A Review of Selected Presentations From the 60th American Society of Hematology Annual Meeting • December 1-4, 2018 • San Diego, California
Efficacy of Mogamulizumab By Prior Systemic Therapy in Patients With Previously Treated Cutaneous T-Cell Lymphoma: Post Hoc Analysis From the Phase 3 MAVORIC Study
Cutaneous T-cell lymphoma (CTCL) consists of a group of rare non-Hodgkin lymphomas that occur primarily in the skin.1 The 2 most common subtypes are mycosis fungoides and Sézary syndrome. As CTCL progresses, it becomes systemic and is associated with a poor prognosis. Targeted therapies are being developed to provide effective options for the treatment of CTCL. Mogamulizumab is a humanized monoclonal antibody directed against the CC chemokine receptor 4 (CCR4) with a defucosylated Fc region that enhances antibody-dependent cellular cytotoxicity. Moga-mulizumab demonstrated efficacy and acceptable tolerability in an early study of patients with peripheral T-cell lymphoma (PTCL) or CTCL.2
The international, open-label phase 3 MAVORIC trial (Study of KW-0761 Versus Vorinostat in Relapsed/Refractory CTCL) compared mogamulizumab vs vorinostat in patients with previously treated mycosis fungoides or Sézary syndrome.3 Eligible patients had an Eastern Cooperative Oncology Group performance score of 1 or lower and adequate renal, hepatic, and hematologic function. Mogamulizumab at 1.0 mg/kg was administered weekly during the first 28-day cycle and on days 1 and 15 of subsequent cycles. Vorinostat at 400 mg was administered daily. Prior to randomization, patients were stratified by CTCL subtype and disease stage. Baseline characteristics, including the number and type of prior systemic therapies, were similar between the 2 arms. Patients in both arms had received a median of 3 prior systemic therapies. The analysis of progression-free survival (PFS), the primary endpoint, was based on results from 372 patients. PFS was 7.7 months with mogamulizumab vs 3.1 months with vorinostat (hazard ratio, 0.53; 95% CI, 0.41-0.69; P<.0001). The objective response rate (ORR) was also superior with mogamulizumab, at 28% vs 5% (P<.0001). Among the 133 patients who crossed over from vorinostat to mogamulizumab owing to disease progression or intolerance, the ORR was 31%.
A post hoc analysis evaluated the effect of prior therapy on clinical response among the 186 patients randomly assigned to mogamulizumab in the MAVORIC trial.4 The confirmed ORRs were 25% in those treated with 1 prior therapy, 35% in those treated with 3, and 30% in those treated with more than 6. The most common systemic therapies received immediately prior to study enrollment were oral bexarotene (25%), chemotherapy (24%), methotrexate (11%), interferon-α (9%), extracorporeal photopheresis (9%), and romidepsin (9%). The ORRs based on prior systemic therapy ranged from 38% in patients treated with romidepsin to 20% in those treated with bexarotene (Figure 1). Romidepsin and vorinostat are both inhibitors of histone deacetylase (HDAC). The ORRs in these patients suggest that prior treatment with an HDAC inhibitor does not adversely affect response to mogamulizumab.
In the MAVORIC trial, the median duration of response was 14 months. Based on the patients’ prior systemic therapy, the median duration of response to mogamulizumab ranged from 9.4 months in those who had received interferon-α to 13.6 months in those who had received methotrexate (Figure 2). In the mogamulizumab arm, 150 patients had received prior treatment that was immunostimulatory (n=32), immune neutral (n=55), or immune inhibitory (n=63). In these patients, the median time from immediate prior therapy to study entry was 44 days (range, 0-1094). Based on a logistic regression model and using the immune-neutral cohort as a comparator, ORR did not vary according to prior treatment with immunostimulatory or inhibitory agents. The authors concluded that the clinical response to mogamulizumab treatment in the MAVORIC trial was not influenced by the number or class of prior systemic therapies.
References
1. Welborn M, Duvic M. Antibody-based therapies for cutaneous T-cell lymphoma. Am J Clin Dermatol. 2019;20(1):115-122.
2. Ogura M, Ishida T, Hatake K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32(11):1157-1163.
3. Kim YH, Bagot M, Pinter-Brown L, et al; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.
4. Zinzani PL, Horwitz SM, Kim YH, et al. Efficacy of mogamulizumab by prior systemic therapy in patients with previously treated cutaneous T-cell lymphoma: post hoc analysis from the phase 3 MAVORIC study [ASH abstract 1619]. Blood. 2018;132(suppl 1).
The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma
Preclinical data suggest that spleen tyrosine kinase (SYK) is an oncogenic driver in some T-cell lymphomas. Patients with primary PTCL frequently express SYK, either in its native form or as a fusion protein with inducible T-cell kinase (ITK), and activating mutations in the JAK/STAT pathway are also common.1,2 Cerdulatinib is an orally available, adenosine triphosphate (ATP)-competitive inhibitor of SYK, JAK1, JAK3, and Tyk2, with IC50 values of 32 nM for SYK and 0.5 nM to 12 nM for the JAKs.3 After phase 1 dose-escalation studies4,5 and pharmacokinetic/pharmacodynamic modeling, a dose of 30 mg twice daily was chosen for cerdulatinib in phase 2 studies. In a phase 2a study, cerdulatinib was associated with ORRs of 61% in CLL and of 46% in follicular lymphoma, and inhibition of SYK/JAK signaling and markers of inflammation correlated with the degree of tumor reduction.6 Two grade 3 dose-limiting toxicities occurred.
Cerdulatinib at 30 mg twice daily was evaluated in an open-label, multicenter phase 2a study of patients with relapsed or refractory B-cell or T-cell malignancies.7 The study included 45 patients with PTCL and 29 with CTCL. In the PTCL cohort, patients had a median age of 65 years (range, 21-84), and 64% were male. Patients had received a median of 3 prior therapies (range, 1-12), and half were refractory to their most recent therapy. Twenty-seven percent of PTCL patients had undergone prior stem cell transplant. In the CTCL cohort, patients were a median age of 62 years (range, 24-79 years), and 66% were male. The median number of prior therapies was 4 (range, 1-13), and 55% of patients were refractory to their most recent therapy. Three percent of CTCL patients had undergone prior stem cell transplant.
In the evaluable CTCL cohort, 21 patients had mycosis fungoides and 6 had Sézary syndrome. The ORRs for these patients were 29% (6/21) and 17% (1/6), respectively. As determined by the modified Severity Weighted Assessment Tool (mSWAT) in 23 patients, the ORR was 48% (Figure 3). Pruritus scores also improved with treatment.
Among the 41 evaluable PTCL patients, the ORR was 34%, including a complete response (CR) rate of 27%. Among 27 evaluable CTCL patients, the ORR was 26%, including a CR rate of 7%. Eight responding PTCL patients remained on the study drug for at least 3 months. In 5 patients, the duration of response was 6 months or longer. The most common subtypes in the evaluable PTCL cohort were angioblastic T-cell lymphoma/follicular helper T cells and PTCL not otherwise specified. The ORRs in these subtypes were 57% (8/14) and 15% (2/13), respectively. Among 3 patients with adult T-cell leukemia/lymphoma (ATLL), responses included 1 CR and 1 partial response (PR).
Among the entire cohort of 74 patients, the most common treatment-emergent adverse events (AEs) of grade 3 or higher were lipase increase (23%), amylase increase (18%), and sepsis/bacteremia (8%).
References
1. Feldman AL, Sun DX, Law ME, et al. Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia. 2008;22(6):1139-1143.
2. Bisig B, Gaulard P, de Leval L. New biomarkers in T-cell lymphomas. Best Pract Res Clin Haematol. 2012;25(1):13-28.
3. Coffey G, Betz A, DeGuzman F, et al. The novel kinase inhibitor PRT062070 (cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014;351(3):538-548.
