Meeting Key Challenges in the Diagnosis and Treatment of Cutaneous T-Cell Lymphoma: Highlights from an Expert Roundtable
Meeting Key Challenges in the Diagnosis and Treatment of Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas (CTCLs) are a rare group of heterogeneous non-Hodgkin lymphomas comprising several different types of malignancies that present with diverse characteristics, clinical courses, and prognoses.1,2 The most common forms are mycosis fungoides (MF), primary cutaneous CD30+ lymphoproliferative disorders (including primary cutaneous anaplastic large-cell lymphoma [pcALCL] and lymphomatoid papulosis [LyP]), and Sézary syndrome (SS).1 CTCL is associated with significant morbidity and diminished quality of life (QoL) attributed to severe pruritus, and social deprivation.3-5
The definitive diagnosis of CTCL is often challenging because of nonspecific clinical and pathologic features, requiring integration of clinical, histopathologic, immunophenotyping, and molecular data.2,6 Several treatment options exist for CTCL, with treatment selection depending on patient and disease characteristics and comorbidities, as well as efficacy and potential toxicities of treatment.7 The most appropriate treatment for early-stage CTCL is skin-directed therapies, such as psoralen plus UVA radiation (PUVA), narrow-band UVB, and topical corticosteroids. Advanced-stage disease usually requires systemic treatment, which is primarily guided by prognostic features and patient-specific factors, and includes biologic agents and targeted therapies as initial options, and chemotherapy after their failure. Retinoids, interferon alpha, and methotrexate are some first-line systemic therapies for patients with CTCL.7,8 Despite international consensus guidelines, “gold standard” treatment approaches for CTCL have yet to be defined, resulting in a high demand for prospective randomized controlled trials. Moreover, agents such as vorinostat, romidepsin, and pralatrexate have been used to treat CTCL but produce a response in only 30% to 34% of patients, which is not sustained, underscoring the need for more effective treatment options.9-11
On March 20, 2018, a virtual roundtable comprising a panel of 6 internationally renowned CTCL experts convened to gain insight into key challenges in the diagnosis and treatment of the disease. Roundtable participants included the following key opinion leaders in the management and dermatopathology of CTCL: (1) Reinhard Dummer, MD, University Hospital Zürich, Switzerland; (2) H. Miles Prince, MBBS, MD, FRACP, FRCPA, Epworth Healthcare and Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia; (3) Pietro Quaglino, MD, Department of Medical Sciences, University of Turin, Italy; (4) Julia Scarisbrick, MBChB, FRCP, MD, University Hospital Birmingham, United Kingdom; (5) Rudolf Stadler, MD, PhD, University Medical Center, Johannes Wesling, Minden, Germany; and (6) Rein Willemze, MD, PhD, Leiden University Medical Center, The Netherlands.
The expert panel deliberated on key challenges in making a timely and accurate diagnosis of CTCL, issues related to CD30 testing, and treatment approaches for patients with CTCL who require systemic therapy. Moreover, the panel revisited data on the latest trials in CTCL (with brentuximab vedotin and mogamulizumab), focusing on the role of these agents in the treatment paradigm. This white paper provides an overview of highlights from the roundtable, including discussions and recommendations from the participating experts.
Key Challenges in the Diagnosis of CTCL
The expert panel identified several challenges in diagnosing CTCL in the real-world setting. The panel indicated that the length of time between a patient’s first visit to a physician and the diagnosis of CTCL is variable and depends on the type of CTCL, the stage of disease, and the responsible physician (ie, a dermatologist, primary care physician [PCP], or infrequently, an oncologist). Making a diagnosis of CTCL typically takes approximately 3 years,12 largely because early-stage CTCL often resembles benign inflammatory conditions, such as eczema or parapsoriasis.6
Dr Quaglino pointed out that “if a patient presents with large nodular lesions such as in ALCL (>2 centimeters) then everybody will go for a biopsy very early. However, in the case of other variations and presentations, the diagnosis can be difficult and the time to diagnosis might be very long.”
