Refractory Cutaneous T-cell Lymphoma Research Articles

Safety and effectiveness of mogamulizumab in relapsed or refractory CC chemokine receptor 4-positive peripheral T-cell lymphoma and relapsed or refractory cutaneous T-cell lymphoma: A post-marketing surveillance in Japan.

Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and≥70years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.

Abstract 3201: Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies

Abstract The histone deacetylase inhibitors (HDACi) have long been regarded as an important class of drugs for treating T-cell lymphoid malignancies (TCL). Romidepsin (Romi), a bicyclic peptide, was approved for patients with relapsed or refractory cutaneous (CTCL) and peripheral T-cell lymphomas (PTCL). Unfortunately, the approval of Romi for relapsed/refractory PTCL was withdrawn due to a negative Phase 4 post-marketing requirement. Given its potent activity against Class I HDACs, Romi is considered one of the most effective HDAC inhibitors studied and used in patients with TCL. Herein, we report on a first-in-class nanoparticle of Romi (NanoRomi) with a superior safety and efficacy profile compared to the free drug in preclinical models of PTCL and large granular lymphocyte leukemia (LGLL). We developed a first-in-class NanoRomi using our proprietary amphiphilic di-block copolymer-based nanochemistry platform. NanoRomi was characterized in cell viability, flow cytometry, and western blotting (WB) assays to determine the concentration-effect relationships with regard to the induction of apoptosis and histone acetylation in cell lines representative of TCL and LGLL, as well as primary LGLL patient PBMC samples. In addition, we performed extensive in vivo modeling using murine xenografts of CTCL, including repeated dose toxicity, biodistribution, efficacy, and survival studies. Cytotoxicity assays demonstrated superior/comparable activity of NanoRomi (IC50: 1.1-2.3 nM) compared to free Romi (IC50: 4.8-10.6 nM) across all PTCL and LGLL cell lines studied, while in primary LGLL samples, NanoRomi exhibited superior cytotoxicity (2-fold) compared to Romi. WB analysis showed that NanoRomi induced apoptosis and increased acetylation of histone H3 and H4 in a time and concentration-dependent manner in cell lines representing CTCL, ALK+-ALCL, and LGLL. Repeat dose toxicity studies in CTCL xenografts confirmed that the overall tolerability of NanoRomi was substantially better than Romi. Tracking studies with a fluorescent dye (DiO) in the NanoRomi demonstrated preferential localization of NanoRomi in tumors of mice compared to the normal organs after 6 hours of drug administration. NanoRomi exhibited superior efficacy in the murine CTCL xenograft models, including a significant improvement in overall survival compared to Romi. Collectively, these data show that NanoRomi exhibits markedly superior pharmacokinetics, tolerability, and efficacy in models of TCL. We anticipate that the improved activity and tolerability of NanoRomi relate to the altered pharmacologic profile and superior bioavailability of the drug, which optimizes the effects of the drug for its influence on epigenetic biology. This unique platform offers the prospect of improving the tolerability and efficacy of epigenetic treatment strategies in these challenging diseases. Citation Format: Ipsita Pal, Anuradha Illendula, Andrea Joyner, Tess M. Deddens, Deepthi P. Damera, Todd E. Fox, Marya E. Dunlap-Brown, Kallesh D. Jayappa, Thomas P. Loughran, David J. Feith, Owen A. O'Connor. Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3201.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study

AbstractTargeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of patients with CTCL, creating an urgent need for new and effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and, thus, represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and, specifically, kill CTCL cells. To translate these findings to applications in a clinical setting, we performed a multicentric phase 2 study evaluating oral DMF therapy in 25 patients with CTCL stages Ib to IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). End points were safety and efficacy. We evaluated skin involvement (using a modified severity weighted assessment tool [mSWAT]), pruritus, quality of life, and blood involvement, if applicable, as well as translational data. Upon skin analysis, 7 of 23 (30.4%) patients showed a response with >50% reduction in the mSWAT score. Patients with high tumor burden in the skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB–inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable, with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase 3 study or real-life patient care as well as in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT02546440.