4. Flinn I, Hamlin PA, Strickland DK, et al. Phase 1 open-label dose escalation study of the dual SYK/JAK inhibitor cerdulatinib (PRT062070) in patients with relapsed/refractory B-cell malignancies: safety profile and clinical activity [ASCO abstract 8531]. J Clin Oncol. 2015;33(suppl).
5. Hamlin PA, Farber CM, Fenske TS, et al. The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B‐cell malignancies [EHA abstract 62]. Haematologica. 2016;101(s1).
6. Hamlin PA, Cheson BD, Farber CM, et al. The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2a study in patients with relapsed/refractory B- and T-cell non-Hodgkin lymphoma (NHL) [EHA abstract PF437]. Haematologica. 2018;10e(s1).
7. Horwitz SM, Feldman TA, Hess BT, et al. The novel SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in a phase 2a study in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma [ASH abstract 1001]. Blood. 2018;132(suppl 1).
Long-Term Clinical Benefit to Anti-CCR4 Mogamulizumab: Results From the Phase 3 MAVORIC Study in Previously Treated Cutaneous T-Cell Lymphoma
A post hoc analysis assessed the safety and efficacy of moga-mulizumab in the MAVORIC trial based on patients’ prior treatment exposure.1,2 The analysis included 184 patients randomly assigned to mogamulizumab. Patients had a mean time of exposure to mogamulizumab of 275.2 days (standard deviation, 292.2 days) and a median exposure of 170.0 days (range, 1-1617 days). The duration of exposure was less than 72 days in 28%, between 72 and 170 days in 22%, between 171 and 351 days in 26%, and longer than 351 days in 24%. Based on quartile assessment, long-term exposure was defined as longer than 351 days.
The rates of confirmed response increased with exposure to mogamulizumab. In the cohort of patients with less than 72 days of exposure, the ORR was 2.9% among mycosis fungoides patients, 0% among Sézary syndrome patients, and 1.9% overall. Among patients with more than 351 days of exposure, the ORR was 66.7% among mycosis fungoides patients, 83.3% among Sézary syndrome patients, and 75.6% overall (Figure 4). The clinical benefit rate, including CRs, PRs, and stable disease, was 46.2% in patients with the shortest exposure to mogamulizumab vs 95.6% in patients with the longest exposure (Figure 5). Among the patients who had a best response of stable disease, 43.8% had received at least 171 days of treatment.
Rates of treatment-emergent AEs in the 4 cohorts were 26.6%, 18.5%, 23.4%, and 21.7% from the shortest to longest exposure. The rates of serious AEs were 6.5%, 3.3%, 6.0%, and 4.3%. Among patients with the longest exposure to mogamulizumab, the most common treatment-related AEs were drug eruption (20.0%), thrombocytopenia (11.1%), stomatitis (8.9%), and anemia (8.9%). Most grade 3 AEs occurred during the first 2 exposure quartiles (ie, prior to 171 days of exposure). The median time to onset of an AE of grade 3 or higher was 109 days. Drug eruption was defined as a skin rash that the investigator considered to be possibly, probably, or definitely related to the study drug. In patients receiving mogamulizumab, skin rashes of grade 2 or higher were biopsied if necessary to distinguish between a drug eruption and a new area of lymphoma. In the mogamulizumab arm, 45 patients experienced drug eruptions, which included 9 grade 3 events and 36 grade 1/2 events. The median time to a drug eruption event was 107 days. Twenty-five patients in the mogamulizumab arm experienced thrombocytopenia, and all cases were grade 1/2. The median time to onset of thrombocytopenia was 43 days. Patients with autoimmune diseases were excluded from the MAVORIC study. However, a safety physician identified 3 patients with a possible autoimmune disease and 2 with a definite autoimmune disease.
References
1. Bagot M, Dalle S, Sokol L, et al. Long-term clinical benefit to anti-CCR4 mogamulizumab: results from the phase 3 MAVORIC study in previously treated cutaneous T-cell lymphoma (CTCL) [ASH abstract 2901]. Blood. 2018;132(suppl 1).
2. Kim YH, Bagot M, Pinter-Brown L, et al; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.
IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sézary Syndrome: Results From a Multicenter Phase 1 Trial
IPH4102 is a humanized antibody that binds to KIR3DL2, a member of the killer immunoglobulin-like receptors expressed on lymphocytes.1 KIR3DL2 shows restricted expression on normal immune cells but is widely expressed on CTCL cells, with significantly increased expression on Sézary cells compared with lymphoid cells from healthy donors. Preclinical studies have shown that IPH4102 mediates antitumor activity through antibody-dependent cellular cytotoxicity and phagocytosis.2 In mice inoculated with CTCL tumor cells expressing KIR3DL2, treatment with IPH4102 improved survival and reduced tumor growth compared with controls. IPH4102 was also shown to kill Sézary cells ex vivo.
A first-in-human, phase 1 trial evaluated IPH4102 in patients with refractory CTCL.3 The dose-escalation/expansion trial evaluated 10 dose levels of IPH4102, up to 10 mg/kg, in an accelerated 3 + 3 design. The study included all CTCL subtypes. Enrolled patients had received at least 2 prior systemic therapies. Skin disease assessments relating to quality of life were made using the Skindex-29 instrument.4 Based on central testing, KIR3DL2 expression of at least 5% in the skin and/or blood was required for enrollment in the dose-escalation phase. Any level of KIR3DL2 expression was permitted for enrollment in the cohort expansion. IPH4102 was administered once per week for 4 weeks, then every 2 weeks for 10 administrations, followed by administration once every 4 weeks thereafter. The primary endpoint was safety. Key secondary endpoints included best global response, PFS, duration of response, quality of life, and biomarker analyses.
Thirty-five patients with Sézary syndrome were enrolled, 20 in the dose-escalation cohort and 15 in the expansion cohort. Their median age was 70 years (range, 37-90 years). Based on central testing of frozen tissue, 20% of patients had evidence of large-cell transformation. KIR3DL2 expression was observed in the skin of 77% of patients and in the blood of 94%. The median time from the diagnosis of Sézary syndrome was 23 months (range, 6-268 months). The median number of prior therapies was 2 (range, 1-9). Prior treatments included an HDAC inhibitor in 37% and mogamulizumab in 20%.
The maximum tolerated dose was not reached. The recommended phase 2 dose was 750 mg. The ORR was 42.9% (95% CI, 28.0%-59.1%). The best change in mSWAT score is shown in Figure 6, and the best global response is shown in Figure 7. The median duration of response was
13.8 months (95% CI, 7.2 months to not reached), and the median PFS was 11.7 months (95% CI, 8.1 months to not reached). Among 28 Sézary syndrome patients without large-cell transformation, the ORR was 53.6% (95% CI, 35.8%-70.5%), the median duration of response was 13.8 months (95% CI, 7.2 months to not reached), and the median PFS was 12.8 months (95% CI, 8.2 months to not reached). Among the 7 patients who had received prior treatment with mogamulizumab, the ORR was 42.9% (95% CI, 15.8-75.0 months), the median duration of response was 13.8 months (95% CI, 7.2 months to not reached), and the median PFS was 16.8 months (95% CI, 8.1 months to not reached). Based on measures of symptoms as well as emotional and functional scores, patients with a CR, PR, or stable disease showed marked improvement during the course of the study. Pruritus scores improved not only in patients with a CR or PR, but also in patients with stable disease. Exploratory studies showed corresponding decreases in aberrant T cells and reductions in the level of KIR3DL2-positive, CD4-positive T cells during treatment with IPH4102.