Optimally, the diagnosis of CTCL involves a collaborative effort between the (dermato)pathologist and the treating physician and requires taking a careful history; performing a physical examination; obtaining skin biopsies for histopathology, immunohistochemistry, and molecular analysis; and, in the case of erythroderma, an assessment of peripheral blood for the presence of malignant T-cells.13 The panel emphasized the importance of documenting a clinicopathologic correlation for the accurate diagnosis of CTCL.
Indeed, European Society for Medical Oncology (ESMO) clinical practice guidelines on the diagnosis and treatment of primary cutaneous lymphomas (PCLs), which were released in June 2018, indicate that the diagnosis and classification of PCLs should always be based on a combination of clinical, histologic, immunophenotypic, and genetic data.2 Demonstration of clonal T-cell receptor or immunoglobulin gene rearrangements in skin lesions or peripheral blood may be a valuable adjunct in select cases. However, clinical and histopathologic features are, in most cases, the most important deciding factors for therapeutic planning.2 A suggested algorithm for diagnosis and staging of these malignancies is also provided in the 2018 ESMO guidelines.
According to Dr Quaglino, “the major problems in diagnosing CTCL, particularly in the early stages, are that in the majority of cases there is not a clinically specific interpretation of the lesion. If I send the pathologist a skin biopsy with dermatitis or patches, it could be difficult for the pathologist to make a correct diagnosis without a clinical correlation.”
In this context, Dr Stadler stressed that “the most important thing is to have a team that includes the clinician and the dermatopathologist, who work closely together to see the complete clinical picture and then do the right biopsy from the right edges of the lesion. Also, you need to perform several biopsies to get the microscopic picture. If you have one lesion, just by histopathology it is impossible to distinguish, for example, ALCL and LyP.”
Specifically, the experts pointed out that differentiating early-stage MF versus benign inflammatory dermatoses remains a significant challenge in daily practice, as is the diagnosis of SS, because its histology is often nonspecific and requires correlation of clinical symptoms with peripheral blood investigations. Overall, the panel reinforced the need for multidisciplinary team involvement to make clinicopathologic, hematologic, and genotypic assessments for accurate diagnosis/staging of CTCL.
The panel agreed that early diagnoses may have very important treatment implications, such as avoiding incorrect treatment and negatively affecting eventual clinical outcomes. Dr Dummer pointed out, “Early diagnosis is not as relevant for the very early stages in some cases, especially of MF and LyP, since the overall treatment strategy is not different between MF and eczema, and we don’t know if early, aggressive treatment will change the outcome and the course of the disease. Over-diagnosis of CTCL is a realistic challenge.” However, the panel cautioned that a wrong diagnosis may be detrimental to patients.
Dr Quaglino noted that “sometimes, patients may be incorrectly treated with cyclosporine or other immunosuppressive treatments, which is not good if the patient has systemic lymphoma. For example, a patient who had SS received treatment for erythrodermic psoriasis and received cyclosporine and TNF [tumor necrosis factor] inhibitors due to a wrong diagnosis.” The panel clarified that the treatment goal continues to be establishing the diagnosis as early as possible and preventing the disease from progressing.
Dr Scarisbrick explained, “Early diagnosis is essential to prevent treatment delay, mistreatment, and a deleterious effect on quality of life due to itching, pain, and disfigurement. For patients with advanced-stage disease, rapid diagnosis is critical, particularly for SS and for stage IVA2-IVB patients who have a median survival of just 12 to 36 months from the time of diagnosis. No individual treatments are curative and eligible patients should be referred for assessment for allogeneic bone marrow transplant because that is their best chance for long-term survival.”
Indeed, findings of a Takeda market research analysis, reflecting real-world clinical practice, indicate prolonged time between initial patient presentation and CTCL diagnosis because of misdiagnosis, late referrals, and lengthy testing time.14 The analysis found that patients typically consult first with a PCP or dermatologist, who often does not suspect CTCL and misdiagnoses it as a benign inflammatory condition such as eczema, rosacea, allergy, or rash. The analysis also revealed that diagnostic testing is typically initiated by a dermatologist and includes a blood test and skin biopsy.
