Volume 9, Issue 11, Supplement 26 November 2011
Peripheral T-Cell Lymphomas: Diagnosis and Treatment Options
Proceedings From a Live Roundtable, August 17, 2011, Kauai, Hawaii
Moderator
Bruce D. Cheson, MD
Deputy Chief
Division of Hematology-Oncology
Head of Hematology
Lombardi Comprehensive Cancer Center
Georgetown University Hospital
Washington, DC
Discussants
Steven M. Horwitz, MD
Medical Oncologist
Memorial Sloan-Kettering Cancer Center
New York, New York
Dennis D. Weisenburger, MD
Director, Hematopathology
University of Nebraska Medical Center
Omaha, Nebraska
A CME Activity Approved for 1.25 AMA PRA Category 1 Credit(s)-TM
Release Date: November 2011
Expiration Date: November 30, 2012
Estimated time to complete activity: 1.25 hours
Project ID: 8400
Abstract: Peripheral T-cell lymphomas are a collection of rare diseases, most of which have a poor prognosis. The basic categories include precursor lymphoid neoplasms (eg, lymphoblastic lymphoma); mature natural killer/T-cell neoplasms and extranodal lymphomas, including enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma. The most common varieties are the nodal types, which include peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphomas, and angioimmunoblastic T-cell lymphomas. Each of the subtypes has characteristic clinical manifestations. The frequencies of the subtypes vary by geographic region. The diagnosis can be difficult, and the World Health Organization classification system was recently evaluated to assess its clinical applicability and reproducibility for peripheral T-cell lymphomas and natural killer/T-cell lymphomas. At least 10% of patients are incorrectly diagnosed by local laboratories, and many subtypes need better diagnostic markers and criteria. Currently, an increasing number of effective and tolerable therapies are becoming available, including pralatrexate, brentuximab vedotin, romidepsin, and bendamustine. Accurate diagnosis is necessary to allow appropriate treatment, as exemplified by patients with anaplastic large cell lymphoma that expresses high levels of CD30, who have high response rates to brentuximab vedotin. Patients with peripheral T-cell lymphoma should be enrolled in clinical trials when possible. New medications should be incorporated into therapies in well-designed clinical trials to develop appropriate safety and efficacy data.
Supported through an educational grant from Allos Therapeutics and Seattle Genetics
Sponsored by the Postgraduate Institute for Medicine
Disclaimer
Funding for this clinical roundtable monograph has been provided through an educational grant from Allos Therapeutics and Seattle Genetics. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.
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Introduction to Peripheral T-Cell Lymphomas
Bruce D. Cheson, MD
The classification schemes for lymphomas have evolved in the past 50 years.1,2 Initially, the Rappaport classification simply made a distinction between Hodgkin and non-Hodgkin lymphoma3; Lukes and Collins modified this classification in 1974.4 Also in 1974, the Kiel classification, which distinguished between B-cell and T-cell origin, was published.5 In the 1980s, the National Cancer Institute (NCI) working formulation defined 3 grades of lymphoma. In 1994, important subtypes of B-cell and T-cell lymphomas were identified with the Revised European-American Lymphoma (REAL) classification.6 This classification was further refined in the World Health Organization (WHO) classification currently in use.7
Classification of Aggressive T-Cell Lymphomas
The T-cell and natural killer/T-cell lymphomas (NK/TCL) are now recognized as having several distinct categories, which include precursor lymphoid neoplasms, such as T-lymphoblastic leukemias/lymphomas; mature NK/T-cell neoplasms, which are cutaneous, primarily mycosis fungoides; extranodal, such as NK/T-cell type; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma. The nodal types are the most common, and include peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphomas, and angioimmunoblastic T-cell lymphomas (AITLs). The other subtypes occur in just a small percentage of patients. The leukemic versions include adult T-cell leukemia/lymphoma (ATLL), aggressive NK cell leukemias, and T-cell prolymphocytic leukemias.
Occurrence of T-Cell Lymphomas
The T-cell lymphomas are relatively uncommon. In the United States, there are approximately 66,000 new cases of non-Hodgkin lymphoma each year8; peripheral T-cell lymphoma (PTCL) represents approximately 10–15% of these cases.9 Some estimates indicate that the incidence of PTCL is growing,10 which may be driven by an aging population.