CD38 Targeting Holds Potential for the Treatment of Aggressive Refractory Cutaneous T-Cell Lymphomas

CD38 Targeting Holds Potential for the Treatment of Aggressive Refractory Cutaneous T-Cell Lymphomas

Proteasome Inhibitors Interact Synergistically with BCL2, Histone Deacetylase, BET, and Jak Inhibitors against Cutaneous T-Cell Lymphoma Cells

Cutaneous T-cell lymphoma (CTCL) is often refractory to treatment at advanced stages with blood involvement ( Dummer et al., 2021 Dummer R. Vermeer M.H. Scarisbrick J.J. Kim Y.H. Stonesifer C. Tensen C.P. et al. Cutaneous T cell lymphoma. Nature Reviews Disease Primers. 2021; 7: 61 Crossref PubMed Scopus (22) Google Scholar ). We have previously revealed the synergistic cytotoxic effects of inhibiting BCL2, HDAC, BET, and/or JAK in patient-derived CTCL cells and CTCL cell lines, suggesting potential advantages of a spectrum of combination treatment strategies for this disease ( Cyrenne et al., 2017 Cyrenne B.M. Lewis J.M. Weed J.G. Carlson K.R. Mirza F.N. Foss F.M. et al. Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients. Blood. 2017; 130: 2073-2083 Crossref PubMed Scopus (36) Google Scholar , Kim et al., 2018 Kim S.R. Lewis J.M. Cyrenne B.M. Monico P.F. Mirza F.N. Carlson K.R. et al. BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. Oncotarget. 2018; 9: 29193-29207 Crossref PubMed Scopus (35) Google Scholar , Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ). Proteasome inhibitors target multiple pathways including protein degradation to cause cytotoxicity and have been utilized in other hematologic malignancies. They have demonstrated efficacy as a single agent in a small phase II trial of patients with relapsed or refractory CTCL ( Zinzani et al., 2007 Zinzani P.L. Musuraca G. Tani M. Stefoni V. Marchi E. Fina M. et al. Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology. 2007; 25: 4293-4297 Crossref PubMed Scopus (236) Google Scholar ), as well as in limited combinations during preclinical studies ( Yumeen et al., 2020 Yumeen S. Mirza F.N. Lewis J.M. King A.L.O. Kim S.R. Carlson K.R. et al. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv. 2020; 4: 2213-2226 Crossref PubMed Scopus (19) Google Scholar ) and early clinical trials ( Holkova et al., 2017 Holkova B. Yazbeck V. Kmieciak M. Bose P. Ma S. Kimball A. et al. A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leuk Lymphoma. 2017; 58: 1349-1357 Crossref PubMed Scopus (15) Google Scholar ). Herein, we share our expanded preclinical assessment of the synergistic activity of proteasome inhibitors when used with the BCL2 inhibitor venetoclax, HDAC inhibitor vorinostat, BET inhibitor mivebresib, or JAK inhibitor fedratinib. We reveal that the cytotoxic effects from combination treatment were greater than additive when assessed in patient-derived CTCL cells. Furthermore, we demonstrate an increase in apoptosis pathway activation with combination treatment and explore the gene expression changes underlying these synergistic effects.

Advanced stage cutaneous T-cell lymphoma treated with high-dose external beam radiation therapy: A case report.

The treatment for advanced-stage or refractory cutaneous T-cell lymphoma (CTCL) is largely palliative. Due to the rarity of the disease, there are few randomized controlled trials and large-scale prospective studies. Therefore, the treatment of advanced-stage CTCL remains challenging. A 64-years-old man who had received narrowband UVB phototherapy for several years presented with a generalized rash with widespread polycyclic erosions and painful ulcers on his hands and feet. We restaged him as stage III CTCL. He was treated with high-dose radiation for curative purposes and 3-dimensional conformal radiation therapy to both hands and feet. At the 2-year follow-up after the end of radiotherapy, the irradiated skin had recovered to normal soft, smooth skin with localized fibrosis and hypopigmented skin. He reported an excellent quality of life, and his hands and feet were free to move. CTCL at an advanced stage could require dose escalation with local radiotherapy for curative purposes. High-dose 3-dementional conformal radiation therapy could be effective and has tolerable toxicities.

