As part of our coverage of the American Society of Clinical Oncology (ASCO) Annual Meeting held June 1–5 in Chicago, ONCOLOGY spoke with Narjust Duma, MD, a hematology and oncology fellow at the Mayo Clinic in Rochester, Minnesota, who served as lead author on a study of sex differences in the tolerability of anti–programmed death 1 (anti–PD-1) immunotherapy among patients with metastatic melanoma.

What led you to examine sex differences in the tolerability of immunotherapy?

 Most research projects start at the bedside. During my time on the inpatient oncology service, I observed several patients with grade 3 immune-related adverse events admitted to the hospital. After several weeks, we noticed most of the patients were women receiving immune checkpoint inhibitors.

While this sample was skewed towards severe adverse events in a tertiary center, we decided to investigate if our observation was the same in the outpatient setting.[1]

2. Among patients at the Mayo Clinic Rochester who received anti–PD-1 immune checkpoint immunotherapy for metastatic melanoma, you found that premenopausal women had a higher rate of immune-related adverse events (IRAEs) leading to treatment discontinuation than postmenopausal women, and that both groups of women had higher rates than men, correct?

 Yes, despite a small sample size (30 premenopausal women), we observed that premenopausal women had higher rates of IRAEs and were more likely to discontinue their anti–PD-1 agent due to toxicity (irrespective of the clinical benefit they had obtained from the treatment).

These differences were observed when comparing [premenopausal patients] with postmenopausal women and men with metastatic melanoma.

3. The differences were limited to lower-grade (grade 1 and 2) IRAEs, correct?

 We did not observe differences in IRAEs higher than grade 3, meaning most of the difference came from grade 2 adverse events. One of the challenges while conducting studies like ours is that grade 1 adverse events are often under-documented. We hope to continue our work in this area and conduct a large prospective study where data regarding adverse events of all grades will be well documented and later analyzed.

4. Did the site of metastasis affect IRAE risk?

 Previous observations suggested that patients with liver metastases were more likely to develop IRAEs. In our cohort, we did not find a correlation between liver, lung, or brain metastases and risk of developing IRAEs. We are planning to conduct further analysis regarding the association of primary tumor location and IRAEs.

5. Were there trends for specific types of IRAEs?

 When analyzing IRAEs in subcategories (by organ involvement), we observed that women were more likely to develop endocrinopathies such as hypothyroidism, adrenal insufficiency, etc. In the general population, women are more likely to develop hypothyroidism during their lifetime compared to men.

 Perhaps sex as a biologic variable plays an important role in the development of IRAEs and in the differences between the sexes in this area. Further studies are necessary to understand the etiology of these mechanisms and the role of sex hormones in the development of IRAEs.

7. Were there demographic or clinical variables in addition to patient sex that affected IRAE risk?

 We conducted a multivariable analysis to try to identify other risk factors for the development of IRAEs. We did not observe any significant association besides sex. Included in the analysis were specific tumor characteristics and mutations; history of prior radiation, chemotherapy, or colony-stimulating agents; and comorbidity indexes. None of these were statistically significant.

8. How did IRAEs affect patient outcomes?

 We failed to observe a meaningful difference in progression-free survival between the women with IRAEs and those without, but this could have been in part due to our small sample size in the premenopausal group.

On the other hand, we captured a trend towards better progression-free survival in men who developed IRAEs, suggesting an association between immune system “hyperactivation” and response to therapy. We are collecting more data from our sites in Florida and Arizona with the hope of increasing our sample size. This project has been an enterprise-wide effort.

9. What implications do your team’s findings have for the use of immune checkpoint blockade regimens in women?

 At this time, we believe we need further studies to better understand our observations, but these findings bring attention to a very important issue: women are biologically different and may require closer monitoring while receiving treatment with anti–PD-1 therapy for metastatic melanoma. As more trials utilizing anti–PD-1 agents are opening every day, we hope that the data regarding adverse events will be reported by sex and that larger studies can be conducted with the existing data.

How should your findings affect monitoring for immune checkpoint inhibition–associated IRAEs?