These observations were echoed in a patient perspective provided by Susan Thornton, a patient with CTCL who is the CEO of the Cutaneous Lymphoma Foundation.15 She revealed that “Patients often shuffle between PCPs and community dermatologists who cannot distinguish CTCL from benign dermatologic conditions, especially in early disease…If the PCP/dermatologist doesn’t suspect CTCL, he won’t refer the patient to an expert or center of excellence, leaving the patient without a firm diagnosis.” The panel commented that these issues occur mainly in community-based, nonuniversity hospitals, because of the lack of coordination between the pathologist and the dermatologist and the lack of education of healthcare providers regarding CTCL.
Current Challenges in CD30 Testing
The panel also discussed current challenges in CD30 testing, including those relating to recognition that the test should be ordered in the first place; standardization in testing procedures and reporting of results; sample collection; interpretation of results; and the impact of CD30 testing results on patient management. Foremost, the panel suggested that CD30 testing in CTCL is not universally performed in most EU countries, and pathologists and physicians often do not routinely include it in their workups. A Seattle Genetics US market research analysis conducted in 2016 found that the majority of physicians in community hospitals and private practice do not perceive value in ordering the CD30 test and are not explicitly ordering it in the first place. Instead, they are leaving it to the discretion of the pathologist as to whether to perform the test.16 The analysis also reported that approximately 40% of pathologists in community hospitals and private practice do not believe CD30 testing is valuable in CTCL and do not include it in their workups.16 During the discussion, the expert panel emphasized the need to integrate CD30 testing into every immunodiagnostic panel. Specifically, the experts stressed the importance of distinguishing between the role of CD30 as a diagnostic tool and as a target for treatment. Dr Quaglino noted that CD30 testing is important for distinguishing CTCL subtypes, and that although CD30 is not critical for diagnosing MF, it is useful in selecting treatment for the disease.
Dr Willemze pointed out that reimbursement and financial motivation may also influence pathologists in their decision to include CD30 in diagnostic workups; this may be a country-specific phenomenon based on each country’s reimbursement system. Dr Stadler commented that “this issue might become more important in the future, since the availability of an increasing number of molecular tests and companion diagnostics will likely increase the burden on pathology departments.”
The expert panel specified that standardization is lacking in CD30 immunostaining procedures, as each laboratory has its own process with different sensitivity and threshold/cutoff values. The experts noted that CD30 expression varies in different types of lesions (patch/plaque vs tumor) and over time, which makes biopsy of the appropriate lesion critical to achieving the correct CD30 test result. They stated that collection and testing of a single sample may result in false-negative CD30 results.
However, the Seattle Genetics US market analysis found that approximately 38% of laboratories tested only 1 sample for CD30 (~16% collected only 1 sample; ~22% collected multiple samples, but tested only a single sample for CD30).16 In this context, the experts said that the need for continual testing depends on the stage of disease, with 1 CD30+ staining sufficient for early-stage disease. However, repeated testing may be warranted in cases of disease progression or when treatment with an anti-CD30 antibody is being considered in a patient with MF and the initial CD30 test result is negative.
There was also a focused discussion on the threshold used to define CD30 positivity and the lack of standardization in reporting CD30 test results. The Seattle Genetics US market research analysis found that the threshold for CD30 positivity was not standardized and varied widely, with approximately half of pathologists using a cutoff value of ≥20% of neoplastic cells staining positive for CD30 to report CD30 positivity.16 Moreover, a recent study found that CD30 expression in CTCL is highly variable.17
The experts described the different ways CD30 tests are reported in their countries. In The Netherlands and Germany, CD30 positivity is reported as a percentage, with a qualitative designation on which types of cells are positive (ie, whether they are large cells, small cells, or scattered infiltrates). In the United Kingdom, test reports indicate positivity or negativity as a percentage of CD30+ cells of the atypical lymphocytes, and include a detailed description of CD30+ cell morphology. In Italy, CD30 positivity is stated as present in the majority or minority of the cell infiltrate or only in the large cells, whereas in Switzerland the reports are typically not very consistent in reporting CD30 staining. These observations clearly highlight the need for standardization of CD30 testing procedures and reporting.
