation. The prognosis for relapsed disease remains dismal due to chemo-refractoriness and limited therapeutic options. Herein, we review the current landscape of novel therapeutic agents with a focus on relapsed and refractory ATL including their mechanisms of action, resistance, and clinical efficacy.

1.0. Introduction

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that is endemic to Southwestern Japan, the Caribbean basin, Central Africa, South America and the Indigenous populations of Northern and Central Australia. HTLV-1 is transmitted predominantly vertically through breastfeeding; sexual intercourse and parenteral transmission are additional modes of spread. Although the worldwide prevalence of HTLV-1 infection is high with current estimates of 5 to 10 million infected estimates, less than 5% will develop HTLV-1 associated peripheral T cell lymphoma subtype, Adult T leukemia lymphoma (ATL). Risk factors for evolution to ATL in carriers include high proviral loads (>4% of infected mononuclear cells), advanced age and family history of ATL.

HTLV-1 primarily infects CD4⁺ T cells through direct cell-to-cell transmission, leading to lifelong infection in asymptomatic carriers. The viral proteins Tax and HBZ are critical for the proliferation and maintenance of infected cells. The immunomodulatory effect of HBZ shifts infected cells to a regulatory T cell phenotype [1]. The typical infected individual has between 10⁴ to 10⁵ distinct clones of HLTV-1-infected cells with many clones persisting indefinitely. After a long latency period of several decades, malignant transformation of a single or multiple clones occurs through multistep mutations in pathways like TCR, JAK/STAT, and NOTCH, resulting in progression to ATL [2].

ATL is a clinically heterogenous disease in presentation and survival. It has been historically classified using the Shimoyama classification into four subtypes: chronic, smoldering, lymphomatous, and acute/leukemic. The acute and lymphoma types are considered aggressive diseases with poor median survival times ranging from 6 to 12 months. There is a subset of chronic type that are considered aggressive as they have similar survival to acute and lymphoma type with chemotherapy (JCOG9109 trial). They have unfavorable features that include at least one of the following: low serum albumin, high serum lactate dehydrogenase concentration or high serum urea concentration. Although chronic favorable and smoldering are considered indolent forms, long term survival in a large Japanese cohort remains poor with a median survival of 5.4 and 2.9 years respectively. There were no plateaus seen in the long-term survival of indolent ATL. Nearly half of all patients with chronic and smoldering transformation to acute ATL with a median transformation time of 19 months. Even though prognostic factors have been identified in ATL, they have not been clinically impactful because of the dismal prognosis in the aggressive ATL subtypes irrespective of high or low risk variables. Clinically, the Shimoyama classification remains the most relevant since aggressive subtypes progress rapidly without treatment while indolent subtypes can be observed or treated with antiviral therapy.

The only curative approach for aggressive disease at diagnosis remains chemoimmunotherapy to induce remission followed by allogeneic transplant consolidation in eligible patients. Since aggressive disease is chemo-refractory at relapses, novel agents are preferred to induce remission followed by consolidative transplantation. This review highlights novel agents in recent development, their use in the relapsed/refractory aggressive disease, their mechanisms of action, and therapeutic outcomes. Given the poor survival of this rare disease, enrollment in clinical trials (Table 1) is strongly recommended whenever possible.

Table 1:

