Assessing the Emerging Role of Checkpoint Inhibition and Other Immune Therapies in Lymphoma

Transcription

1 CME Assessing the Emerging Role of Checkpoint Inhibition and Other Immune Therapies in Lymphoma Dates of certification: July 31, 2016, to July 31, 2017 Medium: Print with online posttest, evaluation, and request for credit The American Journal of Hematology/Oncology Editorial Board Debu Tripathy, MD Professor and Chairman Department of Breast Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX Disclosure: Grant/research support from Genentech/Roche, Pfizer, Puma Biotechnology Inc, and Novartis (clinical trial support contracted to the University of Southern California and MD Anderson Cancer Center); consultant for Eisai, OncoPlex Diagnostics, Merck, and Novartis. Faculty Anas Younes, MD Professor and Chief, Lymphoma Service Division of Hematologic Oncology Memorial Sloan Kettering Cancer Center New York, New York, USA Disclosure: Grant/research Support: Novartis, Johnson & Johnson, Curis; Other: Honorarium from: Bayer; Bristol-Myers Squibb, Celgene, Janssen, Sanofi, Seattle Genetics, Takeda, Millennium Staff/Planner Disclosures and Conflict of Interest Resolution The staff of Physicians Education Resource, LLC (PER ), and the editorial staff of The American Journal of Hematology/Oncology have no relevant financial relationships with commercial interests to disclose. It is the policy of PER to ensure fair balance, independence, objectivity, and scientific objectivity in all of our CME/CE activities. In accordance with ACCME guidelines, PER requires everyone who is in a position to control the content of an educational activity, including spouses/partners, to disclose all relevant financial relationships with any commercial interest to participants as part of the activity planning process. PER has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity. Overview This activity is designed to inform physicians about the emerging role of checkpoint inhibition and other immune therapies in the treatment of lymphoma. Target Audience This activity is directed toward hematologists, medical oncologists, nurses, and nurse practitioners who manage and treat patients with lymphoma. Surgical oncologists, radiation oncologists, pathologists, fellows, physician assistants, and other healthcare providers interested in the treatment of lymphoma are also invited to participate. Learning Objectives After participating in this CME/CE activity, learners should be better prepared to: Describe the unmet needs in the treatment of patients with lymphoma Review recent developments in the field of immunology with respect to lymphoma treatment Review current and emerging clinical trial information concerning the use of investigational immunotherapeutic approaches for lymphoma treatment Accreditation/Credit Designation Physicians Education Resource, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physicians Education Resource, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians Education Resource, LLC, is approved by the California Board of Registered Nursing, Provider #16669 for 1.0 Contact Hour. This activity is funded by PER. Instructions for Participation/How to Receive Credit: 1. Read the article in its entirety. 2. Use the QR code or type into your Web browser to access the posttest. 3. Complete and pass the posttest with a score of 70% or higher. 4. Complete the evaluation and request for credit. Participants may immediately download a CME or CE certificate upon successful completion of these steps. Off-Label Disclosure and Disclaimer This continuing medical and nursing education activity may or may not discuss investigational, unapproved, or off-label uses of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only and is not meant to substitute for the independent medical judgment of a physician or nurse relative to diagnostic, treatment, and management options for a specific patient s medical condition. Disclaimer The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians Education Resource, LLC. Contact information for questions about the activity: Physicians Education Resource, LLC 666 Plainsboro Road, Suite 356 Plainsboro, NJ Phone: (888) info@gotoper.com 24 JULY 2016