Efficacy and Safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd) is a recombinant fusion protein of diphtheria toxin and human interleukin-2. Dd was approved and marketed as ONTAK in the US from 1999-2014 for treatment of pts with relapsed/refractory CTCL. ONTAK was voluntarily taken off the market in 2014 due to manufacturing difficulties. E7777 was developed as a result of a refined manufacturing process and has an increased percentage of protein monomer species, with a concomitant decrease in levels of misfolded protein and protein aggregates. E7777 has ~1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK and is considered a new drug by the FDA. Methods: Objectives: Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial designed to assess efficacy and safety of E7777 in patients with relapsed/refractory CTCL. E7777 was given IV at 9 mcg/kg/day (established from Lead-in) over 60 min for 5 days every 21 days up to 8 cycles. Key inclusion/exclusion criteria included histopathologic diagnosis of CTCL (MF or SS); ECOG performance status 0 or 1; no prior exposure to ONTAK. The primary efficacy endpoint was objective response rate (ORR; CR+PR) per Independent Review Committee (IRC) assessment based on Global Response Score GRS (Olsen, et al., 2011). Secondary efficacy endpoints included duration of response (DOR), time-to-response (TTR), skin response (according to modified Severity Weighted Assessment Tool [mSWAT]), safety and tolerability of E7777, PK, and immunogenicity. Exploratory objectives included progression free survival (PFS), time to progression (TTP), pruritus improvement, and quality of life assessment. Results: A total of 112 patients with CTCL stage I-IV were enrolled in the study: 21 in the Lead-in and 91 in the Main Study. The primary efficacy population is comprised of 69 patients with stage I-III CTCL treated at 9 mcg/kg/day. Median number of prior anticancer therapies in Study 302 were 4.0 (range: 1 to 18). Forty-five patients (65.2%) received ≥4 prior anticancer therapies. Approximately half (34 of 69; 49.3%) of patients had prior exposure to 1 or more FDA-approved targeted therapeutics: romidepsin, brentuximab, or mogamulizumab. Demographic and baseline characteristics of patients included a median age of 64 (range 28-87); ECOG status 0 (56.5%) and 1 (43.5%); Race: 72.5% White, 18.8% Black; 9% Other. There disease stages were 43.5% IA/IB/IIA; 34.8% IIB; and 21.7% IIIA/IIIB. The median (range) number of cycles of E7777 received was 6.0 (1, 42). The primary efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR. ORR (95% CI) by Investigator was 42.3% (30.6%, 54.6%), with 8.5% achieving a CR (Table 1). DOR was at least 6 months for 13 (52.0%) responders and at least 12 months for 5 (20.0%) responders. TTR was rapid (median=1.41 months); the majority of responders (~70%) had a response after 1 to 2 cycles of treatment. Treatment with E7777 did not demonstrate any new or unexpected safety findings as compared to prior ONTAK experience. Most patients (98.6%) experienced at least 1 TEAE. Most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles, then decreased and remained low/stable over the remainder of therapy. Key adverse events of special interest (AESIs) associated with ONTAK in the past (i.e. capillary leak syndrome, hepatotoxicity, infusion reaction, and visual impairment) were primarily Grade 1/2 in our current study and will be discussed in detail in a separate abstract. Conclusions: In study 302, E7777 at a dose of 9 mcg/kg/day demonstrated clinical efficacy and clinically meaningful benefit in heavily pre-treated patients with relapsed/refractory CTCL. The ORR of 36.2% per IRC (42.3% by investigator assessment) showed that a substantial proportion of these heavily pretreated patients experienced clinical benefit after E7777 treatment similar to ONTAK. The observed tumor responses were rapid, durable, and deep. A BLA submission to the FDA is planned for the 2nd half of 2022. E7777 will provide a novel, efficacious, safe, and non-cross-resistant therapeutic option for CTCL patients who have failed other treatments and thus fulfill a serious unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Tolerability of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd), a recombinant fusion protein composed of diphtheria toxin fragments and human interleukin-2 was approved and marketed (as ONTAK) in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. Manufacturing improvements (to decrease the presence of misfolded and aggregated proteins) resulted in a new, more bioactive formulation, E7777. It is considered a new drug by the FDA and required a new registrational clinical trial. Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial in which the primary efficacy and safety of E7777 were assessed. Here, we report the safety results of E7777. Methods: E7777 was given at 9 mcg/kg/day for 5 days every 21 days up to 8 cycles in patients with relapsed/refractory CTCL. Key inclusion/exclusion criteria: histopathologic diagnosis of CTCL; ECOG PS 0 or 1; no prior exposure to ONTAK. Evaluation of safety included incidence and severity of treatment-emergent AEs (TEAEs), and adverse events of special interest (AESIs). Key AESIs include capillary leak syndrome (CLS), infusion reaction, visual impairment (these three AEs were listed as Box warnings in the ONTAK label); and hepatotoxicity. Results: The Primary Efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR; detailed efficacy data will be presented in a separate abstract. In the subset of patients with Stage I-III disease (n=69), the median age was 64 years and the median number of E7777 cycles received was 6 (range 1 to 42); 66 patients had mycosis fungoides and 3 had Sezary syndrome, and 39 (57%) had disease of stage IIb or worse. The most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Thirty patients (43.5%) had a Grade ≥3 TEAE (90% Grade 3; 10% Grade 4)). The most common serious adverse events (≥ 5%) were capillary leak syndrome (10%) and infusion reactions (9%). Overall, the mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles. Most patients [92.8%] had at least 1 AESI (mostly Grade 1/2). Overall, 22 patients (31.9%) experienced AESIs that were Grade ≥3; (7.2%) had drug discontinuation; (4.3%) had drug dose reduction, and (26.1%) had drug dose interruption. Fourteen patients (20.3%) had CLS. CLS was defined as the occurrence of at least 2 of the following: hypotension, edema, or serum albumin < 3.0 g/dL. CLS was Grade 1 in 2.9%, Grade 2 in 11.6%, Grade 3 in 4.3%, and Grade 4 in 1.4%. Nine patients (13.0%) underwent drug modification: (4.3%) discontinued E7777; and (10.1%) had either dose reduction or temporary dose interruption. CLS typically occurred in the first 1/2 cycles. Risk/severity of CLS was mitigated by fluid management; confirmation of serum albumin levels (≥ 3.0 g/dl); close monitoring of weight, edema, and BP; early drug interruption; and rapid initiation of diuretic therapy on recovery. Fifty-one patients (73.9%) had an AESI related to infusion reaction. Grade 1 in 43.5%, Grade 2 in 26.1%, and Grade 3 in 4.3%. One patient (1.4%) had study drug discontinuation, and (11.6%) had either study drug dose reduction or interruption. In the event of infusion-related reactions, systemic corticosteroids may be added to premedication for subsequent E7777 infusions. Nine patients (13.0%) had an event related to visual impairment; all were AEs of blurred vision, which was Grade 1 in 11.6% and Grade 2 in 1.4%; no Grades 3, 4, or 5. One patient (1.0%) had drug interruption; no events led to study drug dose reduction. Twenty-five patients (36.2%) had AESI related to hepatoxicity. The TEAEs were Grade 1 in 17.4%, Grade 2 in 7.2%, Grade 3 in 11.6%, and no Grade 4/5. The majority of hepatic adverse events were elevations in transaminases that occurred within the first or second cycle, resolved without medical intervention, and did not require treatment discontinuation. Conclusion: No new safety signals were observed with E7777 when compared to the safety profile of ONTAK. There is no evidence of cumulative toxicity. Most patients had at least 1 TEAE which were mostly Grade 1/2. Specific AESIs: CLS, infusion reactions, and visual impairment (prior ONTAK Box warnings) were mostly Grade 1/2 and effectively managed. Overall, E7777 was well-tolerated with the use of pre-medications, close patient monitoring, and prompt initiation of supportive measures and drug management. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pembrolizumab in Combination with Epigenetic Therapy Is Safe and Active in Heavily Treated Patients with Peripheral T-Cell Lymphoma (PTCL) and Cutaneous T-Cell Lymphoma (CTCL): Preliminary Results from the Embolden Trial