Selected Trials in ATL

Trial Details	Patient Eligibility	Intervention
Phase 1, single center study with Lenalidomide and EPOCH (NCT04301076) at the NCI, United States; n=30	Treatment naïve aggressive ATL Relapsed patients who had: Received no more than 1 cycle of chemotherapy Prior treatment with AZT, IFN, bexarotene or mogamulizumab	Induction: Lenalidomide with EPOCH every 21 or 28 days (Lenalidomide is D1–14 for 21 day cycles and D1–21 for 28 day cycles) for up to 4 cycles Maintenance: Patients with CR, PR, or SD can receive up to 2 additional cycles of Lenalidomide with EPOCH and/or 2 years of Lenalidomide maintenance at the discretion of the investigator
Phase 1 single center with Mogamulizumab with IL-21 expanded, off-the-shelf, third party NK cells (NCT04848064) in the United States; n=12	Patients with ATL relapsed past at least 1 standard chemotherapy Patients with relapsed cutaneous T cell lymphoma after 1 prior systemic therapy	Mogamulizumab on Day −7 with Fludarabine and Cyclophosphamide lymphodepletion (Days −5 to −3) followed by NK cell infusion (starting Day 0) every 2 weeks for six infusions. Mogamulizumab on Days 0, 7, 14, 28 and then every 2 weeks
Phase 1/2 multicenter study of BMS-986369 (NCT06035497) in Japan; n=85	Relapsed or Refractory T cell lymphoma Phase 2 has two cohorts: ATL and PTCL respectively	Oral CELMoD, BMS-986369 (golcadomide) with dose and schedule to be determined
Phase 1 single center study of Anti-CD7 allogenic CAR T cells (WU-CART-007) in CD7+ hematologic malignancies in the United States (NCT05377827); n=54	Multiple cohorts for dose expansion including: Cohort A: Relapsed or refractory T-NHL after at least 2 lines of therapy including ATL Cohort B: AML	Lymphodepletion regimen followed by a single dose of allogenic WU-CART-007
Phase 1/2 multicenter study of CD70 allogeneic CAR T in relapsed/refractory hematologic malignancies (NCT06492304)	Relapsed or refractory T cell lymphoma (including ATL), B cell lymphoma or AML after 1 line of therapy	CTX131 (CD70-directed T-cell immunotherapy comprised of allogeneic T cells genetically modified ex vivo using CRISPR-Cas9 gene editing components
Phase 2 single center study of hydroxychloroquine in ATL patients with skin lesions (JPRN-jRCTs071220095)	Chronic favorable or smoldering ATL Peripheral lymphoid tumorr refractory to local treatment	Hydroxychloroquine 200 mg daily
Single center phase 1 study of CD7 CAR T cells in T cell lymphoma and leukemia (NCT05620680); n=20	Relapsed/refractory T cell lymphoma OR leukemia Lines of therapy not specified	Autologous CD7 CAR T at doses of 0.5–2×10^6 cells/kg
Phase 2 single center study of Autologous Dendritic Cell Vaccine Therapy Targeting HTLV-1 Specific Antigen for ATL (JPRN-jRCT2073210013); n=34	Pre-treated ATL patient with the following criteria: PR or better Aggressive ATL Pretreatment with chemo and/or radiotherapy Positive for any of HLA-A*0201, *2402, *1101, or *0207	ATL-DC-101 administered subcutaneous of near the regional lymph node. ATL-DC-101 is administered 3 times with two-week interval at a dose of 5.0 × 10^6 cells.

Aggressive ATL denotes acute, lymphoma and unfavorable chronic subtype.

NCI, national cancer institute; ATL, adult T cell leukemia lymphoma; AZT, azidothymidine; IFN, interferon; CR, complete response; PR, partial response; SD, stable disease; NK, natural killer; PTCL, peripheral T cell lymphoma; CELMoD, cereblon E3 Ligase Modulatory Drugs; CAR T, chimeric antigen receptor T; NHL, non-Hodgkin lymphoma; AML, acute myeloid leukemia

2.0. Small molecule inhibitors/targeted therapies

2.1. Enhancer of zeste homolog (EZH) inhibitors

Valemetostat is a novel and potent dual inhibitor of EZH2 and EZH1. ATL epigenetic studies demonstrate downregulation of tumour suppressor genes is driven by polycomb-repressive complex 2 (PRC2)-mediated trimethylated at histone H3Lys27 (H3K27me3). Since PRC2 includes EZH1 or EZH2 as the enzymatically active core subunits, dual EZH inhibitors such as valemetostat can reverse global accumulation of H3K27me3 in ATL cells by reducing the number of inactivated genes to the level of normal CD4⁺ cells.