2 ASSESSING THE EMERGING ROLE OF CHECKPOINT INHIBITION AND OTHER IMMUNE THERAPIES IN LYMPHOMA The American Cancer Society estimates a diagnosis of 81,080 new cases of lymphoma (Hodgkin lymphoma [HL, 8,500 cases] and non-hodgkin lymphoma [NHL, 72,580 cases]), and an estimated 21,270 deaths from lymphoma this year. 1 While most patients with HL can be successfully treated with chemotherapy, radiotherapy, or combined chemoradiotherapy, these treatment options are associated with important short and long-term toxicities such as infertility, cardiovascular damage, and secondary malignancies. Though some patients are cured, there remains an unmet need for treatments in patients who develop refractory disease after stem cell transplant. 2 An enhanced understanding of the interaction between the immune system and tumors has led to the development of novel and powerful forms of cancer immunotherapy in the recent few years. Recognition of negative regulatory immune checkpoints, such as the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways, has led to the discovery of novel therapies targeting these specific pathways. These treatments predominately involved the development of monoclonal antibodies (mabs) directed against the immune receptors or ligands, and are capable of reversing tumor-induced immune-suppression, thereby, effectively enhancing the antitumor response at the priming (CTLA-4) or tissue effector (PD-1) phase. 3 Checkpoint inhibitors have emerged as an important therapeutic class in several malignancies including hematologic. Based on the success of PD-1 blocking mabs in the treatment of solid tumors, phase 1 studies evaluating the efficacy of these agents were initiated in several hematologic malignancies as well. For example, one of the studies tested the safety and activity of the anti-pd-1 mab nivolumab in patients with relapsed or refractory (R/R) lymphoid malignancies including non-hl (NHL), and classical HL (chl). 4 In May this year, the US FDA granted accelerated approval to nivolumab for the treatment of patients with chl that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and posttransplantation brentuximab vedotin. 5 The approval was based on two single-arm, multicenter trials of nivolumab in adults with relapsed or refractory chl. In patients previously treated with autologous stem cell transplant (ASCT) and posttransplantation brentuximab vedotin (BV), treatment with single-agent nivolumab demonstrated good response; the median time-to-response was 2.1 months, and the estimated median duration of response (DOR) was 8.7 months. 5 Most recently, data from the Checkmate 205 study that evaluated the efficacy and safety of nivolumab in pts with chl who had received BV after progression following ASCT was presented at the ASCO 2016 annual meeting. In this study, treatment with nivolumab demonstrated durable responses, high response rate (66% by independent radiologic review committee), and acceptable safety profile. Progression free survival (PFS) and overall survival (OS) data were also encouraging in this heavily pretreated population. Additionally, good efficacy was observed in patients with no prior BV response. 6 Another anti-pd-1 mab checkpoint inhibitor, pembrolizumab, has demonstrated similarly impressive results in chl. In a recently described phase Ib study enrolling extensively pre-treated chl patients who had undergone five or more prior lines of therapy, and had received prior BV (NCT , KEYNOTE-013), treatment with pembrolizumab demonstrated an overall response rate of 66% was reported. 7,8 Most recently, at the 2016 ASCO Annual Conference, data from the KEYNOTE-087 study which aimed to confirm clinical activity of pembrolizumab in chl pts were presented. In this study, ORR was 80% with pembrolizumab in patients with prior BV therapy failure and 70% in R/R chl patients who had undergone ASCT and subsequent BV therapy. 9 Beyond HL, there are also emerging data suggesting that checkpoint blockade therapy with PD-1-blocking antibodies may be effective in NHL. 10 In a phase II single-arm international study of checkpoint inhibitor pidilizumab in R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma after ASCT, the overall response rate was 51%. Subsequently, pidilizumab was evaluated in combination with rituximab in a phase II single-arm open label study, and an overall response rate of 66% was reported. 7,11 Another emerging concept surrounds combining immune checkpoint inhibitors with immuno-modulators or targeted agents, based on the rationale that small molecules directed at various signaling pathways involved in malignancy affect immune responses. Preclinical data combining anti-pd-l1 antibodies and the bruton s tyrosine kinase inhibitor ibrutinib has shown promising activity in lymphoma, which, in turn, has opened the doors for clinical studies evaluating the combination of immunotherapy with immunomodulators or targeted agents such phosphoinositide (PI) 3-kinase inhibitors and others. 7 Currently, atezolizumab (MPDL3280A), an anti-pdl1 (PD-1 ligand) antibody, is being evaluated in combination with the anti-cd20 antibody obinutuzumab in patients with R/R follicular lymphoma (FL) and DLBCL (NCT ). 12 Several other novel checkpoint inhibitors or other immunotherapies are in various stages of development. Beyond PD1 antibodies, a checkpoint inhibitor currently being investigated in lymphoma includes antibodies directed against lymphocyte-activation gene-3 (LAG-3) (NCT ). 13 Additional immunotherapeutic approach being investigated in lymphoma includes the chimeric antigen receptor (CAR) T-cell therapy, which uses autologous infusion of genetically engineered T cells that express chimeric antigen receptors targeting surface antigens, such as CD19. CAR T-cell therapy is currently being investigated for lymphoma treatment based on the promising preliminary data. 14 There are several novel therapeutic options including different immunotherapy approaches that are currently being investigated in lymphoma, and the standard of care for lymphoma will continue to evolve as new agents are approved. Some of the challenges that the practitioners may face in the future may include determining the most optimal approach (sequencing/combination) and personalizing VOL. 12, NO. 7 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 25