The most common AEs of any grade were peripheral edema (29%), asthenia (26%), and fatigue (23%). The only grade 3/4 AE considered definitely related to treatment was lymphopenia, which occurred in 2 patients (6%). Four patients developed 5 AEs of grade 3 or higher that were considered possibly related to treatment, including grade 5 hepatitis, grade 4 sepsis, grade 3 lymphopenia, and grade 3 hypotension.
References
1. Battistella M, Leboeuf C, Ram-Wolff C, et al. KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting. Blood. 2017;130(26):2900-2902.
2. Marie-Cardine A, Viaud N, Thonnart N, et al. IPH4102, a humanized KIR3DL2 antibody with potent activity against cutaneous T-cell lymphoma. Cancer Res. 2014;74(21):6060-6070.
3. Bagot M, Porcu P, William BM, et al. IPH4102; an anti-KIR3DL2 monoclonal antibody in refractory Sézary syndrome: results from a multicenter phase 1 trial [ASH abstract 684]. Blood. 2018;132(suppl 1).
4. Chren MM. The Skindex instruments to measure the effects of skin disease on quality of life. Dermatol Clin. 2012;30(2):231-236, xiii.
Evaluation of Symptom and Side Effect Bother in Cutaneous T-Cell Lymphoma Patients Treated With Mogamulizumab or Vorinostat
CTCL presents as patches, plaques, tumors, or erythroderma and may be accompanied by pruritus.1,2 Advanced CTCL is typically associated with significant morbidity and impaired quality of life.3,4 The MAVORIC trial protocol included preplanned analyses of patient-reported outcomes gleaned from the Functional Assessment of Cancer Therapy–General (FACT-G),
Skindex-29, and 2 measures of pruritus: EQ-5D-3L and ItchyQoL.5 The results from these questionnaires showed a greater improvement in quality of life at 6 months with mogamulizumab vs vorinostat (P<.05).
Patient-reported outcomes collected during the MAVORIC trial were analyzed for changes during the course of treatment.6 Individual symptom items captured by Skindex-29 and toxicity items in FACT-G were evaluated with longitudinal generalized estimation equations using data through cycles 5 or 6. Baseline characteristics were generally well-balanced between the mogamulizumab and vorinostat arms of the MAVORIC trial.
Within 6 treatment cycles, the patients treated with mogamulizumab were more likely to experience a 1-grade improvement in painful skin (odds ratio [OR], 1.74; 95% CI, 1.180-2.572; P=.0216), side effect bother (OR, 1.28; 95% CI, 0.810-2.020; P=.0122), and lack of energy (OR, 2.20; 95% CI, 1.461-3.309; P=.0505; Figure 8). Items that showed potential improvement with mogamulizumab over vorinostat included general cancer pain (OR, 1.38; 95% CI, 0.922-2.063; P=.0799) and irritated skin (OR, 1.34; 95% CI, 0.909-1.978; P=.2176). The results suggested that, over the course of treatment, mogamulizumab provided a symptom benefit that was superior to that of vorinostat.
References
1. Horwitz SM, Olsen EA, Duvic M, Porcu P, Kim YH. Review of the treatment of mycosis fungoides and sézary syndrome: a stage-based approach. J Natl Compr Canc Netw. 2008;6(4):436-442.
2. Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas: frequent, often severe and difficult to treat. Acta Derm Venereol. 2010;90(1):12-17.
3. Beynon T, Radcliffe E, Child F, et al. What are the supportive and palliative care needs of patients with cutaneous T-cell lymphoma and their caregivers? A systematic review of the evidence. Br J Dermatol. 2014;170(3):599-608.
4. Demierre MF, Gan S, Jones J, Miller DR. Significant impact of cutaneous T-cell lymphoma on patients’ quality of life: results of a 2005 National Cutaneous Lymphoma Foundation Survey. Cancer. 2006;107(10):2504-2511.
5. Kim YH, Bagot M, Pinter-Brown L, et al; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.
6. Hudgens S, Porcu P, Quaglino P, et al. Evaluation of symptom and side effect bother in cutaneous T-cell lymphoma patients treated with mogamulizumab or vorinostat [ASH abstract 3592]. Blood. 2018;132
(suppl 1).
Phase 1/2 Trial of Durvalumab and Lenalidomide in Patients With Cutaneous T-Cell Lymphoma: Preliminary Results of Phase I Results and Correlative Studies
Many cancer types are characterized by the presence of exhausted T cells within the tumor microenvironment.1 T-cell exhaustion often involves overexpression of inhibitory receptors such as programmed death 1 (PD-1) on the T cell and concomitant overexpression of the ligand (PD-L1) on tumor cells. By increasing the expression of PD-L1, tumors avoid immune surveillance and elimination. A study of primary T cells from CTCL skin biopsies showed increased PD-1 expression on CD4-positive T cells compared with skin from healthy donors.2 Genome-wide mRNA expression analysis showed that checkpoint inhibition mRNA expression was increased in CTCL stage T3/T4 samples compared with earlier-stage samples. Durvalumab is a human monoclonal antibody that binds to PD-L1, preventing its engagement with PD-1.3 In a xenograft mouse model containing coimplanted human T cells, durvalumab inhibited tumor growth through a mechanism that was dependent on the presence of T cells.
A phase 1/2 trial evaluated the combination of durvalumab with or without lenalidomide in patients with CTCL.4 Patients were enrolled in sequential cohorts to receive a fixed dose of durvalumab (1500 mg every 4 weeks) either alone or in combination with escalating doses of lenalidomide (up to 20 mg daily). Serial skin and blood samples were collected to evaluate the impact of treatment on the tumor microenvironment. Objectives of the ongoing study are to evaluate the correlation between clinical response and resistance by evaluating PD-1 clustering at the single molecular level and to assess the expression of PD-L1 and inducible T-cell costimulator (ICOS) on both pretreatment primary cells from skin explants and formaldehyde-fixed, paraffin-embedded skin tissue from clinical trial participants.
The 9 enrolled patients had a median age of 54 years (range, 29-59 years), and 7 were male. One patient had stage IIB disease, 7 had stage II disease, and 1 had stage IIIA disease. Eight patients had mycosis fungoides and 1 had aggressive cytotoxic CTCL. Patients had received a median of 3 prior systemic therapies and a median of 4 prior skin-directed treatments. The median follow-up was 7 months (range, 1 to 18+ months).
As measured by the mSWAT, 7 patients showed improved skin disease, including 2 patients who achieved a PR with greater than 90% improvement by mSWAT. Three patients experienced disease progression, and 5 patients remained on treatment. Peripheral blood mononuclear cells were harvested from a patient with Sézary syndrome and then incubated with durvalumab plus lenalidomide for 72 hours. Immunoblotting showed a small decrease in PD-L1 expression. This patient’s cells were also depleted of CD3-positive T cells and then stimulated with interferon-γ, which led to increased expression of PD-L1 and ICOS. Exposure to lenalidomide and durvalumab inhibited the expression of PD-L1 and ICOS. Exposure to lenalidomide was associated with decreased expression of pSTAT3, and exposure to durvalumab was associated with decreased expression of pSTAT1. The combination of lenalidomide plus durvalumab will be further evaluated in CTCL patients in the phase 2 portion of the trial.
Nonhematologic AEs of any grade included tumor flare reaction (n=9), other skin reactions (n=6), fatigue (n=5), rash (n=4), and skin pain (n=3). Hematologic AEs included leukopenia (n=5) and anemia (n=3). A grade 3 maculopapular rash occurred in 1 patient. All other AEs were grade 1/2. No serious AEs or dose-limiting toxicities occurred.