Treating CTCL with Systemic Therapy
Currently, no evidence-based algorithm exists for the systemic treatment of CTCL, with available treatment practice guidelines recommending consideration of a range of therapies. The recently published ESMO guidelines indicate that the choice of treatment for CTCL depends on the type and the stage of the disease.2 Controlled clinical trials in CTCL are almost nonexistent because of the heterogeneity and rarity of the disease (with the exception of some trials designed to evaluate recently marketed drugs). Therefore, recommendations are largely based on retrospective cohort studies and expert opinions discussed during consensus meetings of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the International Lymphoma Radiation Oncology Group, including consensus recommendations for clinical end points and response criteria in MF/SS. Based on recommendations derived from these groups, the ESMO guidelines provide a recommended algorithm for the treatment of MF and SS based on stage of disease, as well as for primary cutaneous CD30+ lymphoproliferative disorders.2
Anti-lymphoma activity in CTCL has been observed with the use of nonchemotherapeutic agents such as α-interferon, bexarotene, histone deacetylase (HDAC) inhibitors (eg, vorinostat, romidepsin, panobinostat, and belinostat), and the monoclonal antibody alemtuzumab.9,10,18-22 For patients with MF who require first-line systemic therapy, the EORTC guidelines recommend consideration of α-interferon, retinoids, or low-dose methotrexate (stage IIB, IIIA, and IIIB); for stage IVA and B disease, chemotherapy (eg, gemcitabine, pegylated liposomal doxorubicin, CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone], and CHOP-like polychemotherapy) may be considered.7 The EORTC guidelines recommend systemic treatment for SS with α-interferon or retinoids in combination with other treatment modalities, such as extracorporeal photophoresis (ECP) or PUVA, low-dose methotrexate, or chlorambucil plus prednisone.7 The EORTC, ISCL, and USCLC consensus treatment recommendation for patients with pcALCL presenting with numerous, disseminated, or stigmatizing skin lesions is low-dose methotrexate, or chemotherapy where there is extracutaneous spread; methotrexate is recommended for LyP with numerous and/or generalized lesions.23
In a retrospective analysis of a CTCL database with 198 patients with MF/SS who were undergoing systemic therapies, investigators reported that the median time to next systemic treatment (TTNT) was only 3.9 months for single- or multiagent chemotherapy, 8.7 months for α-interferon, and 4.5 months for HDAC inhibitors.8 It is also noteworthy that, in contrast to systemic lymphomas, multidrug systemic chemotherapy regimens such as CHOP are largely ineffective in most CTCL subtypes, resulting in short-lived efficacy at the cost of further immunosuppression.8 Moreover, a large, multicenter, retrospective study showed that there exists considerable treatment heterogeneity in advanced MF/SS, and that chemotherapy as initial treatment is associated with a higher risk for death and/or change of therapy and thus, other therapeutic options are preferable as a first-line treatment approach.24
However, in the real-world setting, community providers have limited awareness of consensus treatment guidelines or standard of care, leading to inappropriate treatment.25 A physician survey on CTCL treatment conducted in 2017—which included 63 dermatologists/oncologists and 191 hematologists/oncologists in the EU, Japan, and Brazil—found that there was no single standard of care.25 It also revealed that CHOP or similar regimens were the most frequently used first-line systemic regimen and was more frequently used by hematologists/oncologists for CTCL, especially for pcALCL. This is in direct variance with the published EORTC guidelines, which do not recommend CHOP as first-line treatment of CTCL, and restrict its use only to certain settings, including as second-line treatment of stage IVA/IVB MF.7 The expert panel expressed surprise and disappointment with these real-world practices—particularly the inappropriate use of CHOP, which is associated with a high risk for infectious complications—and emphasized the need for continued physician education in this area. In this regard, the recently published ESMO guidelines clearly summarize their recommendations for the diagnosis and pathology/molecular biology, staging and risk assessment, treatment, and follow-up and long-term survivorship of the most common forms of CTCL, which should be of value to treating physicians and dermatopathologists.2