Valemetostat is currently approved and available for use only in Japan for the treatment of R/R ATL based on a phase 2 trial of 25 patients of whom all but one had prior exposure and 24% were refractory to Mogamulizumab [3]. Responses were impressive in this heavily pre-treated population with a median of 3 prior lines of therapy including nearly universal exposure to anthracycline chemotherapy with 48% overall response rate (ORR), 20% complete responses (CR), median progression free survival (PFS) of 7.4 months, median overall survival (OS) of 16.4 months and median duration of response not reached. Response rates were similar in the mogamulizumab refractory group and in the 32% of patients with prior lenalidomide exposure. Promisingly the ORR was similar in refractory disease as compared to relapsed disease at 45.5% and 37.5% respectively. Response rates were higher in the acute subtype with ORR of 62.5%. It is difficult to infer efficacy in the other subtypes given small numbers; ORR of 16.7% (1/6) for lymphoma and 33.3% (1/3) for unfavorable chronictype. Although efficacy by disease compartment was superior in peripheral blood with ORR of 89% compared to 50% in nodal or extranodal disease, the CR rate was similar between both compartments due to a higher rate of PR in blood. Longer term follow-up is necessary to evaluate durability given survival data is limited by median follow-up of 6.5 months at data cut-off. Given the high response rates in refractory disease, valemetostat, is an excellent option for ATL patients that have progressed on mogamulizumab or lenalidomide. A major advantage of Valemetostat is rapid response with median time to response of 1.4 months allowing early evaluation of failure of therapy. Valemetostat had an expected safety profile with the main ≥grade 3 toxicities being hematological predominantly thrombocytopenia managed with supportive care or dose modification [3]. VALENTINE-PTCL01 is a phase 2 global open-label, single arm study of valemetostat in relapsed peripheral T cell lymphoma including ATL has reported preliminary results with high response rates in T follicular helper cell phenotype and angioimmunoblastic T cell lymphoma. Following valemetostat’s 2022 approval in Japan, the trial shifted its ATL cohort endpoint from efficacy to safety, recognizing that disease characteristics vary between Japanese patients and those in Europe and USA. Treatment-emergent adverse events were comparable to the phase 2 trial in Japan with no new safety signals; efficacy data in the ATL cohort was not reported. [4].

The modest efficacy of valemetostat in ATL is diminished by acquired resistance. Yamagishi et al demonstrated through multilayered omics in the pivotal Japanese phase 1 and phase 2 trials that long term valemetostat in responding ATL patients results in emergence of resistant clones [5]. These clones often develop acquired mutations in the PRC2 complex leading to increased H3K27me3 expression. Alternative mechanisms of resistance in the absence of PRC2 complex mutations in other cases are due to loss of function TET2 and increased expression of DNMT3A.

2.2. Immunomodulators

Lenalidomide is an oral immunomodulatory agent with pleotropic antitumor effects including stimulation of natural killer cell function. Promising action of lenalidomide in B cell lymphoma and subsequently peripheral T cell lymphoma was the rational basis for investigation in ATL. Two large prospective studies conducted in Japan have established lenalidomide as a valid therapeutic option for treating R/R ATL [6, 7]. These data are extrapolated for use ex-Japan and are endorsed by consensus guidelines in the US [8]. The ATLL-001 study dose escalated lenalidomide in a 3+3 fashion in 14 patients, ultimately selecting 25 mg daily as the maximum tolerate dose based on toxicities observed. Prior allogeneic transplantation was exclusionary. Hematologic toxicities predominated, including neutropenia (85%; grade 3, 62%) and thrombocytopenia/anemia (each 77%; grade 3 thrombocytopenia, 31%). Rash and liver chemistry abnormalities were the most common non-hematologic toxicities. Among response evaluable patients, 43% responded at a median time of 1.8 months of therapy.

Based on the ATLL-001 study, the subsequent phase 2 ATLL-002 study was performed and treated 26 patients at an initial dose of 25 mg daily. Prior alloHCT was again exclusionary. The overall response rate was 42% with 19% CR and responses were observed across Shimoyama subtypes and across compartment of disease (skin, blood, and tumor). The median duration of response was not reached, belying the relatively durable responses observed. Grade 3/4 hematologic toxicity was observed: thrombocytopenia in 23% of patients and neutropenia in 65% of patients.