3 CME treatment based on predictive biomarkers such as PD-L1 as they become available. Dr. Anas Younes, MD, a medical oncologist and Chief of Memorial Sloan Kettering s Lymphoma Service at New York, NY provided his insights and point on view on the emerging role of checkpoint inhibition and other immune therapies in lymphoma. Moderator: What are some of the unmet needs in the treatment of lymphoma? Dr Younes: It depends on the disease subtype. There are a lot of areas of unmet medical needs in lymphomas. Let us discuss Hodgkin lymphoma, as an example. So even though we can cure up to 80 to 85 percent of all patients with Hodgkin lymphoma with currently available modern therapy, the unmet medical need here is to further improve the cure rate, and to reduce treatment related toxicity. So we definitely want to cure all patients, not just 85 percent. But also we need to improve the safety of the curative regimens. It is well-established that chemotherapy and radiation therapy do have side effects. Some of them are delayed effects, including cardiovascular complications and second malignancies. Immunotherapy could fit in that role by not only improving the cure rate but could potentially improve the safety of the curative regimens. The same applies to non-hodgkin lymphoma as well. One of the most curable subtypes of non-hodgkin lymphoma is the diffuse large B-cell lymphoma, where standard R-CHOP Chemotherapy can cure about 50 percent of the patients. So incorporating new, effective drugs in the RCHOP regimen is highly desirable and needed. And the question is, of course, that everyone wants to find an answer to is whether additional immune therapy-based treatment, on top of what we already have, let s say rituximab, would do the trick and would improve the cure rate, and that s an area under investigation by many investigators in the centers. Moderator: What impact can checkpoint inhibitors have in the treatment of lymphomas in general? Dr Younes: There are two goals that we keep in mind when we try to incorporate new agents, such as checkpoint inhibitors, in the treatment of patients with lymphoma. And if we can t improve the cure rate, the second alternative goal is to improve the overall outcome of treatment, especially in non-curable lymphomas such as the follicular lymphomas and the mantle cell lymphomas by prolonging the duration of remission, for example. And also when we want to change a treatment strategy, we always keep in mind the potential safety of these regimens. And immune checkpoint inhibitors will need to be tested to determine whether they can achieve our goals. Moderator: Results from the phase 2 Checkmate 205 study 6 that evaluated nivolumab therapy in classical Hodgkin s lymphoma were presented recently at this year s ASCO. Would you be able to share some of the key takeaways from this study? Dr Younes: As you probably remember, there were two highly cited phase 1 trials with checkpoint inhibitors, and those were with pembrolizumab and nivolumab. And the Hodgkin lymphoma part was sort of a subset of patients in a larger phase 1 trial that included different types of hematologic malignancies, including myelodysplastic syndrome, multiple myeloma, and non-hodgkin lymphoma, and Hodgkin lymphoma. In the phase 1 trial of nivolumab, the initial report included 23 patients with Hodgkin lymphoma, and remarkably, 87 percent of the patients responded with about 17 percent achieving complete response. Approximately 70 percent of the patients who responded had a prior exposure to brentuximab vedotin, which up till then was the only FDA-approved agent for the treatment of relapsed Hodgkin lymphoma. Although the number of Hodgkin lymphoma patients was only 23, this data generated tremendous interest and enthusiasm that led to the phase 2 trial that you re referring to, which is the Checkmate 205 study. The data that was reported at ASCO was specific for Hodgkin lymphoma patients who had failed both autologous transplant and brentuximab vedotin. The trial included 80 patients and the overall response rate was 66 percent and the complete response rate was 9 percent. So it confirmed in a way the data that was reported initially from the phase 1 trial. And based on this data, in May 2016, the FDA gave approval for nivolumab for the treatment of patients with relapsed Hodgkin lymphoma