Background: Peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Our group previously demonstrated that combinations of epigenetic modifiers such as histone deacetylase inhibitors (HDACi), hypomethylating agents and pralatrexate produced potent synergy in pre-clinical models of PTCL, which produced compelling activity in early phase clinical studies. We have demonstrated that epigenetic modifiers, such as decitabine and 5-azacytidine (Marchi et al; Br. J. Haematol. 171, 2015) induces the expression of cancer testis antigens and established that pralatrexate acts as an immunomodulatory agent affecting genes involved in cytokine production, viral response and apoptosis. These pre-clinical data suggest a role for the incorporation of the immune-checkpoint inhibitor, pembrolizumab, to epigenetic backbones. Herein, we report on the differential clinical activity of adding the immune checkpoint inhibitor, pembrolizumab, to decitabine, pralatrexate, or the combination and we describe the role of cytokines as a biomarker of treatment response. Trial Design & Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with relapsed and refractory PTCL and CTCL. A standard 3+3 dose-escalation was applied in the doublet Arms (A and C) while a DLT-adapted partial order continual reassessment method (POCRM) for dose-finding with combinations of agents was applied in the triplet Arm (Arm B). We evaluated the cytokine profile using a Luminex-based immunoassay on serum samples obtained from trial patients on days 1, 8 and 15 during cycle 1 of treatment. Quantitative changes in 25 unique cytokines were evaluated, and these changes were correlated with clinical outcomes. Results: We enrolled 15 patients with six patients in Arm A, four in Arm B, and five in Arm C. All patients that received at least one dose of drug were evaluable for toxicity. One dose limiting toxicity (DLT) was observed in Arms A and B (grade 3 thrombocytopenia and febrile neutropenia, respectively). In Arm C, three DLTs were observed including one patient with grade 3 hyponatremia and rash; one patient with grade 4 thrombocytopenia, neutropenia, and anemia; and one patient with grade 4 neutropenia. There were no treatment related deaths. Nine patients out of 15 were evaluable for response at the time of this analysis. Of these nine evaluable patients, one achieved a complete remission (Arm B), two achieved partial remission (1 in Arm A, 1 in Arm B), one had stable disease (Arm C), and five experienced disease progression (2 in Arm A, 1 in Arm B, and 2 in Arm C). Interestingly, two of the three responses were seen in patients who received the triplet of pralatrexate, decitabine, and pembrolizumab (Arm B) and one response was seen in a patient treated with pralatrexate and pembrolizumab (Arm A). The serum cytokine profile revealed significant changes in only five of the 25 cytokines surveyed. Of the five cytokines, three pro-inflammatory cytokines, TNFα, MIP-3α and IL-10, measured at day 1 pre-treatment exhibited significantly higher levels (p= 0.0001, 0.0008 and 0.003 respectively) compared to healthy controls. Trial patients who responded to treatment (PR/CR) in either Arms demonstrated a decline in serum levels of TNFα and IL-10 by day 15 of cycle 1, whereas non-responders (PD/SD) showed stable to increased levels of both TNFα (Figure 1) and IL-10. Conclusion: These preliminary data suggest that the integration of pembrolizumab into an epigenetic backbone is safe and demonstrates encouraging responses in heavily pretreated patients with PTCL and CTCL. Pharmacodynamic data suggests that certain cytokines might have predictive value as biomarkers of disease response and progression. Interestingly, patients that responded (PR/CR) to the study drugs displayed a decline in cytokine levels, highlighting the prognostic implications of these cytokines. Additional pharmacodynamic studies, including flow cytometry of peripheral blood mononuclear cells, and pharmacokinetic studies are ongoing. Clinical trial registry NCT03240211. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response to Brentuximab Vedotin by CD30 Expression in Non-Hodgkin Lymphoma.