From a patient perspective, Susan Thornton indicated that a major source of frustration and anxiety for patients is the uncertainty surrounding which treatment will work for them, particularly when a treatment stops working after an initial response. Other important treatment considerations for patients include access to and convenience of treatment, cost issues/insurance reimbursement, and management of psychosocial and QoL issues.15
Emerging Agents for Systemic Therapy in CTCL
Current systemic therapies for CTCL are associated with suboptimal clinical outcomes and provide a short duration of response, with overall response rates (ORRs) ranging between 30% and 40%, median TTNT of 3.9 months, and an average of 3 prior lines of therapy.8-10,26,27 Clearly, there is a need for treatment approaches that can provide durable objective responses and prolong progression-free survival (PFS) for patients with CTCL. The advent of brentuximab vedotin and mogamulizumab seeks to fill this medical gap. The clinical trial data that led to the approval of brentuximab vedotin and the recently reported data on mogamulizumab, as well as expert insights on their clinical relevance for the management of CTCL, were discussed by the panel of experts.
Adcetris® (brentuximab vedotin)
Brentuximab vedotin (Adcetris®) is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody (SGN-30) attached by a protease-cleavable dipeptide linker to a microtubule disrupting agent, monomethyl auristatin E.28 The European Medicines Agency (EMA) approved brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma following autologous stem-cell transplantation (ASCT), or following at least 2 prior therapies when ASCT or multiagent chemotherapy is not a treatment option, or who are at increased risk for relapse or progression following ASCT. It is also indicated for the treatment of relapsed or refractory systemic ALCL and CD30+ CTCL after at least 1 prior systemic treatment.29
The approval of brentuximab vedotin for CD30+ CTCL was based on the results of the ALCANZA trial, which was an open-label, randomized phase 3 trial of brentuximab vedotin versus physician’s choice (methotrexate or bexarotene) in 131 patients with CD30+ MF or pcALCL who had received ≥1 systemic therapy (or radiotherapy for pcALCL).30,31 Eligible patients (N = 131) received intravenous brentuximab vedotin 1.8 mg/kg once every 3 weeks, for up to sixteen 3-week cycles, or physician’s choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m² once per day) for up to 48 weeks (Figure 1).30 The primary end point was the proportion of patients in the intention-to-treat (ITT) population achieving an objective global response lasting 4 months or more (ORR4), per an independent review facility.
Most baseline characteristics in the 2 arms were well-balanced; however, there were more patients with stage IVB MF and extracutaneous pcALCL in the brentuximab vedotin group than in the physician’s choice group. In the overall ITT population, there were 97 (76%) patients with MF and the median number of prior systemic therapies was 2.30 At a median follow-up of 22.9 months, brentuximab vedotin significantly improved ORR4 versus physician’s choice (56.3% vs 12.5%), showing a between-group difference of 43.8% (95% confidence interval [CI], 29.1-58.4; P <.0001) (Table 1).30
The ORR4 benefit with brentuximab vedotin was maintained across subgroups, including pcALCL or MF, and whether the physician’s choice for an active comparator was methotrexate or bexarotene. These results were achieved with a median of 12 cycles (~9 months) of brentuximab vedotin. A higher proportion of patients treated with brentuximab vedotin achieved an objective response than those treated with physician’s choice (67% vs 20%; P <.0001); 15.6% of patients achieved a complete response with brentuximab vedotin versus 1.6% with physician’s choice (adjusted P = .0046). Moreover, 77% of patients with MF (37/48) in the brentuximab vedotin arm had a ≥50% reduction in modified Severity Weighted Assessment Tool (mSWAT) score versus 41% of patients with MF (20/49) in the physician’s choice arm, and 63% of patients with pcALCL (10/16) in the brentuximab vedotin group had 100% reduction in mSWAT score.30