after failing both autologous transplant and brentuximab vedotin. Moderator: Data from phase 2 KEYNOTE-087 study 9 evaluating pembrolizumab therapy in classical Hodgkin s lymphoma were also presented recently at this year s ASCO. How do these compare with Checkmate 205 study? Dr Younes: Yes, and remarkably a similar story. Initially pembrolizumab was tested in a multi-cohort phase 1 trial that included also Hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, and myelodysplasia. And like nivolumab, in a small number of patients, 29 patients treated in that phase 1 trial, 29 patients had relapsed Hodgkin lymphoma, and the overall response rate was 66 percent, and the complete response rate was 21 percent and in patients who relapsed or were exposed to brentuximab vedotin, the response rate was also high with pembrolizumab, was 66 percent. So, again, based on this very promising data, a phase 2 trial, the registration trial, was initiated and also had multiple cohorts. In reference to prior autologous transplants, brentuximab vedotin, brentuximab was given before after transplant and so forth. But at ASCO, 30 patients this was still ongoing trial 30 patients were treated with pembrolizumab, 200 mg intravenously given every three weeks. And the overall response rates from this ongoing trial was 70 percent and the CR rate was 20 percent. If you look at the data again for nivolumab phase 2 trial and then the pembrolizumab, the ongoing trial, it s remarkable similarity with nivolumab overall response rate 66 percent, pembrolizumab overall response rate was 70 percent. It s amazing the similarities between these two agents JULY 2016

4 ASSESSING THE EMERGING ROLE OF CHECKPOINT INHIBITION AND OTHER IMMUNE THERAPIES IN LYMPHOMA Moderator: Can brentuximab vedotin be potentially used in combination with PD-1/PD-L1 targeted agents and at what stage of the treatment. Why or why not? Dr Younes: Everybody wants to know the answer for this question because if you look at brentuximab vedotin as single agent in patients who relapsed at autologous transplant, overall response rate is 74 percent and the CR rate is about 34 percent. And now we have PD-1 inhibitors giving a high response rate, 66 or 70 percent, with slightly lower CR rate. We have two highly active agents and the question, are they combinable? The trials are ongoing right now in different settings. One setting is in relapsed after frontline therapy before autologous stem cell transplant, and the second one is after autologous stem cell transplant. So, these trials are ongoing and if the combination can be given within safety, then I think this may become a new doublet that one could build on to develop future treatment regimens. Moderator: What is the potential of rationale for combining checkpoint inhibitors with other therapies in lymphoma? Do we have any data so far supporting any such combinations? Dr Younes: There s no data to support. These are ongoing clinical trials. So, for example, checkpoint inhibitors are being combined with frontline regimens like ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin). In untreated patients with Hodgkin lymphoma they re being combined with radiation therapy; in patients with follicular lymphoma, the PD-L1 inhibitor is being combined with CHOP-based regimens in newly-diagnosed diffuse large B-cell lymphoma. Same thing being combined with bendamustine-based regimens in untreated follicular lymphoma. There s combination with lenalidomide and rituximab or obinutuzumab in relapsed follicular lymphoma. These trials are ongoing using different combination regimens, and everybody is interested to find out how these regimens will perform in terms of safety and efficacy. So it will take about a year or two before we find support. Moderator: Do we have any data supporting the role of CAR-T cell therapy in the treatment of lymphoma? Dr Younes: A very important question. Can we further activate engineered T cells to be more effective killers, especially in the settings where CAR-T cell has not shown very high efficacy, for example, in diffuse large B cell lymphoma, CAR-T cells have shown modest efficacy but not as striking as in ALL. And the question, is it because T cells are not optimally activated? And if so, can we further activate engineered T cells by adding checkpoint inhibitors? Clinical trials are currently being conducted to ask this question. The other question that comes to mind is, yes, we may be able to activate T cells, and we may enhance their efficacy, but do we also increase the toxicity of CAR-T cells knowing that CAR-T cells have some unusual toxicity profile? I don t know, we ll find out. I mean the trials are being done and everybody is keeping eye on both efficacy and safety of this approach. Moderator: What does the future hold for checkpoint inhibitors specifically with respect to treatment of lymphoma and patient selection? Dr Younes: The future is a) add on to preexisting regimens, and