BackgroundThe safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV.Patients and MethodsWe analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients.ResultsAcross all 5 studies, 140 (50.9%) patients had tumors with CD30 expression <10%, including 60 (21.8%) with undetectable CD30 by IHC. No significant differences were observed for any study in overall response rates between patients with CD30 expression ≥10% or <10%. Median duration of response was also similar in the CD30 ≥10% and <10% groups for all studies.ConclusionsIn this analysis of studies across a range of CD30-expressing lymphomas, CD30 expression alone, as measured by standard IHC, does not predict clinical benefit from BV, making the determination of a threshold level of expression uncertain.

Continuous low-dose gemcitabine in primary cutaneous T cell lymphoma: A retrospective study.

The aim of our retrospective study was to evaluate the efficacy of a continuous therapy with a lower dosage of gemcitabine compared to those usually administered in patients with cutaneous T cell lymphomas (CTCL). Twenty-two patients received different dosages of gemcitabine. Dosage and schedule of the drug were chosen on the basis of clinical features. Gemcitabine was given at 1000 mg every 15 days in 13 patients (four mycosis fungoides [MF], nine Sezary syndrome [SS]); at 1000 mg at days +1, +8, +15 in six cases (three MF, three SS). All patients had been previously treated: four patients had received both skin directed and systemic treatments. Eighteen patients had received photopheresis, IFN, chemotherapy and immunotherapy. The objective response rate (CR + PR) among all patients was 54.5% (12 of 22 patients) with a CR of 4.5% (one of 22 patients) and a PR of 50% (11 of 22 patients). Patients with SS had an ORR of 61.5% (eight of 13 patients) with one CR (7%) and seven PR (53.8%); patients with MF showed an ORR of 55.6% (five of nine patients) but no patients experienced CR (0%). The schedule with the highest efficacy and the lowest toxicity profile was 1000 mg every 15 days. Median progression free survival and overall survival in all patients were 17 and 45 months respectively. Gemcitabine was generally well tolerated. We have demonstrated that a much lower dose of gemcitabine (1000 mg once every 15 days) in patients with advanced-stage and refractory CTCL can lead to a durable response, with tolerable and manageable adverse effects.