Median PFS per European Medicines Agency criteria was 16.7 months in the brentuximab vedotin group versus 3.5 months in the physician’s choice group (hazard ratio [HR], 0.270 [95% CI, 0.169-0.430]; P <.0001; adjusted P <.0001), corresponding to an impressive 73% risk reduction for disease progression. Brentuximab vedotin also significantly improved patient-reported symptoms, including skin symptoms as assessed by Skindex-29, versus physician’s choice, with a mean maximum reduction from baseline of 27.96 versus 8.62, respectively (adjusted P <.0001).30
In patients with MF, CD30 expression varied considerably among patients and in different lesions in individual patients. Because of this, multiple baseline biopsies (≥2) were taken from patients with MF at enrollment. Patients were deemed to be CD30+ if ≥1 biopsy samples had ≥10% CD30+ malignant cells or lymphoid infiltrate by central review. Brentuximab vedotin demonstrated consistent efficacy benefit, even in patients whose lowest scoring biopsy (CD30min) was <10%; 44% of the enrolled patients with MF had ≥1 biopsy samples that scored as <10% CD30+.32
Commenting on these data, Dr Prince stated, “patients who have even low levels of CD30 expression can do extremely well with brentuximab, as long as the treatment and side effects are being managed carefully.”
Grade 3/4 adverse events (AEs) were reported in 41% of patients in the brentuximab vedotin group and 47% of patients in the physician’s choice group; peripheral neuropathy (PN) was the most common AE associated with brentuximab vedotin and was observed to be generally reversible and manageable in most cases (Figure 2).30,33
All of the experts agreed that the PFS data of the ALCANZA trial were particularly impressive. He stated, “I think brentuximab data is a game changer. I think it is a drug that gives us a very, very durable response, particularly in MF. It should be called upon early. It’s generally well-tolerated.” He also indicated that although ORR4 is the primary clinical end point, the PFS data are the most clinically relevant. Dr Quaglino concurred, “I think that the most impressive finding from the study was the PFS duration, because it is one of the major challenges in the treatment of these patients.” He noted that “there are 2 very separate populations that the drug will benefit—the MF population and the anaplastic group. It will really be able to select patients who are not doing well on radiotherapy.”
There was an important discussion about the possibility of using brentuximab vedotin at lower doses and for longer periods of time to expand its use to a larger target population. Dr Dummer noted, “Brentuximab challenges all the available first-line systemic therapies in several types of cutaneous lymphomas, and particularly in the case of irradiation resistance or in patients who do not qualify for irradiation. However, a major question is, do we really need this high a dosage? This is especially important because we want to continue to treat patients for a longer time period, so we have to find a way to reduce the overall dose to improve the possibility of longer treatment. And for this, we need additional data because it will be very hard to stick to the treatment schedule of the ALCANZA trial.”
In this context, Dr Prince indicated that he had experience with lower doses of brentuximab—1.6, 1.3, and 1.0 mg/kg—which are still effective and allow management of treatment-related AEs such as fatigue and PN.
Dr Stadler also shared that his treatment strategy is to use brentuximab for 4 cycles at the ALCANZA-recommended dose, then reduce the dose to 1.2 mg/kg for an extended period of time for as long as the patients continue to benefit.34 The experts advised that further clinical studies be conducted with lower doses of brentuximab for longer periods of time to enable an acute therapy and a maintenance approach with this agent.