 The treatment landscape of multiple malignancies has changed with the introduction of immune checkpoint inhibitors. Clinical practices should adapt to these changes. Our questions regarding adverse events are shifting away from the traditional nausea, vomiting, etc to the new-rashes, joint pain, and cough, for example.

ASCO recently released guidelines for the treatment of IRAEs; we invite everyone to review them. Consistent practices would allow our patients to receive the best care independent of whether they are treated at a tertiary center or in a community practice.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Duma N, Paludo J, Enninga EA, et al. Sex differences in tolerability to anti-PD1 therapy. Are we all equal? J Clin Oncol. 2018;36(suppl):abstr 9547.

 Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36:1714-68.

In this interview, we discuss a study of sex differences in the tolerability of anti–programmed death 1 immunotherapy among patients with metastatic melanoma.

Narjust Duma on How Gender Affects the Tolerability of Immunotherapy

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of diseases, with low incidence and unique epidemiology and pathobiology; they are usually clinically aggressive, with poor outcomes. There have been significant advances in our understanding of the molecular and signaling alterations seen in these malignancies. These observations have led to novel therapeutic strategies that have had a meaningful impact on outcomes. This two-part series highlights the most important aspects of PTCLs and describes current treatment options and investigative opportunities. Part 1 will cover PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma (ALCL), and breast implant–associated ALCL. Part 2 will cover extranodal natural killer/T-cell lymphoma, enteropathy-associated T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, adult T-cell leukemia/lymphoma, and hepatosplenic T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) constitute approximately 10% to 20% of non-Hodgkin lymphomas. They are heterogeneous, with more than 20 subtypes, including T-cell and natural killer cell diseases, and most exhibit aggressive behavior and have an unfavorable prognosis.[1-4]

PTCLs have a higher incidence in males, Caucasians, and adults aged 50 to 60 years.[5-9] Over the last decade, there has been an increase in the incidence of PTCLs, which could be partially explained by diagnostic advances and the aging of the population.[10] Several studies have demonstrated the epidemiologic variability found across different geographic populations (Figure 1). The incidence of each subtype is influenced by age, gender, and ethnicity.[3,5,8] Additional risk factors are a family history of hematologic malignancies, immune perturbations (autoimmune etiology or inflammatory response), alcoholism, and smoking.[8,9,11]

Based on clinical presentation, a PTCL may be characterized as one of four subtypes: nodal, extranodal, leukemic, or cutaneous. These subtypes differ in morphology, immunohistochemical phenotype, gene expression profile, and clinical outcome.[4,12] Part of the current World Health Organization (WHO) classification for PTCLs is described in Table 1.[4]

The complexity of the histologic classification and the low incidence explain why diagnosing PTCL is challenging.[3,13] An experienced hematopathologist is essential for an accurate diagnosis and subclassification, as is combining morphologic evaluation with immunohistochemical analysis.[1,5,14-16] Molecular and genetic studies are important tools for distinguishing subtypes.[13]

Once diagnosed, a patient’s risk should be stratified based on clinical, laboratory, and imaging findings.[13] It is crucial to consider the patient’s age, performance status, and comorbidities, because these will have an impact on treatment decisions.

The International Prognostic Index (IPI), specifically devised for assessing the prognosis of aggressive B-cell lymphomas, has also been applied to PTCL and in general correlates with overall survival (OS).[7,17] The Prognostic Index for T-cell lymphoma (PIT), developed by Gallamini et al[18] in 2004, is based on these investigators’ study of Italian patients with PTCL not otherwise specified (PTCL-NOS; Table 2). Although the PIT has already been modified, both these indexes have significant shortcomings. They were developed with small cohorts and before PTCL treatment improved, and they did not differentiate between subgroups.[10,15,18]

In general, patients with PTCL have a poor prognosis. Complete responses are expected in only half of patients, and relapses are common.[9,17] For this reason, autologous stem cell transplant (autoSCT) is often indicated in first remission.[13]

The nodal subtypes of PTCL occur predominantly in patients from Europe and North America, and of these, PTCL-NOS is the most common histology.[8,10] The median age at presentation is approximately 60 years, with a male predominance. Clinically, most patients present with advanced disease.[13]