References
1. Rubio Gonzalez B, Zain J, Rosen ST, Querfeld C. Tumor microenvironment in mycosis fungoides and Sézary syndrome. Curr Opin Oncol. 2016;28(1):88-96.
2. Querfeld C, Leung S, Myskowski PL, et al. Primary T cells from cutaneous T-cell lymphoma skin explants display an exhausted immune checkpoint profile. Cancer Immunol Res. 2018;6(8):900-909.
3. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3(9):1052-1062.
4. Querfeld C, Zain JM, Wakefield DL, et al. Phase 1/2 trial of durvalumab and lenalidomide in patients with cutaneous T cell lymphoma (CTCL): preliminary results of phase I results and correlative studies [ASH abstract 2931]. Blood. 2018;132(suppl 1).
Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice Irrespective of CD30 Level or Large Cell Transformation Status in the Phase 3 ALCANZA Study
Brentuximab vedotin is approved in the United States for the treatment of CD30-positive lymphoproliferative diseases, including previously treated primary cutaneous anaplastic large cell lymphoma and CD30-expressing mycosis fungoides.1 The international, open-label phase 3 ALCANZA trial (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) evaluated the efficacy and safety of brentuximab vedotin vs conventional therapy in previously treated patients with CD30-positive primary cutaneous anaplastic large cell lymphoma or mycosis fungoides.2 Patients randomly assigned to the experimental arm received brentuximab vedotin (1.8 mg/kg) once every 3 weeks for up to 16 cycles of 3 weeks each. Patients in the control arm received their physician’s choice of methotrexate (5-50 mg once per week) or bexarotene (200 mg/m2 daily) for up to 48 weeks. The study randomly assigned 66 patients to brentuximab vedotin and 65 to the physician’s choice of treatment. After a median follow-up of 22.9 months, an objective global response lasting at least 4 months was achieved by 56.3% of patients in the brentuximab vedotin arm vs 12.5% of patients in the physician’s choice arm (P<.0001), achieving the primary endpoint. Median PFS was also superior with brentuximab vedotin (16.7 vs 3.5 months; P<.0001).
A post hoc analysis of patients with mycosis fungoides from the ALCANZA trial was conducted, with a focus on patients with large-cell transformed (LCT) mycosis fungoides.3 LCT mycosis fungoides is characterized by the presence of large cells with enlarged nuclei, and the diagnosis is made when the biopsy of a mycosis fungoides lesion shows the presence of at least 25% large cells.4 LCT mycosis fungoides carries a poor prognosis and a mean 5-year survival of less than 20%. Although CD30 expression is more common in LCT mycosis fungoides compared with untransformed mycosis fungoides, the expression is variable.5 The objectives of the post hoc analysis were to determine the proportion of mycosis fungoides patients with LCT mycosis fungoides, to measure the efficacy of brentuximab vedotin in patients with LCT mycosis fungoides, and to evaluate the efficacy and safety of brentuximab vedotin according to transformed status and CD30 expression levels. The ALCANZA trial enrolled 50 mycosis fungoides patients into each treatment arm, and 48 per arm were evaluable for LCT status. In each arm, 17 patients (35%) had LCT mycosis fungoides. LCT was observed most frequently in patients with stage IIB disease.
Based on at least 2 biopsies taken at a single time point, median CD30 expression levels varied. In the physician’s choice arm, the median level of CD30 expression was 15.0% (range, 1.0%-71.7%) in patients without LCT vs 35.0% (range, 6.3%-97.5%) in patients with LCT. In the brentuximab vedotin arm, the median CD30 expression level was 15.0% (range, 3.8%-70.0%) in patients without LCT vs 50.0% (range, 3.0%-95.0%) in patients with LCT. LCT mycosis fungoides was less common among patients with low levels of CD30 expression (13%-18%) and was most common among patients with higher levels of CD30 expression (56%-64%; Figure 9). Patients with LCT mycosis fungoides were more likely to achieve an ORR lasting at least 4 months compared with LCT-negative patients, both in the brentuximab vedotin arm (65% vs 39%) and in the standard treatment arm (18% vs 6%). Median PFS was superior with brentuximab vedotin vs physician’s choice in patients with LCT mycosis fungoides (15.5 vs 2.8 months) and in those without LCT (16.1 vs 3.5 months). Among LCT mycosis fungoides patients treated with brentuximab vedotin, those who achieved an ORR lasting at least 4 months had a higher median level of CD30 expression (65%) compared with patients who did not attain an ORR lasting at least 4 months (20%). In both treatment arms, the presence of LCT mycosis fungoides did not impact the rate of AEs, including AEs of grade 3 or higher, drug-related AEs of grade 3 or higher, or serious AEs.
References
1. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc; 2018.
2. Prince HM, Kim YH, Horwitz SM, et al; ALCANZA study group. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390(10094):555-566.
3. Kim YH, Prince HM, Whittaker S, et al. Superior clinical benefit of brentuximab vedotin in mycosis fungoides versus physician’s choice irrespective of CD30 level or large cell transformation status in the phase 3 ALCANZA study [ASH abstract 1646]. Blood. 2018;132(suppl 1).
4. Pulitzer M, Myskowski PL, Horwitz SM, et al. Mycosis fungoides with large cell transformation: clinicopathological features and prognostic factors. Pathology. 2014;46(7):610-616.
5. Vergier B, de Muret A, Beylot-Barry M, et al; French Study Group of Cutaneious Lymphomas. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. Blood. 2000;95(7):2212-2218.
Mechanistic Analysis of Prolonged Negative Impacts of Anti-CCR4 Antibody Mogamulizumab on Regulatory T-Cell Homeostasis After Allogeneic Hematopoietic Stem Cell Transplantation
ATLL is a highly aggressive malignancy of CD4-positive cells caused by the human T-cell leukemia virus type 1.1 The normal counterpart of ATLL cells is considered to be CD4+Foxp3+ regulatory T cells (Treg). After allogeneic hematopoietic stem cell transplant, Treg cells play a key role in suppressing graft-vs-host disease. Mogamulizumab binds to CCR4 and is used for the treatment of ATLL. Mogamulizumab depletes Treg cells for several months. A recent study of patients with aggressive ATLL evaluated the effect of mogamulizumab treatment prior to hematopoietic stem cell transplant.2 The study included 996 patients who had undergone allogeneic hematopoietic stem cell transplant; 86 of these patients had received prior treatment with mogamulizumab. Among the latter patients, the final dose of mogamulizumab was administered at a median of 45 days prior to allogeneic hematopoietic stem cell transplant. The use of mogamulizumab before allogeneic hematopoietic stem cell transplant was associated with an increased risk of grade 3/4 acute graft-vs-host disease (relative risk, 1.80; P<.01), and these patients were also more likely to be refractory to systemic corticoid treatment for their graft-vs-host disease (relative risk, 2.09; P<.01). One-year overall survival was also reduced in patients who had received prior treatment with mogamulizumab (P<.01). Because Treg cells express CCR4, suppression of Treg cells by mogamulizumab and subsequent poor recovery may underlie the negative impact of mogamulizumab on allogeneic hematopoietic stem cell transplant.
A small study investigated the relationship between mogamulizumab and the activity of Treg cells in patients with ATLL.3 The study included 3 patients who received mogamulizumab before allogeneic hematopoietic stem cell transplant, 1 patient who received mogamulizumab after transplant to treat early relapse of adult T-cell leukemia/lymphoma, and 2 patients who did not receive treatment with mogamulizumab. Peripheral blood samples were obtained before hematopoietic stem cell transplant and afterward (at 2, 4, 6, 8, and 12 weeks and every 3 months thereafter).