b) develop sort of chemotherapy-free combination strategies. For example, combining checkpoint inhibitors with lenalidomide or bispecific targeted antibodies. We have a trial combining ibrutinib plus PD-1 inhibitors. And there are several versions of this combination going on in different, again centers, and so forth. So not only we re looking at adding checkpoint inhibitors to traditional chemotherapy regimens, we are also combining them with small molecules or other immune therapy drugs to determine the safety and efficacy of these new regimens. Moderator: Besides checkpoint inhibitors and CAR-T cell therapy, what are some of the other promising/emerging immunotherapeutic approaches that have shown promise in lymphoma? Dr Younes: We talked about CAR-T cells and how they are also promising. And checkpoint inhibitors are very promising. And now there s also emergence of bispecific antibodies, BiTE antibodies, BiTE blinatumomab was the first one approved by the FDA for the treatment of ALL. But there are now newer versions of these bispecifics that are sort of a larger molecules that have a longer half-life, so they can be given by short intravenous infusions rather than by the continuous infusion as is the case with blinatumomab. And then, as mentioned before, there are now attempts to combine multiple immune therapy modalities CAR-T cells plus checkpoint inhibitors, or bi-specific antibody plus checkpoint inhibitors, or checkpoint inhibitors plus small molecules. Most of these combinations are based on solid preclinical data, and we are all awaiting the results of the clinical trials. REFERENCES 1. American Cancer Society (ACS). Cancer facts and figures Accessed June 21, Engert A, Böll B. Is there a role for immunotherapy in Hodgkin s disease? Hematology Meeting Reports. 2008;2(5): Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125(22): doi: / blood Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS ) in patients with relapsed or refractory lymphoid malignancies [Abstract]. Presented at 56 th ASH Annual conference. December 6-9 th 2014; San Francisco, CA [Abstract #291]. 5. US FDA. Nivolumab (Opdivo) for Hodgkin Lymphoma. 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5 CME ucm htm. Accessed June 20, Younes A, Santoro A, Zinzani PL, et al. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (chl) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV) - A phase 2 study. J Clin Oncol. 2016; 34(suppl; abstr 7535). Presented at: 2016 ASCO Annual Meeting. 7. Thanarajasingam G, Thanarajasingam U, Ansell SM. Immune checkpoint blockade in lymphoid malignancies. FEBS J. 2016;283(12): doi: /febs Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK- 3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Blood. 2014;124(abstract 290). Presented at: 56 th ASH Annual Meeting and Exposition. 9. Chen RW, Zinzani PL, Fanale MA, et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R chl): phase 2 KEYNOTE087 study. J Clin Oncol. 2016; 34(suppl; abstr 7555). Presented at: 2016 ASCO Annual Meeting. 10. Kline J, Bishop MR. Update on checkpoint blockade therapy for lymphoma. J Immunother Cancer. 2015;3:33. doi: /s Westin JR, Chu FL, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15: doi: /S (13) ClinicalTrials.gov. NCT A safety and pharmacology study of atezolizumab (MPDL3280A) administered with obinutuzumab in patients with relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. NCT Accessed June 21, ClinicalTrials.gov. NCT Safety study of anti-lag-3 in relapsed or refractory hematologic malignancies. Accessed June 21, Grover NS, Park SI. Novel targeted agents in hodgkin and non-hodgkin lymphoma therapy. Pharmaceuticals (Basel). 2015;8(3): JULY 2016

6 Call for Papers For immediate consideration, send a cover letter, manuscript complete with references, graphs, and artwork to Anthony Berberabe (aberberabe@mjhassoc.com). Researchers who are interested in publishing their work should consider The American Journal of Hematology/Oncology. The rapid pace of discovery in the field of oncology presents practicing oncologists with the difficult challenge of implementing novel research findings into clinical practice. To accelerate the translation of academic advances to communitybased practice, The American Journal of Hematology/ Oncology aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practicing oncologists gain a better understanding of how these advances are changing the treatment landscape for both solid and hematologic malignancies. The editors are pleased to consider manuscripts on a wide range of topics related to the journal s mission. Articles of interest include: Original research Reviews State-of-the-Art Updates Emerging Guidelines Editorials and perspectives Pivotal Trials New Technologies Case Reports Detailed descriptions of each category can be found in the Instructions for Authors at Volume 12 Number J O U R N A L O F T H E O F F I C I A L ajho METASTATIC BREAST CANCER Assessing Treatment