The 2018 ESMO guidelines suggest that brentuximab vedotin represents a step toward personalized therapy in CTCL, in that it is used specifically to treat CD30+ advanced-stage refractory or relapsed CTCL, including patients with cutaneous ALCL and those with MF/SS; it is also used with the purpose of bridging eligible patients to an allogeneic stem-cell transplant (aSCT).2
Mogamulizumab is a monoclonal antibody that targets CCR4, a cell-surface antigen that is overexpressed on malignant T-cells. In early US studies, mogamulizumab demonstrated a tolerable safety profile and an ORR up to 37% in relapsed T-cell lymphomas.35 The open-label, multinational, randomized, phase 3 MAVORIC trial evaluated mogamulizumab versus vorinostat in patients with previously treated CTCL.27,36 Eligible patients included those with stage IB-IVB MF or SS, an Eastern Cooperative Oncology Group performance status 0 to 1, failure of ≥1 prior courses of systemic therapy (including anti-CD4 antibody or alemtuzumab), and without large-cell transformation; CCR4 expression was not a requirement for participation (NCT01728805) (Figure 3).36
Enrolled patients (N = 372) were stratified by disease type (MF or SS) and stage (IB/II or III/IV) and randomized 1:1 to receive either mogamulizumab 1.0 mg/kg weekly for 4 weeks, then every other week until progression, or vorinostat 400 mg once daily. Patients treated with vorinostat were allowed to cross over to mogamulizumab upon progression or intolerable toxicity. The primary end point was PFS by investigator assessment using a global response score; secondary end points included ORR, duration of response (DOR), patient-reported outcomes (QoL), crossover ORR, and safety.
In the ITT population (N = 372), there was equal distribution of patients with MF/SS in both arms, with a majority of participants having late-stage/advanced CTCL and a median of 3 prior systemic therapies.36 By investigator assessment, mogamulizumab treatment was associated with a significant PFS improvement versus vorinostat: median PFS 7.7 months (95% CI, 5.7-10.3) versus 3.1 months (95% CI, 2.9-4.1); HR 0.53 (95% CI, 0.41-0.69; P <.0001), which was corroborated by independent review (Table 2).36 Mogamulizumab-treated patients also achieved higher ORR (28.0% vs 5%; P <.0001) and longer DOR (14.1 months vs 9.1 months) than those treated with vorinostat. The PFS, ORR, and DOR benefits also extended to predefined subgroups, including disease type (SS or MF) and disease stage. Clinical activity in the blood compartment (ORR = 68%) was higher than in the skin (ORR = 42%), lymph node (ORR = 17%), or viscera (ORR = 0%) compartments in the mogamulizumab arm, suggesting that it would be particularly effective in SS, especially for those with a high tumor burden in the peripheral blood.
Greater reductions were reported in mSWAT score and superior best global response with mogamulizumab versus vorinostat. In terms of patient-reported outcomes, mogamulizumab therapy showed statistically significant improvements in patient-reported Skindex-29 symptom scores versus vorinostat. The safety profile for mogamulizumab was consistent with previous reports, with >20% of patients treated with mogamulizumab experiencing treatment-emergent AEs such as infusion-related reactions (33.2%), drug eruptions (23.9%), diarrhea (23.4%), fatigue (23.4%), and nausea (15.2%) (Table 3).36
The experts pointed out that vorinostat was not an appropriate comparator to use in the study since it is not approved by the EMA for MF or SS. Moreover, the time to progression (TTP) and ORR values observed in the vorinostat arm were significantly lower than previously reported in the vorinostat pivotal trial.9 Nevertheless, the benefit of mogamulizumab was especially pronounced in the leukemic population (SS) that is exceptionally difficult to treat. Dr Dummer noted that he expects this agent to be used frequently in patients with SS.
The 2018 ESMO guidelines also suggest that mogamulizumab may represent a step toward personalized therapy of CTCL since it targets the CCR4 chemokine receptor.2 However, as noted above, CCR4 expression was not a requirement for patient participation in the MAVORIC trial.36
General Approaches to Systemic Therapy of CTCL in 2018—A Conversation with the Experts
At the outset, the panel stressed that, as a general treatment principle to systemic therapy in CTCL, the use of nontoxic systemic drugs combined with skin-directed therapy should be used as first-line treatment. Elaborating, Dr Prince stated, “The points that I would make are that skin-directed therapy should be used where possible, chemotherapy and immunosuppressives should be avoided, and biologic agents used where possible.” The panel also emphasized the need to increase incorporation of α-interferon into treatment plans as systemic therapy for patients with CTCL.