Peak levels of mogamulizumab were dependent on the total dose administered. Residual ATLL cells in the blood quickly decreased after administration of mogamulizumab. After the final dose of mogamulizu-mab, levels of the antibody gradually declined, with an average estimated half-life of 11.2 days. A faster clearance rate was observed in a patient with high tumor burden (half-life, 5.2 days) and in a patient who received plasma (half-life, 8.4 days). Expansion of Treg cells failed in all 3 patients who had received prior treatment with mogamulizumab, but was successful in the patients who had not. Delayed recovery of Treg cells was observed for up to 30 months after mogamulizumab treatment, even when the antibody was no longer detectable.
References
1. Phillips AA, Harewood JCK. Adult T cell leukemia-lymphoma (ATL): state of the art. Curr Hematol Malig Rep. 2018;13(4):300-307.
2. Fuji S, Inoue Y, Utsunomiya A, et al. Pretransplantation anti-CCR4 antibody mogamulizumab against adult T-cell leukemia/lymphoma is associated with significantly increased risks of severe and corticosteroid-refractory graft-versus-host disease, nonrelapse mortality, and overall mortality. J Clin Oncol. 2016;34(28):3426-3433.
3. Sando Y, Matsuoka KI, Meguri Y, et al. Mechanistic analysis of prolonged negative impacts of anti-CCR4 antibody mogamulizumab on regulatory T cell homeostasis after allogeneic hematopoietic stem cell transplantation [ASH abstract 3400]. Blood. 2018;132(suppl 1).
Phase 1 Trial of Cobomarsen, an Inhibitor of Mir-155, in Cutaneous T-Cell Lymphoma
MicroRNAs are noncoding RNA molecules that regulate gene expression. Quantitative analysis of microRNA expression levels yielded an expression profile that distinguishes CTCL from benign skin disorders.1 MicroRNA-155 is overexpressed in CTCL skin lesions and is a regulator of several signaling pathways that are activated in CTCL cells, including the JAK/STAT, NF-κB, and phosphoinositide 3-kinase (PI3K) pathways. Cobomarsen is a 14-nucleotide locked nucleic acid that inhibits the activity of miR-155.2 In vitro studies showed that cobomarsen inhibited survival and increased apoptosis in CTCL cell lines.
A phase 1 study investigated the safety and tolerability of cobomarsen in patients with mycosis fungoides.3 The open-label, dose-ranging study evaluated intratumoral, subcutaneous, and intravenous administration of cobomarsen and characterized the drug’s pharmacokinetic profile. During part A of the study, intralesional injections were administered at 75 mg per dose. Part B evaluated larger doses: 300 mg administered as a bolus injection, plus 600 mg and 900 mg administered as 2-hour infusions. The initial loading dose of cobomarsen was administered 3 times during week 1, followed by weekly dosing thereafter.
The 43 enrolled patients had a median age of 59 years, and two-thirds were male. Patients had biopsy-proven mycosis fungoides of stage I, II, or III. Patients with LCT mycosis fungoides were included. All patients were refractory or intolerant to standard therapy. During study participation, patients could continue to receive stable doses of standard therapy. The trial excluded patients with evidence of clinically meaningful visceral, nodal, or blood involvement of CTCL.
Twenty-five patients received cobomarsen in addition to other treatment and 18 received cobomarsen monotherapy. Patient enrollment into the various dosing cohorts is shown in Table 1. In patients treated up to 23 months, there was no evidence of immunosuppression. There were no consistent changes to T-cell or B-cell subsets, monocytes, or eosinophils. Increased levels of natural killer cells occurred in some patients treated with cobomarsen at 900 mg. Plasma concentration curves revealed a long terminal elimination phase. Cobomarsen showed linear kinetics, with dose-proportional increases in the maximum concentration and the area under the curve. No evidence of accumulation was observed at any of the doses tested and by any route of administration. Plasma trough values reached steady-state within 12 to 16 weeks of cobomarsen administration, consistent with a terminal half-life of approximately 2.5 to 3 weeks. Antidrug antibodies were detected in 3 patients, and these patients had increased trough values.
Gene expression analysis identified a profile encompassing 122 mRNAs that were regulated in common after treatment with cobomarsen. Pathways with altered expression included the PI3K/AKT, JAK/STAT, and NF-κB pathways, and expression of genes involved in apoptosis increased. Lesions from patients in part A of the study that were injected with cobomarsen had improved scores of Composite Assessment of Index Lesion Severity, and the proportion of tumor cell clones decreased by day 9. In most patients, expression of miR-155 was elevated compared with normal skin. The highest levels of miR-155 were observed in mycosis fungoides lesions with the highest density of neoplastic cells. Both intralesional and systemic treatment with cobomarsen led to a decrease in the expression of miR-155 to below detectable levels in most patients. The mSWAT score improved in 92% of patients (33/36). Fifty-two percent of patients who received more than 6 doses of cobomarsen had a PR, defined as a reduction of at least 50% in the mSWAT score. Among the 13 patients who achieved a PR, 69% maintained the response for at least 4 consecutive months. The mean duration of response was 259 days (range, 48 to 560+ days).
No serious AEs were attributed to cobomarsen. Four patients experienced 8 serious AEs, all of which were unrelated to study treatment. Thirty-nine patients (90.7%) reported at least 1 nonserious AE. The total number of reported AEs was 307, and 89.6% were grade 1/2. Among the 32 grade 3/4 AEs, 14 AEs in 6 patients were considered related to treatment with the study drug. Among all 43 patients, the most common AEs of any grade were fatigue (26%) and neutropenia (19%). Pruritus and tumor flare were each observed in 16% of patients.
References
1. Ralfkiaer U, Lindahl LM, Litman T, et al. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Res. 2014;34(12):7207-7217.
2. Seto AG, Beatty X, Lynch JM, et al. Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma. Br J Haematol. 2018;183(3):428-444.
3. Foss FM, Querfeld C, Kim YH, et al. Phase 1 trial of cobomarsen, an inhibitor of Mir-155, in cutaneous T cell lymphoma [ASH abstract 2903]. Blood. 2018;132(suppl 1).
Highlights in Cutaneous T-Cell Lymphoma From the 60th American Society of Hematology Annual Meeting: A Hematologist’s Perspective
Bradley Haverkos, MD, MPH
Assistant Professor of Medicine
Blood Cancer and BMT Program
Division of Hematology
University of Colorado School of Medicine
Aurora, Colorado
Presentations on cutaneous T-cell lymphoma (CTCL) at the 60th American Society of Hematology (ASH) meeting offered valuable insight into the management of these patients. Several analyses examined the use of mogamulizumab. Other studies focused on novel approaches and biomarker-driven treatment strategies. A key theme across many of the studies was to identify characteristics associated with response to therapy.
Mogamulizumab
A post hoc analysis by Dr Pier Luigi Zinzani evaluated how prior therapy impacted response to treatment with mogamulizumab in the phase 3 MAVORIC trial (Study of KW-0761 Versus Vorinostat in Relapsed/Refractory CTCL).1,2 The MAVORIC trial met its primary endpoint. Progression-free survival was 7.7 months with mogamulizumab vs 3.1 months with vorinostat (P<.0001).
Mogamulizumab is a monoclonal antibody that targets the chemokine receptor CCR4. The mechanism of action relies on antibody-dependent cellular cytotoxicity (ADCC). Preclinical studies suggested that histone deacetylase (HDAC) inhibitors can downregulate CCR4 and potentially suppress the activity of natural killer cells, which could negatively impact the ADCC mechanism of action.3 In the analysis by Dr Zinzani, no prior treatments, including HDAC inhibitors, had a significant impact on responses or duration of response.1 The immunologic activity of the drug had no impact, nor did the time from immediate prior systemic therapy. The prior systemic treatment had been administered a median of 90 days before initiation of mogamulizumab. It will be interesting to see if a closer interval between the prior drug and mogamulizumab will impact the mechanism of action and resultant efficacy. Subsequent studies will assuredly look to identify synergistic combinations with mogamulizumab.