Impact of Mogamulizumab in Real-Life Advanced Cutaneous T-Cell Lymphomas: A Multicentric Retrospective Cohort Study.

Simple SummaryMogamulizumab is a recent monoclonal antibody prescribed in the second line to treat advanced mycosis fungoides and Sézary syndromes. We collected data from all patients who used mogamulizumab in six French university hospitals until 1 September 2021. Our primary objective was to determine the median progression free survival (PFS). Secondary objectives were to consider tolerance regarding side effect occurrence and severity. Twenty-one patients were included, with a median time of follow-up of 11.6 months, and progression-free survival was estimated at 22 months. Twenty patients presented adverse events, of which 10 were severe. The median time between the introduction of mogamulizumab and the first adverse event was 21 days. Our study suggests that mogamulizumab is a significant treatment option to extend PFS in patients with advanced refractory cutaneous T-cell lymphomas (CTCL). The long-term safety of mogamulizumab was determined to be acceptable since we reported few grade III–IV adverse events (AEs) compared to other systemic treatments.Background: Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are rare, aggressive cutaneous T-cell lymphomas that may be difficult to treat. Mogamulizumab is a recent monoclonal antibody targeting the CCR4 receptor expressed on the surface of Sézary cells. It can be prescribed in MF/SS stages III to IV in the second line after systemic therapy or in stages IB-II after two unsuccessful systemic therapies. We lack data on long-term efficiency and potential side effects in real-life conditions. Our study aims to determine efficacy considering the median PFS of advanced CTCL with mogamulizumab. Secondary objectives were to consider tolerance and estimate delay until side effects appeared. Methods: Data on patients with advanced cutaneous T-cell lymphomas were collected since French Authorization, in six French university hospitals. Patients were followed until they stopped mogamulizumab because of relapse or toxicity. For those still treated by mogamulizumab, the end point was 1 September 2021. We excluded 3 patients as they had already been included in the MAVORIC study and data was not available. Results: The median time of follow-up was 11.6 months. Of the 21 patients included, we reported four full-response patients, eight in partial response, one in stability, three in progression, and five were deceased. One patient had visceral progression, and seven had new lymphadenopathy. Progression-free survival was estimated at 22 months. Twenty patients presented adverse events, of which 10 were severe, i.e., grade III-IV. The median time between the introduction of mogamulizumab and the first adverse event was 21 days. Conclusions: Our study suggests that mogamulizumab can give patients with advanced refractory CTCL a consequent PFS, estimated at 22 months. The long-term safety of mogamulizumab was determined to be acceptable since we reported few grade III–IV AEs, comparable with other studies. No other study using real-life data has been performed to investigate the AEs of mogamulizumab.

Preclinical and clinical researches of Denileukin Diftitox (Genetical Recombination) (Remitoro®), a novel agent for T-cell lymphoma

Denileukin Diftitox (DD) is a recombinant fusion protein of diphtheria toxin (DT) fragments and human interleukin-2 (IL-2). DD binds to IL-2 receptor (IL-2R) expressed on tumor cells and is taken up into the cells. Subsequently, DT fragments with adenosine diphosphate ribosylation enzyme inhibit protein synthesis, then ultimately trigger cell death. DD binds to both high- and intermediate-affinity IL-2Rs via IL-2 domain and inhibits growth of human T-cell lymphomas cell lines. E7777, which contains DD as an active component, has improved purity and an increased percentage of active monomer compared with the approved drug E7272 (ONTAK in the US, not approved in Japan). In the phase I clinical study in Japanese patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), the maximum tolerated dose and recommended dose of E7777 were 9 μg/kg/day (administered on Days 1-5 of each cycle) based on the evaluation of dose-limiting toxicity. In the phase II clinical study, the objective response rate was 36.1%, showing comparable efficacy to existing therapies. E7777 showed anti-tumor activity observed across the range of CD25 expression. Grade 3 or higher adverse events (AE) occurred in 94.6%, and serious AE such as capillary leak syndrome and rhabdomyolysis were reported. Therefore, safety monitoring activities have been continued along with alerting related events. Based on these results, E7777 obtained a new drug approval in Japan in March 2021 for the indication of relapsed or refractory PTCL/CTCL.