The panel noted that their choice of systemic treatment for patients was guided primarily by CTCL subtype, stage of disease, biomarkers, disease characteristics (indolent vs aggressive), and comorbidity(ies). As first-line systemic therapy, the panel preferred to use interferon for MF, ECP for SS, methotrexate for rare cases of multifocal pcALCL that cannot be managed by radiotherapy, and methotrexate or a watch-and-wait approach for LyP. In the second-line setting, brentuximab vedotin was their agent of choice for MF (if CD30+), interferon for SS, brentuximab vedotin or methotrexate for pcALCL, and bexarotene for LyP. However, there were widely divergent opinions on optimal treatment in the third-line setting.
Furthermore, the experts indicated that the treatment goals and strategies are different for older versus younger patient populations with advanced disease. The goal in the younger group is to achieve complete remission, with the possibility of eventual aSCT, and brentuximab vedotin may be a valuable bridge to aSCT in these patients. Brentuximab vedotin is also a good treatment option in younger patients since it is associated with high complete remission rates and these patients can tolerate potential PN better. For older patients, brentuximab vedotin is also considered an excellent treatment option, when used with appropriate modifications, and when prior treatment with cytotoxic drugs are taken into account.
Dr Prince shared that, “personally, I find brentuximab well tolerated in older patients as well as in younger patients. I don’t feel age is a predictor of neuropathy (with this drug), but fatigue can be an issue in some patients, and so it is important to be aware of fatigue in older patients.”
Clarifying further, Dr Dummer shared, “I don’t use it [brentuximab] continuously due to the side effects, and so I have to use this powerful drug very intelligently for a small number of cycles, then lower the dose, then increase the intervals. There is an urgent need for a registry collecting the clinical outcomes of various dosing schedules with brentuximab.”
The expert panel considered brentuximab vedotin and mogamulizumab as important additions to the treatment armamentarium for CTCL. To derive maximal clinical benefit in clinical practice, Dr Stadler commented, “We now have powerful drugs like brentuximab vedotin, so we should provide consensus recommendations on how to use this drug so that all the physicians worldwide can use it appropriately. We also have to explain to patients that this drug has side effects and try to minimize them as much as possible.” Dr Quaglino concluded, “I think that we are entering into a new era of treatment in the field of cutaneous lymphoma that is specifically focused on patients with the highest clinical need of effective treatment.”
The primary goals regarding the treatment of patients with CTCL are aimed at prolonging time to progression, reducing disease burden, and improving QoL. Achieving these goals has been challenging, because of issues related to diagnosis, lack of a robust evidence base, and limited effective treatment options. For accurate CTCL diagnosis, the expert panel recommended consultation with a multidisciplinary team that includes dermatologists, oncologists, pathologists, radiation oncologists, and supporting staff. The panel emphasized the importance of making oncologists, dermatologists, and pathologists aware of the need for CD30 testing and its critical role in the diagnosis and treatment selection for CTCL.
The treatment landscape for CTCL has evolved, with the emergence of targeted agents with novel mechanisms of action such as brentuximab vedotin and mogamulizumab. Given the lack of effective treatments for CTCL, these novel agents represent excellent alternative treatment options for patients. Future research efforts to optimize dosing and evaluate combination therapy with other active agents are expected to further improve clinical outcomes with these drugs.
- Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785.
- Willemze R, Hodak E, Zinzani L, et al. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2018;29(Suppl 4):iv30-iv40.
- Sampogna F, Frontani M, Baliva G, et al. Quality of life and psychological distress in patients with cutaneous lymphoma. Br J Dermatol. 2009;160:815-822.
- Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29:2598-2607.
- Demierre MF, Gan S, Jones J, et al. Significant impact of cutaneous T-cell lymphoma on patients’ quality of life. Cancer. 2006;107:2505-2511.
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Trabectedin: a DNA-Binding Agent That Covalently Interacts with the Minor Groove of the DNA Double Helix
Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings.1 Trabectedin binds to the minor groove of DNA and alkylates guanine at the N2 position, bending the helix toward the major groove.2,3 In this manner, it is [ Read More ]
In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone acetyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) [ Read More ]