The incidence of the various histologies differs by geography.11 For example, some areas of Japan with a high endemic rate of human T-lymphotropic virus type 1 (HTLV-1) have a much higher frequency of ATLL than Western countries. Other areas have a higher frequency of other histologies, such as NK/TCL, than Western countries.
Characteristics of Peripheral T-Cell Lymphomas
Patients with PTCL tend to present with unfavorable characteristics, such as advanced stage and high International Prognostic Index (IPI) scores.12 PTCL is more common in men than women, and it tends to occur in patients who are older than 60 years. Approximately 70% of patients present with stage III or IV disease, often with impaired performance status. The majority of patients have both nodal and extranodal involvement. Patients with B-cell lymphomas tend to present more often with B symptoms, bone marrow involvement, skin lesions, and disseminated disease. The diagnosis can be quite difficult, and at least 10% of patients are incorrectly diagnosed by local laboratories. Therefore, a sample obtained via an excisional biopsy (not a fine needle aspirate) should be reviewed by an experienced hematopathologist.
Each of the T-cell lymphomas has characteristic clinical manifestations. For example, patients with the AITLs have diffuse lymphadenopathy, hepatosplenomegaly, and a skin rash.13 Also, they can have hypergammaglobulinemia, autoimmune hemolytic anemia, fevers, and symptoms similar to those seen in vasculitis. The subcutaneous panniculitis-like T-cell lymphomas have skin panniculitis, with tender plaques or subcutaneous nodules.14 The hepatosplenic type is characterized by hepatosplenomegaly, a history of immunosuppression, and a notable lack of lymphadenopathy.15 These patients may have liver failure, a hemophagocytic syndrome, and fever of unknown origin. The NK/TCLs, particularly the nasal type, often present with chronic sinusitis, palatal ulcers, nasal swelling with facial pain, and orbital involvement, and are positive for the Epstein-Barr virus (EBV).16
The other T-cell lymphomas are also unique. ATLL, which is characterized by the HTLV-1 infection, has several clinical subtypes.17 The smoldering type involves the skin with or without pulmonary infiltrates; involvement of other organs is rare. Patients tend to have normal lymphocyte counts, calcium levels, and lactate dehydrogenase (LDH) levels. Patients with chronic ATLL have lymphocytosis involving the skin, lung, liver, and nodes; normal calcium levels; and LDH levels that are normal or only mildly elevated. Patients with acute ATLL generally have symptoms of leukemia, organomegaly, a high LDH level, hypercalcemia, and a rash. The lymphomatous variant involves organomegaly, lymphadenopathy, increased levels of LDH and calcium, and a few circulating cells known as flower cells.18
Prognosis for Peripheral T-Cell Lymphomas
Most PTCL subtypes have a worse prognosis than that seen in typical cases of diffuse large B-cell lymphoma.12 The median overall survival for most PTCL subtypes is approximately 1–3 years, with a 5-year overall survival rate of only about 30%. The exception is patients with anaplastic large cell lymphomas that are positive for anaplastic lymphoma kinase (ALK), who have a 5-year survival rate of approximately 70% with standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Patients with ALK-positive disease tend to fare much better than those with ALK-negative disease, but this outcome may reflect the fact that ALK-positive disease tends to occur in younger patients, and ALK-negative disease tends to occur in older patients.19
The IPI does not apply very well to patients with PTCL-NOS.12 Patients with 1 or no risk factors have an excellent outcome of about 50% survival at 5 years or longer, but patients with 2 or more risk factors do relatively poorly. Gallamini and coworkers developed the Prognostic Index for PTCL unspecified (PIT) prognostic model, which uses age, performance status, LDH level, and bone marrow involvement to divide patients into groups with 0, 1, 2, 3, or 4 risk factors.20 The PIT model discriminates better than the IPI with regard to prognosis. However, there is not yet any clinical validity to modifying therapy on the basis
of the PIT score.
References
1. Pileri SA, Agostinelli C, Sabattini E, et al. Lymphoma classification: the quiet after the storm. Semin Diagn Pathol. 2011;28:113-123.
2. Lymphoma Information Network. Older Lymphoma Classification and Typing Schemes. http://www.lymphomainfo.net/nhl/classify-older.html. Accessed September 14, 2011.
3. Rappaport H. Discussion on: the pathology and nomenclature of Hodgkin’s disease. Cancer Res. 1966;26(6 Part 1):1082-1083.