A Pilot Phase I Trial of IL-21 Expanded Ideal-Donor Natural Killer (NK) Cells in Combination with Mogamulizumab in Patients with Cutaneous T-Cell Lymphomas (CTCL) or Adult T-Cell Leukemia/Lymphomas (ATLL)

A Pilot Phase I Trial of IL-21 Expanded Ideal-Donor Natural Killer (NK) Cells in Combination with Mogamulizumab in Patients with Cutaneous T-Cell Lymphomas (CTCL) or Adult T-Cell Leukemia/Lymphomas (ATLL)

Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study

Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. Trillium Therapeutics.

Tre-O2-10 - Ifosfamide and etoposide in advanced-stage, relapsed or refractory primary cutaneous T-cell lymphomas

Prolonged complete remissions (CRs) are rare in advanced-stage cutaneous T-cell lymphomas (CTCLs). Ifosfamide + etoposide (I+E) have been used to treat lymphomas, combined with platinum-based agents in Hodgkin disease or non-Hodgkin lymphomas including peripheral T-cell lymphomas. Monoclonal antibodies have induced long-term remissions in CTCL but are usually poorly effective in transformed disease Allogeneic haematopoietic stem cell transplantation (alloHSCT) holds a potential for cure but relies on the existence of a pretransplant CR, which may require the use of chemotherapeutic regimens. To our knowledge, to date there are no published data on I+E efficacy and tolerance in advanced refractory CTCL. We performed a retrospective monocentre study on 28 patients with mycosis fungoides (MF, n=15) or Sézary syndrome (SS, n=13) treated with I+E between 2012 and 2019. In this study, I+E showed antitumor activity in these heavily pretreated patients with CTCL, with an ORR of 43%, and no significant difference between the full-dose and reduced-dose regimens in terms of ORR or SAE frequencies, indicating that the reduced regimen may be a suitable option in fragile patients. In conclusion, I+E is a valuable therapeutic option in patients with advanced, refractory CTCL.

Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma.

Simple SummaryCutaneous T cell lymphomas (CTCLs) are a group of blood cancers that cannot be cured with current chemotherapeutical or biological drugs. Patients with advanced disease are severely immunocompromised due to the unchecked expansion of malignant T cells and have low survival rates of less than four years. Hence, new treatment options for CTCLs are urgently needed. In this study the anti-CTCL activity of a new compound, NT1721, was determined in vitro and in two CTCL mouse models. We found that NT1721 increased apoptosis (programmed cell death) in the malignant T cells and reduced tumor growth better than two drugs that are currently clinically used for CTCL treatment (i.e., gemcitabine, romidepsin). These results suggest that NT1721 may represent a potent new agent for the treatment of advanced CTCL.Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs.

Abstract LB134: The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer

Abstract Breast cancer (BC) was considered an immunologically silent tumor, however recent findings suggest that immune cells present in the tumor microenvironment play important roles in tumor growth. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene (Targretin®) is the only rexinoid approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. Other more potent rexinoids have been synthesized, such as LG100268 and LG101506, which will not be tested in clinical trials because of intellectual property issues. Because recent studies have suggested that RXRs are involved in immune regulation, we synthesized novel rexinoids and selected MSU-42011 as a lead compound. MMTV-neu mice with tumors approximately 32 mm3 in volume were treated with control diet or MSU-42011 (100 mg/kg diet) for 10 days. Rexinoid treatment significantly (p=0.0069) reduced tumor fold change normalized to initial volume from 8.33 in controls to 4.80 on treatment. Analysis of the tumor by flow cytometry showed no significant differences in the major immune populations, such as T cells, macrophages and dendritic cells. However, expression of PDL1 was increased in CD11c+, MHC-II+ dendritic cells (5484 vs 7140 MFI, p=0.0456), suggesting engaged dendritic cells in activating cytotoxic T cells. To further elucidate the cross talk between dendritic and T cells, cytokines associated with T cell recruitment and activation were analyzed by RT-PCR. Tumor treated with MSU42011 had a 38.5 fold increase in IL12a expression (p=0.011, n=4), and a 20.8 fold increase in CCL9 (p=ns, n=4), suggesting that dendritic cells are actively recruiting and activating T cells. The activation of cytotoxic T cells was confirmed by a 75.5 fold increase in interferon gamma (p=0.0026, n=4) and a decrease of FOXP3 expression (p=ns, n=4). To test if the effects seen in tumor reduction were dependent on the presence of T cells, CD4 and CD8 were depleted. Depletion of CD4 alone, but not CD8, reversed the tumor reduction induced by MSU-42011. These results show that RXR agonists can be used to modulate immune cell populations in the tumor microenvironment, specifically by recruiting and activating dendritic cells that then activate cytotoxic T cells. We thank the Breast Cancer Research Foundation for support of these studies. Citation Format: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby. The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB134.