Subsequent studies have shown use of lenalidomide post-alloHCT to be effective but with the potential to incite or worsen GVHD, which is unsurprising given its mechanism of action. Sakamoto and colleagues reported outcomes for 4 patients with relapsed ATL post-alloHCT who received lenalidomide: one patient achieved CR but experienced flare of GVHD after one week of therapy; the second achieved stable disease with 29 weeks of therapy; the third patient achieved a CR with therapy but later progressed; and the final patient did not respond and experienced progression of GVHD with therapy. A subsequent report expanded our understanding in this context with 11 patients treated with lenalidomide post-alloHCT [9]. Seven of 11 patients had received mogamulizumab prior to receipt of lenalidomide and 4/11 had active GVHD at time of lenalidomide initiation. Comparable to what was observed in ATLL-002, the overall response rate was 45% including 27% achieving CR. Lenalidomide was associated with incipient GVHD in five patients (45%) and worsened pre-existing GVHD in four and this phenomenon was evident soon after treatment initiation (median, 5 days). Some patients were successfully re-challenged with lenalidomide after pausing for treatment of GVHD. Hematologic toxicity occurred: the rate of grade 4 neutropenia was 36% and grade 4 thrombocytopenia 27%; these abnormalities improved with dose reduction of lenalidomide.

2.3. Histone deacetylase (HDAC) inhibitors

HDAC inhibitors have activity in T-cell lymphoma through epigenetic modulation. Tucidinostat is a benzamide HDAC inhibitor has three mechanisms of action: direct tumor suppression, immunomodulation and epigenetic modification of cellular functions. Based on this, oral tucidinostat was studied in twenty three patients, all of whom were exposed to mogamulizumab with a median of two prior lines of lines therapy, in a phase 2 multicenter trial in Japan for R/R ATL [10]. The study reported a low CR rate of 4.3% but a modest ORR of 30.4%. Responses were only observed in relapsed or recurrent disease, with no responses in refractory ATL. The median PFS was short at 1.7 months, with median OS of 7.9 months and median duration of response of 9.2 months. Responses were markedly superior in the acute subtype with ORR of 46.2% compared to 12.5% in the lymphoma subtype. The median time to treatment response was notably longer than other targeted argents at 3.1 months. Tucidinostat’ s safety profile was consistent with the class effects of HDAC inhibitors, primarily causing hematological side effects. Despite the poor survival outcomes, tucidinostat remains a reasonable option for patients previously exposed to mogamulizumab, given the limited treatment alternatives. Tucidinostat is approved in Japan and China for R/R peripheral T cell lymphoma and for R/R ATL in Japan; it is currently not approved in the United States or Europe.

In the United States, a single center phase 2 trial is evaluating the role of the pan-HDAC inhibitor, belinostat, as consolidation therapy in patients with aggressive ATL who have persistent peripheral blood disease after prior therapy [11]. This trial combines belinostat with zidovudine (ZDV) and interferon (IFN), which together are known to be efficacious in leukemic ATL but have suboptimal response. The planned accrual is 10 patients, and interim results have been published for 6 patients with acute ATL, of whom 3 received prior chemotherapy as well as ZDV and IFN, while the remaining 3 received prior ZDV and IFN alone. Treatment was discontinued in 4 patients due to recurrent ≥ grade 3 hematological toxicities that persisted despite dose reductions, and 2 patients had progressive disease. Of the 4 patients who discontinued therapy, 2 patients maintained partial response and 2 patients achieved CR. Ongoing accrual and longer-term follow-up are necessary to determine the efficacy of HDAC inhibitors in acting as consolidation therapy and eradicating minimal residual disease.