A post hoc analysis from Dr Martine Bagot evaluated data from the MAVORIC trial to identify the best responders.4 Results from the MAVORIC trial, which appeared in the Lancet Oncology, found that treatment with mogamulizumab was associated with higher response rates and potentially more durable responses among patients with Sézary syndrome and other mycosis fungoides patients with blood involvement.2 The post hoc analysis drew the same conclusion. There was significantly more benefit in patients with blood involvement, even at low levels (defined as B1 disease). Patients with Sézary syndrome seemed to have a longer-term benefit. Unsurprisingly, patients with better performance status also had better outcomes. The original report showed that patients with more blood disease had a better response. Mogamulizumab may have efficacy in all stages of disease, but it may be best suited for earlier use in patients with blood involvement. An interesting observation from the post hoc analysis was that there was no significant trend between outcome and the level of CCR4 expression. Therefore, there are currently no data to support checking a patient’s level of CCR4 expression before considering treatment with mogamulizumab. More pertinent factors include the patient’s disease stage, clinical characteristics, and the presence of any blood involvement.
The post hoc analysis by Dr Bagot also evaluated the safety of mogamulizumab. Infusion reaction is the most common adverse event seen with this therapy.4 Longer treatment duration did not significantly increase the rate of adverse events. This important finding suggests that patients who respond to mogamulizumab can receive treatment for long periods without concern for cumulative toxicity.
A study by Dr Yasuhisa Sando evaluated the effect of mogamulizumab before or after transplant in patients with adult T-cell leukemia/lymphoma (ATLL).5 Previous research has identified potential risks when mogamulizumab is administered before and after an allogeneic transplant.6 This risk may relate to a decrease in regulatory T cells (Tregs), which is an on-target effect of mogamulizumab. In the context of an allogeneic transplant, a decrease in Tregs can increase the risk of graft-vs-host disease (GVHD). Patients with ATLL tend to have a poor prognosis, so despite the potential risks, allogeneic stem cell transplant should still be considered. However, close monitoring and further investigation are warranted. For CTCL, the implications are more limited. Mogamulizumab is approved for patients with relapsed or refractory mycosis fungoides or Sézary syndrome treated with 1 or more lines of therapy. The percentage of patients with CTCL who undergo transplant is very small. However, further research should explore ways to potentially mitigate the increased risk of GVHD after an allogeneic transplant in patients treated with mogamulizumab. There may be novel conditioning regimens or donor sources that could be used in this setting to decrease the risk of GVHD.
A subanalysis of the MAVORIC trial evaluated the impact of mogamulizumab and vorinostat on symptoms related to CTCL.7 The analysis identified better symptom control with mogamulizumab as compared with vorinostat. This improvement in symptoms is great for patients. Skin disease and pruritus can be a large burden and significantly impact the patient’s quality of life. Mogamulizumab represents an important advance not only because it increases progression-free survival, but also because it improves symptoms and quality of life. This analysis suggests that mogamulizumab is a much better option for patients than vorinostat.
In conclusion, these studies on mogamulizumab suggest that it is safe overall and improves symptoms. Investigators are still learning which patients may benefit the most from treatment, and are also exploring synergistic combinations.
Brentuximab Vedotin
Dr Youn Kim presented a post hoc analysis of the phase 3 ALCANZA trial (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma), which compared brentuximab vedotin vs the physician’s choice of treatment in patients with mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma.8,9 Brentuximab vedotin is an antibody-drug conjugate that targets CD30. The analysis by Dr Kim aimed to identify the relationship between the status of large-cell transformation and CD30 expression or clinical outcome. The study found that a higher level of CD30 expression may help predict response to brentuximab vedotin. However, responses were also seen in patients with a low level of expression. This conclusion has been the same in other T-cell lymphomas.10 In the setting of large-cell transformation, Dr Kim found that high CD30 expression was somewhat more common, but there were also low expressers. The analysis showed that brentuximab vedotin is safe, tolerable, and effective in patients with large-cell transformation, a population that historically has a poor prognosis. It suggests that brentuximab vedotin may be a good choice for patients with large-cell transformation, particularly those who are CD30-positive.
Reduced Intensity Conditioning for Transplant
A study from Milan examined long-term outcome of a reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplant in patients with mycosis fungoides or Sézary syndrome.11 A similar study performed at MD Anderson Cancer Center suggested that this strategy is effective.12 In the Milan experience, a complete response was seen in 28 of 39 evaluable patients (71%). This study reemphasized that allogeneic transplant remains a potentially curative option for patients, especially those who are young and fit or who have relapsed multiple times. The study identified a fair amount of infectious complications, which were likely related to T-cell depletion from pentostatin and antithymocyte globulins.
Novel Treatment Strategies
A phase 1 trial from Dr Martine Bagot evaluated IPH4102, an anti-KIR3DL2 monoclonal antibody, in patients with Sézary syndrome.13 The trial enrolled patients with KIR3DL2 expression; the dose-escalation phase required expression of 5% or higher in the skin and/or blood, and the cohort expansion permitted any level of expression. The study underscores a wider goal in the field of CTCL: to identify patients who will benefit from specific therapies based not only on their clinical presentation, stage, and symptoms, but also biomarkers that predict response in the tumor tissue. Between 80% to 90% of patients with Sézary syndrome express KIR3DL2. Treatment with IPH4102 led to an overall response rate of 42.9%, which is an encouraging outcome in a biomarker-driven trial, particularly in patients with Sézary syndrome and large-cell transformation, who have a poor prognosis. Importantly, IPH4102 also improved quality-of-life indexes, including the Skindex. In CTCL, the aim of therapy should be not only to treat the disease, but also to improve the patient’s quality of life. IPH4102 had a reasonable safety profile. This therapy will be evaluated in a large phase 2 trial, known as TELLOMAK (T-Cell Lymphoma Anti-KIR3DL2 Therapy) across several patient populations, including those with mycosis fungoides and Sézary syndrome.
Dr Bagot also presented a phase 1/2 study on cusatuzumab (ARGX-110), an antibody that blocks CD70 and CD27.14 The trial enrolled patients with relapsed/refractory CTCL who were CD70-positive. Cusatuzumab showed some encouraging responses, with an overall response rate of 23%. Further studies should clarify any other on-target effects this drug might have when blocking this pathway. Enrollment in future clinical trials may be limited to patients in whom this pathway is pertinent.
A small phase 1/2 trial by Dr Christiane Querfeld evaluated the combination of durvalumab and lenalidomide among 9 patients with CTCL.15 Skin disease improved in 8 patients, and the treatment appeared to be safe. This study included an analysis of expression panels of several immune checkpoint markers. Dr Querfeld evaluated markers in the tumor cells and tumor microenvironment to identify any association with outcome. Responders had detectable levels of programmed death ligand 1 and low expression of inducible T-cell costimulator.
Dr Francine Foss presented a phase 1 study of cobomarsen, an oligonucleotide drug that targets miR-155, in patients with mycosis fungoides.16 The aim of targeting miR-155 is to block several signaling pathways that are active among patients with CTCL. In this study, cobomarsen was given via intratumoral, subcutaneous, and intravenous administration. The encouraging results showed that the modified Severity Weighted Assessment Tool (mSWAT) score improved in 92% of patients treated with systemic therapy. Treatment was well-tolerated. Cobomarsen will be studied in a phase 3 trial.