Is Durability of Response Reported in Refractory CTCL: A Systematic Review

Introduction: Primary cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas derived from T-lymphocytes that infiltrate the skin. In refractory CTCL, treatments generally include systemic therapies in conjunction with skin-directed therapies. Numerous assessment criteria are used to evaluate the efficacy of different therapies administered to patients with CTCL. Robust treatment comparisons in CTCL are currently complicated by differences between studies in the efficacy outcomes reported. A systematic review (SR) was performed to summarise published evidence on the efficacy of treatments in patients with relapsed/refractory CTCL.Methods: A SR was performed in January 2017 to identify clinical studies published in the last 10 years enrolling >20 patients treated for refractory CTCL.Results: In total, 63 publications reporting on 54 unique studies and 21 different therapies for refractory CTCL were included in the SR. The majority of included studies (n=49) were single arm investigations. Five of the studies included were randomised controlled trials (RCT) comparing CTCL therapies. Two RCTs compared multiple doses of a single therapy (bexarotene or denileukin diftitox), two compared multiple therapies (interferon and methotrexate vs interferon and retinoids or brentuximab vs methotrexate or bexarotene), and one was a placebo-controlled trial of denileukin diftitox. Patient cohorts ranged in size from 21 to 216 patients and all patients had recurrent or refractory disease following ≥1 therapy for CTCL prior to the therapy for which data were extracted. The most frequently reported outcomes were objective response rate (ORR) reported in 82% of studies, complete response rate (80%), progression-free survival (52%), duration of response (48%), overall survival (24%) and time to tumour progression (20%) (Table 1). However, not all outcomes were reported for all therapies, outcome assessment criteria were not reported in all studies, and durable responses were rarely reported. In addition, there was substantial heterogeneity between studies in terms of patient characteristics, outcome assessment criteria, study design, and follow-up time. As such, a robust comparison of relative efficacy is not feasible. ORR was the most consistently reported outcome across studies and was reported for 19 different therapies in 44 different studies. The assessment criteria for ORR was reported in 15 studies. ORR is a useful measure of efficacy as it is directly attributable to drug effect and can be assessed in single-arm studies; however, as the time-point for assessment of ORR or the definition of ORR differed between studies or was not reported, the durability of response was difficult to interpret. The novel outcomes, objective global responses lasting at least 4 (ORR4) and 6 months (ORR6), were reported in three and two trials investigating the efficacy of brentuximab vedotin, respectively. ORR4 and ORR6 capture both the proportion of patients achieving a response and response duration as a single measurement and were 51-56% and 34%, respectively, following treatment with brentuximab vedotin. Health-related quality of life was investigated in only one study in which key endpoints, such as Skindex-29 symptom domains, were reported. Adverse events were reported following treatment with all therapies for refractory CTCL. However, there was a lack of consistency in the definition of the severity of adverse events reported.Conclusion: Although progress has been made towards the standardisation of response criteria in CTCL, the evaluation of durability of response to treatment remains inconsistent. The routine use of clearly defined efficacy outcomes in clinical trials is required to enable robust comparisons of therapeutic efficacy. [Display omitted] DisclosuresDalal:Takeda Pharmaceuticals International Co: Employment, Equity Ownership. Mitchell:DRG Abacus: Employment. McCloskey:DRG Abacus: Employment. Zagadailov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Takeda Pharmaceuticals International Co: Employment, Equity Ownership.