2.4. Glycogen Synthase Kinase 3 Beta (GSK3β) Inhibitors

Glycogen synthase kinase 3 alpha (GSK3α) and GSK3β are overlapping serine/threonine kinases that phosphorylate over 100 protein substrates in key cellular signaling pathways including Wnt/β-catenin, Hedgehog, Notch, NF-κB, and PI3K/Ak [12]. Ishikawa et al demonstrated GSK3β, but not GSK3α, is overexpressed in HTLV-1-infected T-cell lines [13]. In vitro treatment with 9-ING-41, a highly selective inhibitor of GSK3β, inhibited the proliferation and survival of HTLV-1-infected T-cell lines through multiple mechanisms including: reactive oxygen species production, DNA damage, cell cycle arrest in the G2/M phase, activation of JNK and p53, inhibition of glycolysis, and suppression of c-Myc, NF-κB, AP-1, Akt, and STAT3/5 signaling. Although this manuscript utilized HTLV-1 infected cells as opposed to ATL cells, further clinical evidence comes from a case report for use of 9-ING-41 in R/R ATL. Hsu and colleagues describe a 43-year-old patient receiving 9-ING-41 as the fourth line of therapy for relapsed ATL who experienced a durable response for 15 months and disease progression associated with a newly acquired TP53 mutation [14]. Selective targeting of GSK3β could be promising in ATL, given its apparent role in immune modulation rather than direct cytotoxicity and is worthy of further study.

3.0. Antibodies and antibody-drug conjugates

3.1. Mogamulizumab

Mogamulizumab is an anti-CC chemokine receptor 4 (CCR4) IgG1 monoclonal antibody with a defucosylated Fc region which enhances antibody-dependent cellular cytotoxicity. As CCR4 is highly expressed on tumor cells with ATL, mogamulizumab progressed to a phase 2 monotherapy study in 29 relapsed CCR4-positive ATL patients. The objective response rate was 50% (31% CR) with markedly different responses by disease compartment: CR was 100% in blood, 63% for skin and 25% for nodal and extranodal lesions. Overall responses were better for chronic type at 83% versus 33% for lymphoma. Although overall responses were modest, durability was limited with median PFS of 5.2 months and OS of 13.7 months. Approval in Japan was based on the high ORR. Mogamulizumab was well tolerated with skin rashes a frequent adverse effect in 63% usually occurring after the fourth infusion. Severity of skin rash was correlated with response as 93% of objective responses and all complete responses were only seen in patients with ≥ grade 2 skin rash [15, 16].

Mogamulizumab has been used as a bridge in relapsed disease to allogeneic transplantation. However, this has been limited by increased frequency and severity of acute graft versus host disease (GVHD) with rates of Grade 3 or 4 acute GVHD at 31% with use of compared to 17% with no use of mogamulizumab prior to transplantation. The largest series of allogeneic transplantation in relapsed ATL reported a median of 45 days between last dose of Mogamulizumab and allogeneic transplantation with interval < 50 days associated with inferior OS on multivariate analysis [17].

Real-world responses in Japan were similar to the pivotal phase 2 study with best ORR of 58%; however, durability was poor with median OS of 5.5 months.. Although, post marketing surveillance found cytomegalovirus (CMV) infection was the most common serious infectious adverse effect including viremia (8%), pneumonia (4%) and sepsis (2%), this data is limited by lack of information on adverse effects by combination therapy versus monotherapy with mogamulizumab. Rates of acute GVHD were more than two times higher at 66% for those who received allogeneic transplantation within 90 days of last dose of Mogamulizumab compared to those transplanted after 90 days at 29% [18].

A phase 2 trial of relapsed ATL in US, Europe and Latin America randomized to mogamulizumab or investigator’s choice of chemotherapy was disappointing with 11% ORR and no CR to Mogamulizumab. The discrepancy with results in Japan is thought to be due to inclusion of refractory patients as opposed to relapsed only in the Japan study and a higher incidence of conventional poor prognostic factors in randomized patients in this study [19]. Mogamulizumab is approved in Europe and the United States (US) for relapsed CCR4+ cutaneous T cell lymphoma and available off-label for ATL in the US based on NCCN compendium listing [20].

Mogamulizumab sequencing is critical as superior outcomes are observed with use in relapsed rather than refractory disease and in earlier lines of therapy. There is limited evidence to suggest the use of histone deacetylase (HDAC) inhibitors prior to mogamulizumab may reduce its effectiveness by downregulating HDAC2 and leading to decreased CCR4 expression. Kitadate et al reported decreased CCR4 expression on ATL, cutaneous T cell and peripheral T cell lymphoma patient samples with disease progression on vorinostat [21]. This was confirmed in various lymphoma cell lines, including ATL, which exhibited reduced mogamulizumab associated ADCC after vorinostat pretreatment. Based on this, it has been suggested that HDAC inhibitors should be sequenced after mogamulizumab; however, this strategy has not been prospectively confirmed given the rarity of the disease.