Dr Steven Horwitz presented a phase 2a study of cerdulatinib, a novel SYK/JAK inhibitor, in patients with relapsed/refractory CTCL or peripheral T-cell lymphoma.17 Cerdulatinib inhibits the JAK/STAT pathway, which appears to be important in some T-cell lymphomas. The overall response rates were 34% in peripheral T-cell lymphoma and 26% in CTCL (29% in mycosis fungoides and 17% in Sézary syndrome). The use of cerdulatinib will be explored further, perhaps in combination with other therapies. It would seem intuitive that cerdulatinib would be most effective in patients whose lymphoma relies on the JAK/STAT pathway. Further analyses will likely examine characteristics of the responders, such as whether they were more reliant on the JAK/STAT pathway or had higher SYK upregulation in the tumor as compared with nonresponders. Cerdulatinib may also affect the microenvironment. It will be important to develop drugs that impact the microenvironment, and to understand how this strategy might be used to treat T-cell lymphomas.
A study by Dr Özlem Önder used mass spectrometry to evaluate the epiproteomic profile of patients with CTCL or Sézary syndrome.18 This type of analysis will have broad implications across many different cancers, providing insight into how to identify which patients will benefit from HDAC inhibitors and how to monitor response by identifying changes in the epiproteomic profile throughout treatment. Dr Önder found that alterations in H4K20 methylation are fairly common in patients with CTCL and Sézary syndrome. This finding has the potential to identify patients who will respond best to HDAC inhibitors. HDAC inhibitors are effective in CTCL overall, and they are very effective in certain subsets of CTCL and Sézary syndrome.
Maintenance After Total Skin Electron Beam Therapy
A retrospective study by Dr Pamela Allen evaluated maintenance therapy after total skin electron beam therapy in patients with CTCL.19 Use of maintenance therapy after total skin electron beam therapy is a common clinical strategy, based on anecdotal evidence suggesting that it appears to prolong response. This study showed that maintenance therapy nearly doubled progression-free survival.
Disclosure
Dr Haverkos has no real or apparent conflicts of interest to report.
References
1. Zinzani PL, Horwitz SM, Kim YH, et al. Efficacy of mogamulizumab by prior systemic therapy in patients with previously treated cutaneous T-cell lymphoma: post hoc analysis from the phase 3 MAVORIC study [ASH abstract 1619]. Blood. 2018;132(suppl 1).
2. Kim YH, Bagot M, Pinter-Brown L, et al; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.
3. Kitadate A, Ikeda S, Abe F, et al. Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas. Haematologica. 2018;103(1):126-135.
4. Bagot M, Dalle S, Sokol L, et al. Long-term clinical benefit to anti-CCR4 mogamulizumab: results from the phase 3 MAVORIC study in previously treated cutaneous T-cell lymphoma (CTCL) [ASH abstract 2901]. Blood. 2018;132(suppl 1).
5. Sando Y, Matsuoka KI, Meguri Y, et al. Mechanistic analysis of prolonged negative impacts of anti-CCR4 antibody mogamulizumab on regulatory T cell homeostasis after allogeneic hematopoietic stem cell transplantation [ASH abstract 3400]. Blood. 2018;132(suppl 1).
6. Sugio T, Kato K, Aoki T, et al. Mogamulizumab treatment prior to allogeneic hematopoietic stem cell transplantation induces severe acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22(9):1608-1614.
7. Hudgens S, Porcu P, Quaglino P, et al. Evaluation of symptom and side effect bother in cutaneous T-cell lymphoma patients treated with mogamulizumab or vorinostat [ASH abstract 3592]. Blood. 2018;132(suppl 1).
8. Kim YH, Prince HM, Whittaker S, et al. Superior clinical benefit of brentuximab vedotin in mycosis fungoides versus physician’s choice irrespective of CD30 level or large cell transformation status in the phase 3 ALCANZA study [ASH abstract 1646]. Blood. 2018;132(suppl 1).
9. Prince HM, Kim YH, Horwitz SM, et al; ALCANZA study group. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390(10094):555-566.
10. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095-3100.
11. Onida F, Saporiti G, Violetti SA, et al. Long-term outcome of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with mycosis fungoides and Sézary syndrome: the Milan experience [ASH abstract 4655]. Blood. 2018;132(suppl 1).
12. Shiratori S, Fujimoto K, Nishimura M, et al. Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome. Hematol Oncol. 2016;34(1):9-16.
13. Bagot M, Porcu P, William BM, et al. IPH4102; an anti-KIR3DL2 monoclonal antibody in refractory Sézary syndrome: results from a multicenter phase 1 trial [ASH abstract 684]. Blood. 2018;132(suppl 1).
14. Bagot M, Maerevoet M, Zinzani PL, et al. ARGX-110 for treatment of CD70-positive advanced cutaneous T-cell lymphoma in a phase 1/2 clinical trial [ASH abstract 1627]. Blood. 2018;132(suppl 1).
15. Querfeld C, Zain JM, Wakefield DL, et al. Phase 1/2 trial of durvalumab and lenalidomide in patients with cutaneous T cell lymphoma (CTCL): preliminary results of phase I results and correlative studies [ASH abstract 2931]. Blood. 2018;132(suppl 1).
16. Foss FM, Querfeld C, Kim YH, et al. Phase 1 trial of cobomarsen, an inhibitor of Mir-155, in cutaneous T cell lymphoma [ASH abstract 2903]. Blood. 2018;132(suppl 1).
17. Horwitz SM, Feldman TA, Hess BT, et al. The novel SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in a phase 2a study in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma [ASH abstract 1001]. Blood. 2018;132(suppl 1).
18. Önder Ö, Wu R, Wysocka M, et al. Epiproteomic landscape and histone code of cutaneous T-cell lymphoma/Sézary syndrome [ASH abstract 780]. Blood. 2018;132(suppl 1).
19. Allen PB, Kudelka M, Switchenko J, et al. Evaluation of maintenance therapy in cutaneous T-cell lymphoma patients receiving total skin electron beam radiation therapy [ASH abstract 1639]. Blood. 2018;132(suppl 1).
Highlights in Cutaneous T-Cell Lymphoma From the 60th American Society of Hematology Annual Meeting: A Dermatologist’s Perspective
Larisa J. Geskin, MD
Associate Professor of Dermatology
Director of the Comprehensive Skin Cancer Center
Division of Cutaneous Oncology
Department of Dermatology
Columbia University Medical Center
New York, New York
Dermatologists often work closely with hematologists to treat patients with cutaneous T-cell lymphoma (CTCL). Several studies presented at the 60th American Society of Hematology (ASH) meeting have the potential to impact management. Studies evaluated the use of mogamulizumab, as well as novel treatments and strategies.
Mogamulizumab
The randomized phase 3 MAVORIC trial (Study of KW-0761 Versus Vorinostat in Relapsed/Refractory CTCL) evaluated mogamulizumab, a CCR4 antibody, in patients with previously treated CTCL.1 Treatment with mogamulizumab led to a median progression-free survival of 7.7 months, vs 3.1 months with vorinostat (P<.0001). The objective response rate was 28% vs 5% (P<.0001). A post hoc analysis of the MAVORIC trial evaluated the number of therapies that patients received before treatment with mogamulizumab.2 The analysis found that the responses were the same regardless of whether patients were heavily pretreated or not. This finding speaks to the unique mechanism of action of mogamulizumab, which does not overlap with that of other therapies. Treatment with prior therapies did not predict or impede the response to mogamulizumab. This analysis provides the clinically important observation that basically any patient may benefit from treatment with mogamulizumab.