PTCL-NOS is not a distinct entity.[13] It can be described as an assortment of histologies with cytologic and phenotypic heterogeneity that cannot be subclassified as other PTCLs.[4,8]

Gene expression profiling has identified three subtypes of PTCL-NOS: 

-overexpressing (associated with the worst prognosis), and PTCLs expressing other cytotoxic genes (Table 3).[3,4,19]

Conventional cytogenetic tests suggest limited recurrent karyotype abnormalities, which in most cases lack disease specificity.[6] MicroRNA profiling is being explored as another alternative for characterization and as an aid in improving our understanding of tumor biology.[16,20]

The treatment regimens developed for PTCL were derived from those designed for B-cell lymphomas.[21-24] In particular, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with or without consolidation radiotherapy, is the regimen most often employed. The addition of etoposide to CHOP (CHOEP or dose-adjusted EPOCH) potentially benefits a subset of younger patients. Although adding etoposide to CHOP does not affect OS, it is associated with improved treatment-free intervals.[22-24]

Other CHOP-based combinations for first-line therapy feature the addition of alemtuzumab, denileukin diftitox, or bortezomib. Other intensive regimens include hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine) and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), but to date, none of these regimens has been shown to be superior to the others.[13]

Due to the heterogeneity of PTCL-NOS and its poor outcomes, there is no standard of care for treatment.[13,25-27] However, most centers will consider consolidation with high-dose chemotherapy and autoSCT.[24]

In cases of relapsed/refractory disease, there are several options for second-line therapy (Table 4).[24] It is important to note that not all are approved by the US Food and Drug Administration for use in PTCL-NOS, and even fewer have been approved for this indication by the European Medicines Agency.

Patients with PTCL-NOS have a poor prognosis, with a 5-year OS rate of approximately 30%.[8] Those with a higher IPI score usually have an even worse OS.[13]

Initially classified as a PTCL-NOS variant, although with some clinical and morphologic features similar to those of angioimmunoblastic T-cell lymphoma (AITL), PTCL characterized by expression of follicular helper T cells has been included in the latest WHO classification as a new entity called follicular T-cell lymphoma (FTCL).[4,28] Although the majority of patients present with advanced disease, a subset has localized disease and mild symptoms.[4]

FTCL typically contains an infiltrate of monotonous lymphoid cells with round nuclei and pale cytoplasm. The lymphoma expresses pan T-cell markers with a CD4+ T helper cell phenotype (eg, PD1 [programmed death 1], CXCL13 [C-X-C motif ligand 13], BCL6 [B-cell lymphoma 6], CD10, and ICOS [inducible T-cell costimulatory]). Similar to AITL, interfollicular CD20+ B immunoblasts with Epstein-Barr virus (EBV) reactivity are present in half of cases. About 20% of cases carry a t(5;9)(q33;q22) translocation, leading to an 

 fusion that appears specific for this entity. The rarity of FTCL makes prognostication difficult, although current data suggest that 50% of patients die within 2 years.[4,28]

AITL is the second most prevalent PTCL. It occurs most often in Europe and North America in persons who are between 60 and 70 years of age.[8] Most patients are symptomatic, with lymphadenopathy, constitutional and associated B symptoms, and often with advanced-stage disease and bone marrow infiltration (more than 70% of cases).[1,2,6,7,18,29,30] AITL has a particular signature, which is associated with hepatosplenomegaly, dysgammaglobulinemia, immune compromise, and cutaneous manifestations (eg, rash).[31,32] The diagnosis often follows an immune event, such as exposure to a medication, an infection, or an allergic reaction.[33] The autoimmune phenomena typical of AITL are likely related to the similarity between neoplastic and follicular helper T cells.[34]