Given its efficacy in the relapsed setting, mogamulizumab has been investigated in Japan in the front-line setting in combination with chemotherapy using the dose intensified mLSG15 regime. This phase 2 randomized controlled multicenter trial in Japan for aggressive ATL compared 24 patients receiving mLSG15 alone against 29 patients receiving mLSG15 and mogamulizumab [22]. The combination therapy showed superior responses, increasing the CR rate by 18% from 33% to 52%. Notably, peripheral blood responses were higher with the combination arm at CR of 100% compared to 50% for skin lesions, contributing to the overall increase in the CR rate. However, the PFS between the two arms was similar. Despite the higher percentage CR observed in the interventional arm, assessing the durability of this response is challenging because the trial was not powered to evaluate survival endpoints and had a short follow-up period. Additionally, the combination resulted in an unacceptable rate of CMV infection and pneumonia at 21% compared to none in the chemotherapy-alone arm. Retrospective studies using older chemotherapy regimens have demonstrated the reactivation of opportunistic infections, such as CMV viremia, is a unique phenomenon in ATL, although CMV disease is rare. The combination intervention of mLSG15 and mogamulizumab likely enhances this phenomenon resulting in increased CMV infections seen [22].

It remains unclear whether the combination of mogamulizumab with chemotherapy is superior to chemotherapy alone for long-term survival. A small retrospective single-center study in Japan, involving 39 transplant-ineligible patients with newly diagnosed aggressive ATL, reported a superior 4 year of OS 46.3% for the mogamulizumab-chemotherapy combination compared to 20.6% for chemotherapy alone [23]. However, a larger single-center retrospective cohort study from a similar region, which included 77 transplant-ineligible ATL patients, compared survival in those treated with the mogamulizumab combined with either mLSG15 or the infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) regimen, as well as with chemotherapy alone [24]. Notably, 87% of the chemotherapy-alone group received mLSG15. In contrast to the previous study, this research found that the mogamulizumab + EPOCH regimen demonstrated superior survival compared to mogamulizumab + mLSG15 and showed similar survival outcomes to the chemotherapy alone group. Despite the limitations of small sample sizes and retrospective designs in both studies, their differing results create uncertainty about whether adding mogamulizumab to chemotherapy provides a definitive survival benefit.

An alternative strategy was evaluated in transplant-ineligible patients by using sequential consolidation therapy with mogamulizumab after chemotherapy, as opposed to combining mogamulizumab with chemotherapy. A phase 2 single-arm multicenter trial assessed 3 cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) every 21 days followed by 8 cycles of mogamulizumab consolidation in 24 patients [25]. The trial reported promising ORR, with a 1-year PFS of 26.6% and a 1-year OS of 52.6%. Although the 1-year PFS was superior to CHOP and similar to the mLSG15 regime in transplant eligible patients, long term survival remains poor [26]. These results indicate that the approach of using abbreviated chemotherapy followed by consolidation with mogamulizumab was not effective in improving long-term survival. Building on these findings, a new regimen was developed to address these limitations. The Moga-CHOP-14 regimen was designed for untreated, transplant-ineligible elderly patients with aggressive ATL. This phase 2 single-arm multicenter trial with 48 evaluable patients who received 6 cycles of mogamulizumab combined with CHOP every 14 days, followed by 2 cycles of mogamulizumab monotherapy as consolidation [27]. The regimen achieved a high CR of 67%, 92% ORR%, with a median PFS of 0.7 years, a median OS of 1.6 years, and a 1-year OS of 66%. The toxicity profile was consistent with the known effects of the combination of mogamulizumab combined with chemotherapy. Although direct head-to-head comparisons are not possible, cross-trial analyses suggest that the Moga-CHOP-14 regimen provides superior 1-year survival compared to the previous regimen. Consequently, this new regimen appears to be a viable alternative for newly diagnosed transplant-ineligible patients and may offer improved outcomes compared to previous approaches.