A post hoc analysis of the MAVORIC trial from Dr Martine Bagot evaluated long-term clinical benefit with mogamulizumab.3 Long-term treatment exposure was defined as lasting beyond 351 days. The primary goal of the analysis was to assess the safety and efficacy of mogamulizumab based on treatment exposure. The analysis found that long-term treatment with mogamulizumab was safe and well-tolerated. The main issue was drug eruption, a skin rash that was considered related to treatment. Drug eruption occurred in 20% of patients treated with long-term mogamulizumab. Thrombocytopenia was reported in 11.1%. All other side effects were observed in less than 10% of patients, and they tended to be low-grade.
The analysis also showed that benefit continued beyond 1 year, and was similar regardless of the patient’s CCR4 expression status.3 The global response rates were high in patients treated with mogamulizumab for longer periods. However, this improvement may not necessarily be attributable to the longer treatment duration. The study raises the question of whether these patients were preselected. They may have characteristics that would allow them to respond better to treatment with mogamulizumab. As mentioned, CCR4 expression status did not predict response, but there may be other factors. Based on this analysis, it is not known whether increased duration of mogamulizumab treatment led to long-term improvements, or whether patients who respond well to mogamulizumab were able to maintain treatment for a longer duration.
An analysis of data from the MAVORIC trial evaluated symptoms and side effect bother in patients with CTCL treated with mogamulizumab or vorinostat.4 The study showed that treatment with mogamulizumab was associated with a stronger likelihood of improvement in skin symptoms, side effect bother, and lack of energy vs vorinostat (odds ratio, >1.0).
Novel Strategies
Dr Steven Horwitz presented a study of the novel SYK/JAK inhibitor cerdulatinib in patients with peripheral T-cell lymphoma (PTCL) and CTCL.5 This type of therapy has not been evaluated in CTCL before. Abnormalities in the SYK/JAK signaling pathway are found in a small proportion of CTCL patients. However, a drug that targets this pathway would likely have high response rates in these patients. The trial enrolled 45 patients with PTCL and 29 patients with CTCL. At the time of the report, 27 patients with CTCL were evaluable for response. The overall response rate was 26%, consisting of a complete response in 7% and a partial response in 19%. These results are impressive. Importantly, responses were seen in patients with mycosis fungoides (6 of 21 patients) and Sézary syndrome (1 of 6 patients). These patients experienced a dramatic improvement in pruritus.
Treatment with cerdulatinib was fairly well-tolerated. The rate of diarrhea was 3% among patients with CTCL, but cases appeared mild. There was an increase in lipase levels, but no cases of frank pancreatitis. No patients with CTCL reported abdominal pain (although it occurred in 9% of patients with PTCL).
Correlation studies are now evaluating which patients are most likely to benefit from cerdulatinib. A phase 2a trial is also being designed.
A phase 1/2 trial by Dr Christiane Querfeld evaluated the combination of durvalumab and lenalidomide in CTCL.6 Dr Querfeld had previously piloted the use of lenalidomide in CTCL, showing some moderate responses.7 The theory was that lenalidomide, as an immunomodulator, might improve outcomes with the programmed death 1 inhibitor durvalumab. The preliminary data, for only 9 patients, suggested that durvalumab and lenalidomide together had better clinical activity than either agent alone. Skin disease improved in 7 patients, with no serious adverse events. These preliminary results are promising. Correlative studies will attempt to identify any patient characteristics associated with response.
Dr Martine Bagot presented results of a first-in-human phase 1 study on IPH4102, an anti-KIR antibody, in patients with CTCL.8 Dr Bagot presented results for 35 patients with Sézary syndrome, a large cohort for this rare disease. The response rate was 42.9%, and the drug was well-tolerated. There were some complete responses in the blood and lymph nodes. A complete response was seen in 2 patients (5.7%), and a partial response was seen in 13 patients (37.2%). An additional 45.7% of patients had stable disease. An interesting finding was that responses were durable. The duration of response was 13.8 months, and some responses were still ongoing at the time of the report. The patients’ quality of life also improved. IPH4102 will be evaluated in a larger phase 2 trial.
The novel therapy cobomarsen, an inhibitor of Mir-155, belongs to a new class of medications known as micro-RNA inhibitors. MicroRNA 155 may be involved in the pathogenesis of CTCL. Dr Francine Foss presented results of a phase 1 trial that evaluated cobomarsen administered intratumorally, subcutaneously, or intravenously to patients with mycosis fungoides (stages 1 to 3).9 Cobomarsen had significant clinical efficacy. The modified Severity Weighted Assessment Tool (mSWAT) score improved in 92% of patients treated with the systemic formulation. Quality of life also improved. The responses were durable, with a mean duration of response of 259 days. The study reported few adverse events and no life-threatening conditions associated with treatment. The study did not reach the maximum tolerated dose.
A correlative study evaluated signatures of the histone deacetylase inhibitor romidepsin by using a novel strategy involving tandem mass spectrometry and quantitative proteomics.10 This study defined some histone codes. In the future, this type of strategy may be used to select patients for treatment with histone deacetylase inhibitors or possibly to identify new biomarkers for novel therapeutic targets.
A phase 1/2 study by Dr Martine Bagot evaluated the novel agent cusatuzumab (ARGX-110) for the treatment of CD70-positive CTCL.11 Cusatuzumab blocks signaling of CD70/CD27, which is needed for tumor cells to proliferate and survive. CD70 is expressed on lymphoma cells; it is considered a good target in cancer because it is not expressed by normal cells. The overall response rate was 23% among 27 patients. In another 31% of patients, disease was stabilized.
Maintenance Therapy After Electron Beam Therapy
A retrospective analysis by Dr Pamela Allen evaluated maintenance therapy after electron beam therapy.12 Not surprisingly, the study found an increase in progression-free survival among patients treated with maintenance therapy. There was a trend toward an improvement in overall survival. This important study validates the current practice, as physicians typically use maintenance treatment after total skin electron beam therapy. A prospective study comparing maintenance vs no maintenance would be needed for confirmation.
Reduced-Intensity Conditioning Before Stem Cell Transplant
Dr Francesco Onida presented a study of reduced-intensity conditioning before stem cell transplant in heavily pretreated patients with mycosis fungoides and Sézary syndrome.13 Stem cell transplant is considered the only curative treatment for CTCL. This is an important study because a large percentage of CTCL patients who undergo stem cell transplant develop adverse events, including infections, graft-vs-host disease, and death. There is a need to improve outcomes and reduce the infectious side effects and overall toxicity. This study found that a reduced-intensity preconditioning regimen was effective and less toxic than the standard strategy. A complete response was seen in 71% of patients, which is high. After a median follow-up of 80 months, a complete response was maintained in 95% of patients.
Brentuximab Vedotin
A study by Dr Youn Kim evaluated how the superior clinical benefit of brentuximab vedotin in mycosis fungoides reported in the ALCANZA trial (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) corresponded to expression of CD30 molecules in large-cell transformation.14,15 This important study reflects a real-life situation. It is sometimes necessary to treat patients who do not have large-cell transformation or who lack the level of CD30 expression required for enrollment in the ALCANZA trial. The analysis by Dr Kim found that while clinical responses were much higher in patients who expressed high levels of CD30 on their cells, there were still some clinical responses observed in patients who had lower CD30 expression. This critical finding shows that the level of CD30 expression is not an absolute predictor of response to brentuximab vedotin. Patients without large-cell transformation or with a lower level of CD30 expression may still benefit from treatment.
Disclosure
Dr Geskin has been a consultant to Therakos and Actelion, and is an investigator on research supported by Kyowa Kirin.
References
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