Pathologic diagnosis is often difficult due to the presence of atypical B cells that are often EBV-positive and simulate Reed-Sternberg cells.[34] As in Hodgkin lymphoma, neoplastic cells are in the minority and the microenvironment of AITL is composed of an infiltration of reactive small lymphocytes, eosinophils, plasma cells, epithelioid cells, immunoblasts, histiocytes, and follicular dendritic cells.[34,35] The hyperplasia of follicular dendritic cells and the high concentration of endothelial venules are also typical histologic changes of AITL; patients with FTCL usually do not have these characteristics, helping us to differentiate between the two groups.[4,8,28] However, the immunohistochemical and genetic abnormalities are similar in both, demonstrating a concordant cellular origin.[28,34] 

 mutations are seen in the majority of patients.[36]

First-line therapy for patients with AITL remains an anthracycline-based regimen, similar to the regimen used for the majority of patients with T-cell lymphomas.[23,24] Complete responses are expected in only half of patients, and relapses are common.[9,17] For this reason, and similar to PTCL-NOS and anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL), high-dose chemotherapy followed by autoSCT has been utilized to consolidate treatment in chemosensitive patients. Those who achieve a complete response have better outcomes. Timing of high-dose chemotherapy and autoSCT remains controversial.[7,12,21,22,30,37,38]

Older or unfit patients should not receive intensive treatment. Although cyclosporine with or without prednisone has provided some short-term benefit, results are not optimal.[13]

Patients with chemotherapy-refractory AITL, similar to those with refractory PTCL-NOS, may respond to a variety of new drugs, available as mono- or combination therapy (Table 4).[25,29,37,39]

ALCL, in particular the ALK-positive subtype, affects a younger population (median age, 35 years).[5,8] Clinically, ALCL can be divided into three subtypes: cutaneous, systemic, and breast implant–associated (BIA).[4,8] Patients with systemic disease usually have generalized lymphadenopathy, characteristic of stage IV disease, and extranodal involvement. Bone marrow, bone, and lung are the sites most often affected.[13] Although ALCL has variable morphologic features, the presence of large, highly irregular cells with wreath-like or horseshoe-shaped nuclei is a hallmark.[40]

CD30 and ALK protein expression are the signature markers of this distinctive entity; these give ALCL unique clinical features and a distinctive prognosis. The rearrangement of the 

 gene is a classic biomarker, present in > 50% of ALCLs and with prognostic significance. The most common rearrangement-t(2;5)(p23;q35)-creates a fusion gene composed of nucleophosmin and ALK.[13] Patients with ALK-positive ALCL have a higher OS rate than ALK-negative patients (OS at 5 years: 70% vs 49%).[8,20,41] However, this survival difference is not seen in patients younger than 40 years.[13]

Other prognostic markers, seen in ALK-negative ALCL, are rearrangements of 

; these are associated with a better and worse prognosis, respectively.[20]

The CHOP-like regimens are also used for ALCL, as first-line treatment in both ALK-positive and ALK-negative patients.[23,37] Patients with ALK-positive ALCL typically have a good outcome.[23,24] For this reason, autoSCT is only indicated for relapse.[37,42] AutoSCT can be considered in ALK-negative patients without rearrangement of 

 (Table 2). To achieve more consistent and durable responses in the first line, studies have explored combining new drugs, such as brentuximab vedotin (an anti-CD30 immunoconjugate) and crizotinib (oral ALK inhibitor), with CHOP. Targeted agents are also used for salvage treatment.[12,29,30,39]

The correlation between breast implants and ALCL has recently been recognized, and BIA-ALCL has been incorporated into the WHO classification as a new provisional entity (Table 1).[4] Different from primary breast lymphoma, BIA-ALCL does not compromise the parenchyma; it presents clinically as a localized seroma involving the implant and is associated with pain and swelling.[4,11] A minority of patients may present with a mass, and in these cases the disease is much more aggressive.[40,43] Irrespective of presentation, systemic symptoms are rare.[44]

There are several theories regarding the etiology and pathogenesis of this rare entity. An inadequate response of the immune system to the implant could explain the lymphomatous proliferation.[43] Implants with a more textured surface are more susceptible to bacterial proliferation, which activates lymphocytes and causes a chronic inflammatory process secondary to a bacterial biofilm infection around the implant. Currently, this is the most compelling theory that has been put forth to explain the development of BIA-ALCL.[43,44] 

 species, gram-negative bacilli found in soil and water, have been associated with nosocomial infections, especially implant-related infection.[11,43]