It is essential to characterize the mechanisms of resistance to mogamulizumab given lack of durable responses. Resistance mechanisms in ATL are not well understood and have been extrapolated from phenotypic and genomic studies at progression on mogamulizumab therapy in cutaneous T cell lymphoma (CTCL). Resistance is due to genomic events disrupting CCR4 leading to CCR4 antigen loss, loss of CCR4 antigen in the absence of detectable genomic events or an undiscovered mechanism with retained high CCR4 expression. The most common cause of resistance in CTCL is low CCR4 expression from the first two mechanisms. Notably, this study is limited by small numbers and targeted sequencing of CCR4 exonic region, rather than other contributing genomic mutations [28].

There is evidence suggesting that mogamulizumab may contribute to an increased risk of opportunistic infections, particularly CMV and Hepatitis B reactivation. A post-marketing surveillance of Food and Drug Administration on adverse events found mogamulizumab had a reporting odds ratio of 56 for CMV-related infections, indicating a 56-fold greater likelihood of reporting such infections compared to other medications [29]. Only alemtuzumab had a higher odds ratio at 70. Despite this high reporting odds ratio, the absolute number of CMV cases were relatively low, with 17 out of 338 (5%) serious adverse effect reports attributed to mogamulizumab. Consistent with prior literature, CMV reactivation is notably prevalent in ATL, and most of the reported CMV cases associated with mogamulizumab were in ATL patients, with a significantly lower incidence in cutaneous T cell lymphoma. While the increased risk of CMV infections with mogamulizumab in ATL is consistent with ATL’s inherent susceptibility to CMV, the specific mechanism by which mogamulizumab exacerbates this risk remains unclear. Given these findings, it is crucial to be vigilant about the risk of opportunistic infections when using mogamulizumab, and to implement proactive screening and early intervention if such infections are suspected.

3.2. Brentuximab-vedotin

Brentuximab-vedotin (BV) is an antibody drug conjugate with an anti-CD30 monoclonal antibody conjugated to the microtubule disrupting drug monomethyl auristatin E [30]. The rationale for BV therapy in ATL is based on 15% to 33% of ATL expressing CD30 [31, 32]. The ECHELON-2 trial was a randomized phase 3 trial leading to the approval of brentuximab vedotin, cyclophosphamide, doxorubicin and prednisone (BV-CHP) in treatment naïve CD30+ peripheral T cell lymphoma after demonstrating superiority to standard of care chemotherapy. As this study was powered to look at PFS in systemic anaplastic large cell lymphoma which accounted for 75% of the patients, recruitment of ATL was limited with only 7 patients [30]. It is challenging to draw meaningful conclusions given such a small number of ATL patients. This was the impetus for a phase 2 study (NCT03264131) incorporating BV into a chemotherapy regime of etoposide with CHP (CHEP) in treatment naïve ATL [33]. Given BV efficacy at any level in clinical trial series[34], patients were considered CD30+ for this trial if there was >1% expression. The responses and survival appear promising with 88% ORR (63% CR), median PFS of 7.1 months and median OS of 12.2 months [33]. Confirmatory phase 3 trial may be necessary given the prior study only had 16 patients. There are only case reports confirming BV efficacy in relapsed ATL [35].

3.3. Cellular and other adoptive immunotherapies:

Chimeric antigen receptor-modified T-cells (CAR-T) are a form of adoptive immunotherapy that has fundamentally changed the treatment landscape of many B-cell non-Hodgkin lymphoma subtypes. However, major challenges have existed for translating these successes for treating T-cell lymphomas, including ATL. These include optimizing target antigen selection, the potential for T-cell fratricide, and instances of hyperprogression that have occurred.

CTX130 is a CD70-directed CAR-T product that has been studied in R/R PTCL (pan-histology) and renal cell carcinoma [36]. In reported data from Iyer and colleagues, 3 patients (17% of study population) had ATL, of which 2 responded: 1 with CR and 1 with initial PR at 28 days post-infusion that later converted to CR with reinfusion at a higher dose level. Toxicity at dose levels 3 and 4 was notable for cytokine release syndrome of grades 1–2 in 8 (80%) patients, neurotoxicity in 3 (30%) patients (also grades 1–2), and grade ≥3 infection in 2 (20%) patients, which are similar toxicities to CAR-T use in B-cell lymphomas.