Response in Metastatic Breast Cancer Shlomit Strulov Shachar, MD, and Hyman B. Muss, MD Abstract Metastatic breast cancer remains incurable, and most patients receive endocrine therapy, chemotherapy, and/ or biologic therapy over the course of their treatment. In spite of a plethora of new approved agents there have been no convincing major advances in the overall survival of patients with metastatic breast cancer, except for those with Human Epidermal Growth Factor Receptor-2 positive tumors. The goals of treatment in the metastatic setting are control or palliation of symptoms and maintaining the highest quality of life. In the last several years there have been major advances in imaging and new technologies, such as the measurement of circulating tumor cells, which have made assessment of treatment response more complicated. In this context, outside of a clinical trial, we will share our recommendations for addressing the challenge of assessing treatment response in patients with metastatic breast cancer. Key words: metastatic breast cancer, treatment, response, imaging Introduction Breast cancer is the most common cancer and is the leading cause of cancer mortality in women worldwide, with more than 1.5 million new cases and over half a million deaths per year. 1 In the United States in 2016, 246,660 new cases of breast cancer are estimated, as well as 40,450 deaths due to metastatic disease. 2 Although there have been major advances in cancer treatment in the last decade, metastatic breast cancer (MBC) remains incurable; the current median survival after initial diagnosis of metastases is 2-3 years, with 5-year survival of about 25% and 10-year survival of about 10%. 3,4 A few studies suggest major improvements in survival in MBC over the last several decades 5,6 while another study, after adjustment for other variables (such as disease-free interval), suggests no major changes. 4 Most newer agents convincingly improve progression-free survival but, with the exception of chemotherapy and anti-human epidermal growth factor receptor 2(HER-2) therapy in women with HER2-positive metastatic disease, they have had none or very modest effects on survival. In one classic study, Bloom and colleagues found that women who were diagnosed with breast cancer in the late 1800s and early 1900s but were never treated had a median survival of 2.7 years. 7 We believe that the modest survival benefit attributed to new systemic therapies is partially due to lead-time bias resulting from earlier diagnosis of metastatic disease with more sophisticated tests (tumor markers) or imaging such as computerized tomography (CT), radionuclide imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET), that can detect metastases early when patients have minimal or no symptoms and a very low tumor burden. 5 This has resulted in many women being candidates for multiple systemic therapies. In deciding on the optimal time for assessing patients with metastatic disease, it is important to be aware of response durations to available therapies. Bonotto et al studied the response durations to first-line and subsequent endocrine therapy or chemotherapy in 472 women with MBC and demonstrated that patients had the longest median progression-free survival to first-line treatment (7 to 9 months); survival decreased by 2 to 4 months for each subsequent line of treatment. 8 These data fit with those of numerous clinical trials, and suggest that the optimal response assessment strategy will vary greatly by type and line of therapy. Treatment options are dependent on tumor phenotypes; while triple-negative tumors will respond only to chemotherapy, patients with HER2-positive tumors will gain a major benefit from adding targeted anti-her2 agents to either endocrine therapy or chemotherapy. 9 Patients with hormone receptor (HR)-positive tumors can have a long progression-free survival with endocrine treatment alone or when combined with biological agents such as mtor inhibitor or CDK4/6 inhibitors. 10,11 There are also a very small percentage of patients who have long-term responses to their metastatic lesions, but these represent a very small minority of those treated. 12 Regardless of the treatment selected in the metastatic setting, therapy is palliative and the goals of treatment are to manage or prevent symptoms, improve quality of life and control disease progression with the least amount of physical, psychologic, or T h e A m e r i c a n J o u r n a l H e m a t o l o g y / O n c o l o g y METASTATIC BREAST CANCER o f Assessing Treatment Response in Metastatic Breast Cancer Shlomit Strulov Shachar, MD, and Hyman B. Muss, MD MALE BREAST CANCER Case Report: Male Breast Cancer Lucy R Khan, BSc (Hons) MB ChB MRCSEd, and J. Michael Dixon, BSc (Hons) MB ChB MD FRCS FRCSEd FRCPEd OBE FOLLICULAR LYMPHOMA How to Refine Treatment Choice in Follicular Lymphoma: From Low-Tumor Burden to High-Risk Follicular Lymphoma Peter A. Riedell, MD, and Brad S. Kahl, MD