Similar to ALK-negative ALCL, BIA-ALCL has an anaplastic morphology, with an immunophenotype that includes expression of CD30, CD4, CD43, CD45, and CD2, and the absence of ALK.[11,44] The expression of SOCS3 (suppressor of cytokine signaling 3) is also identified in BIA-ALCL cases, as in systemic ALCL.[44]

Most often, complete surgical excision, including removal of the implant and capsulectomy, results in an excellent outcome.[40] In contrast, when the lymphoma invades the capsule or is systemic, primary treatment should be complemented with chemotherapy. In these cases, relapse is not uncommon and the prognosis is worse.[11]

To help in therapeutic decision making, there are algorithms based on diagnosis, molecular characterization, and prognosis that provide treatment options for newly diagnosed and relapsed/refractory patients. As mentioned, autoSCT is very important in treatment of PTCL; therefore, the distinction between patients who are “fit/eligible” and those who are “unfit/ineligible” for autoSCT is fundamental when deciding on the best therapeutic approach.[38]

In very unfit or frail patients, delivery of optimal therapy may be impossible; thus, alternative palliative treatments must be considered.[29,38]

Despite the availability of several new drugs, salvage therapy remains a challenge. So far, with the vast majority of new compounds (with the exception of brentuximab vedotin), only short-lasting remissions have been achieved in ALCL. In contrast, allogeneic stem cell transplantation (alloSCT) seems to be associated with promising outcomes (the 5-year freedom from relapse and OS rates are about 50%). AlloSCT should be considered mainly in younger patients with a human leukocyte antigen–matched sibling donor.[13,45] In this context, these new drugs may assume the role of a bridge to transplantation.[45]

However, there are challenges related to alloSCT, including patient eligibility, donor availability, and treatment-related toxicity and mortality; these affect about 40% of cases.[45-47] Advances in alloSCT include an extension of the donor pool-utilizing matched unrelated donors, umbilical stem cell transplants, and haploidentical transplants-to ensure sources for more patients. Reduced-intensity conditioning nonmyeloablative transplants have extended the age and comorbidities of patients who may be considered as candidates for treatment. Improvements in the management of graft vs host disease and the infusion of donor lymphocytes at the time of residual disease and/or relapse have also had a profound effect.[25]

Currently, alloSCT has to be considered for patients with bone marrow involvement, those in partial remission, and those with relapsed/refractory disease. Advances in clinical care, eg, reduced-intensity conditioning and management of graft-vs-host disease, have been associated with a lower mortality rate, making alloSCT a more realistic approach for PTCL patients.[25]

It is important to emphasize that patients with active disease at transplant have worse outcomes, impacting OS.[25] Before advocating transplantation, one must take into account a patient’s performance status and comorbidities.[29,38]

The low incidence and heterogeneity of PTCLs pose a significant challenge in developing effective therapies. Fortunately, advances in our understanding of the critical pathways, the cellular targets, and the role of the microenvironment in these diseases have led to the emergence of both small-molecule agents and biologic approaches that may have a profound impact on their prognosis. In addition, important strides in immunotherapy, including chimeric antigen receptor T-cell therapy and checkpoint inhibitors, potentially in conjunction with stem cell transplantation, hold great promise. PTCLs lend themselves to the application of precision medicine and may serve as a paradigm for future investigators.

Dr. Zain serves as a consultant for Spectrum Pharmaceuticals, and serves as a consultant and on the speakers bureau for Seattle Genetics. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

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This two-part series highlights the most important aspects of PTCLs and describes current treatment options and investigative opportunities. Part 1 will cover PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma (ALCL), and breast implant–associated ALCL.

Peripheral T-Cell Lymphomas: Incorporating New Developments in Diagnostics, Prognostication, and Treatment Into Clinical Practice-PART 1: PTCL-NOS, FTCL, AITL, ALCL

Oncology Vol 32 No 7