A first-in-human study testing a CD5-directed CAR-T therapy in R/R mature PTCLs was reported this year and showed promising efficacy [37]. One patient was a 49-year-old woman with R/R ATL after 5 lines of therapy treated at dose level 3 (1 × 10⁸ cells/m²). Although there was an initial partial response achieved, unfortunately, the patient’s disease did not respond to reinfusion, and she subsequently received alternate therapy. Other potential CAR-T antigen targets for treating ATL include CD3, CD7, CCR4, and CCR8 [38–41] and we await further pre-clinical and clinical investigations in this area to define the role, if any, for CAR-T therapies in the ATL treatment landscape.

4.0. Conclusions and future directions:

The standard-of-care in treatment naïve aggressive ATL has been combination chemotherapy, often with intensive regimens, based on fitness and age. Therapeutic advances from the relapsed setting have been sequenced earlier into the front-line setting with BV-CHP showing promise with the need for a larger confirmatory study [33]. In the front-line setting, mogamulizumab combined with dose intensified chemotherapy has shown high response rates, primarily due to improved clearance of disease from peripheral blood. However, it remains to be seen whether the addition of mogamulizumab improves long-term survival compared to chemotherapy alone. Furthermore, combining mogamulizumab with chemotherapy appears associated with a higher incidence of CMV infections.

There is no one standard of care in R/R ATL, and the aim is to use therapies that maximize response rate and the quality of responses allowing consolidation with an allogeneic transplantation in eligible patients or maintained remissions in others. Immunomodulators and mogamulizumab have been studied in various settings, and cross-trial comparisons are needed to evaluate optimal therapy sequencing. All novel agents are highly effective in clearing peripheral blood disease, have modest efficacy for skin disease and inferior efficacy in clearance of nodal and extranodal disease. Valemetostat stands out as an exception, demonstrating modest efficacy in nodal and extranodal disease as well [4]. For transplant-eligible patients, achieving a high rate of CR is crucial. Valemetostat and mogamulizumab are preferred due to their higher CR rates compared to other immunomodulators. Valemetostat has the advantage of not requiring a lengthy treatment discontinuation period before transplant, unlike mogamulizumab, which must be stopped for 50 days to mitigate the risk of acute GVHD. Additionally, valemetostat has demonstrated greater effectiveness in refractory patients, including those refractory to mogamulizumab, whereas mogamulizumab’s efficacy in refractory disease remains uncertain [4, 15]. For transplant-ineligible patients, the best options remain valemetostat and mogamulizumab due to their much higher rates of CR compared to lenalidomide and tucidinostat [4, 7, 10]; tucidinostat is available only in China and Japan. However, the nuances of these additional therapies are important: lenalidomide has reduced efficacy in patients previously exposed to mogamulizumab, both lenalidomide and tucidinostat are ineffective or have poor efficacy in refractory disease, and tucidinostat demonstrates superior responses in the acute ATL compared to lymphoma subtype [7, 10].

Despite these new agents, ATL remains an urgent area of unmet with poor survival outcomes in both the treatment naïve and relapsed setting. We anticipate future regimes are likely to incorporate different combinations of novel agents particularly those with distinct mechanisms of action and non-overlapping toxicities, to optimize efficacy and minimize side effects. Additionally, while CAR T-cell therapy has proven to be curative in a significant portion of relapsed B cell lymphoma patients without the need for transplantation, its role in T cell lymphomas including ATL is less established. Currently, CAR T-cell therapy in relapsed and refractory T cell lymphomas, including ATL, are mainly used after transplantation or in transplant-ineligible patients. Future advancements may enhance the effectiveness of CAR T-cell therapy in mature T cell lymphomas like ATL, possibly reducing the need for transplantation, similar to its success in B cell lymphomas. Given the rarity of this disease subtype, a concerted and co-operative international approach to trials in ATL is necessary to overcome therapeutic hurdles.