THROMBOCYTOPENIA Complement Blockade with C1 Esterase Inhibitor in Refractory Immune Thrombocytopenia Erin Roesch, MD, and Catherine Broome, MD BREAST CANCER CME-certified enduring materials sponsored by Physicians Education Resource, LLC Recent Developments in the Treatment of HER2- Positive Breast Cancer A Peer-Reviewed Resource for Oncology Education ISSN (print) ISSN (online) 00_AJHO_616_Cover.indd 1 7/28/16 5:16 PM 6 JUNE 2016 FOLLICULAR LYMPHOMA TABLE 2. GELF Criteria GELF Criteria Any nodal or extranodal tumor mass 7 cm 3 nodal sites, each >3cm Presence of B symptoms Splenomegaly Compression or vital organs compromise Significant serous effusions Lymphocyte count >5.0 x 10 9 /L Cytopenias (granulocytes <1.0 x 10 9 /L and/or platelets <100 x 10 9 /L) ly utilized in assessing tumor burden. Patients who harbor 1 or more of the GELF criteria are more likely to require immediate treatment as opposed to a W/W approach. 7 Approach to the Patient With Newly Diagnosed FL The diagnosis of FL should be based on an excisional biopsy of an enlarged lymph node, while a core needle biopsy should be reserved for cases without easily accessible disease (eg, retroperitoneal nodes). On histologic evaluation, FL typically displays a nodular growth pattern with obliteration of the nodal architecture. Diagnosing FL based on fine needle aspirate should be discouraged, as this does not provide an adequate sample for assessment of the nodal architecture and tumor grading. Determining the immunophenotype through either flow cytometry or immunohistochemistry techniques can also aid in the diagnostic evaluation. Classically, FL displays surface immunoglobulin expression and is positive for CD10, CD20, BCL-6, and BCL-2 and lacks CD5 and CD23 expression. 3 FL is characterized by the t(14;18), which results in rearrangement of the immunoglobulin heavy chain on chromosome 14 with the BCL-2 gene on chromosome This translocation leads to overexpression of the BLC-2 gene, which can be detected through conventional cytogenetics, polymerase chain reaction (PCR), or more commonly, fluorescence in situ hybridization (FISH)-based techniques. 3,8 Following diagnosis, a staging evaluation should be pursued in order to determine the burden of disease. PET/CT imaging is currently recommended to determine both the size and fluorodeoxyglucose (FDG) avidity of nodal and extranodal disease. Furthermore, PET imaging may be helpful in detecting large cell-transformation (LCT) in newly diagnosed patients. 9 A bone marrow biopsy to screen for lymphomatous involvement is also recommended as part of the initial staging workup, though this evaluation may be postponed until therapy is required in those being managed with W/W. 10 Additionally, blood work including complete blood counts, chemistries, and LDH should be attained at diagnosis and prior to embarking on therapy. Given the risk of reactivation of the hepatitis B virus, screening for hepatitis B surface antigen, and hepatitis B core antibody should also be performed in every patient prior to considering rituximab therapy. In those with positive screening serology, further testing for hepatitis B antigen or hepatitis B viral DNA is appropriate. 11 When assessing a newly diagnosed FL patient, practitioners must assess disease burden, presence of symptoms attributable to lymphoma, medical co-morbidities, patient preference, and age. An algorithm for approaching newly diagnosed FL patients is depicted in Table 3. Therapy for Symptomatic, High Tumor Burden FL The addition of rituximab to standard chemotherapy has led to significant improvement in progression-free survival (PFS) and overall survival (OS) versus chemotherapy alone and is considered standard of care. 12,13 Immunochemotherapy options in FL have traditionally included R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone), and R-FM (rituximab, fludarabine, and mitoxantrone). 14,15 When these three regimens were compared in a randomized fashion, all 16 JUNE 2016 TABLE 1. Follicular Lymphoma International Prognostic Index Characteristic Prognostic factor (1 point each) Age 60 years Stage Stage III or IV Hemoglobin <12 g/dl Number of nodal sites >4 Serum LDH >Upper limit of normal LDH indicates lactate dehydrogenase TABLE 3. Approaches to the Patient with Newly Diagnosed FL Low Tumor Burden High Tumor Burden Watch/Wait R-chemo +/- MR Asymptomatic versus versus single-agent rituximab Watch/Wait Single-agent rituximab R-chemo +/- MR Symptomatic versus R-chemo MR indicates maintenance rituximab; R-chemo, rituximab-based chemotherapy All manuscripts will undergo peer review, and authors of accepted articles will receive an honorarium and will be required to sign an authorship form disclosing any possible conflicts of interest. To submit an article to The American Journal of Hematology/Oncology or if you wish to speak to an editor, please Anthony Berberabe at aberberabe@mjhassoc.com

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