4. Lukes R, Collins R. Immunologic characterization of human malignant lymphomas. Cancer. 1974;34:1488.
5. Gerard-Marchant R, Hamlin I, Lennert K, Rilke F, Stansfeld AG, Van Unnik JAM. Classification of non-Hodgkin’s lymphomas. Lancet. 1974;2:406-408.
6. Harris N, Jaffe E, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361-1392.
7. Jaffe E, Harris N, Stein H, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth ed. Lyon, France: IARC Press; 2008.
8. American Cancer Society. Cancer Facts and Figures 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf. Accessed September 14, 2011.
9. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin’s lymphomas: distributions of the major subtypes differ by geographic locations. Ann Oncol. 1998;9:717-720.
10. Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst. 2000;92:1240-1251.
11. Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. Peripheral T-cell lymphoma. Blood. 2011;117:6756-6767.
12. International T-Cell Lymphoma Project. International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130.
13. Dogan A, Ngu LSP, Ng SH, Cervi PL. Pathology and clinical features of angioimmunoblastic T-cell lymphoma after successful treatment with thalidomide. Leukemia. 2005;19:873-875.
14. Lee DW, Yang JH, Lee SM, et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinical and pathologic study of 14 Korean patients. Ann Dermatol. 2011;23:329-337.
15. Falchook GS, Vega F, Dang NH, et al. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol. 2009;20:1080-1085.
16. Gualco G, Domeny-Duarte P, Chioato L, Barber G, Natkunam Y, Bacchi CE. Clinicopathologic and molecular features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma, nasal type, with EBV subtyping analysis. Am J Surg Pathol. 2011;35:1195-1203.
17. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991;79:428-437.
18. Matutes E. Adult T-cell leukaemia/lymphoma. J Clin Path. 2007;60:1373-1377.
19. Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood. 1999;93:3913-3921.
20. Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood. 2004;103:2474-2479.
The Importance of Accurate Diagnosis in T-Cell Lymphoma: A Pathologist’s Perspective
Dennis D. Weisenburger, MD
The WHO classification of PTCL and NK/TCL was recently updated to include new categories and new diagnostic criteria,1 although these criteria had not been formally evaluated. This classification is essentially a list of distinctive disease entities that include both actual diseases and syndromes. The WHO classification is based on morphology, immunophenotype, genetic abnormalities, and clinical features. The T-cell and NK-cell lymphomas are grouped together in the WHO classification because they are closely related biologically and share phenotypic and functional properties, such as cytotoxicity. The multiparameter approach of the WHO classification means that disease definition is sometimes heavily dependent upon the clinical features. This approach is due, in part, to the lack of specificity of other parameters and a lack of knowledge regarding molecular pathogenesis.
Frequency and Incidence of Non-Hodgkin Lymphoma Subtypes
The frequency of different non-Hodgkin lymphoma subtypes varies by region.2 Different parts of the world have significant differences in the frequency of PTCL subtypes and NK/TCL. These conditions comprise about 9.5% of all non-Hodgkin lymphomas in North America and Europe, almost 16% in southern Africa, 13.5% in the Middle East, and more than 17% in the Far East.
The annual percent change in the incidence of lymphoid neoplasms from 1992–2001 was compared according to race and sex in the 12 Surveillance, Epidemiology, and End Results (SEER) registries in North America.3 The incidence of B-cell lymphomas increased by only about 0.5% per year. However, across the whole group of T-cell and NK-cell neoplasms, the incidence increased almost 4% per year. The incidence of PTCL increased more than 6% per year. Another study reported that the incidence of PTCL has steadily increased from the early 1990s through 2005.4 In comparison, the incidence of Hodgkin lymphoma has been decreasing slightly over time.3
International Study of Peripheral T-Cell and Natural Killer/T-Cell Lymphomas
Our international study of PTCL and NK/TCL reviewed 1,320 cases of these diseases.2 The purpose of the study was to evaluate the WHO classification and assess its clinical applicability and reproducibility (Table 1). Patients had previously-untreated de novo PTCL or NK/TCL and were age 19 years or older. Patients were excluded if they had mycosis fungoides or Sézary syndrome. The patients presented between January 1, 1990, and December 31, 2002. The cases were consecutive and representative of the geographic region. Tissue biopsies adequate for diagnosis and classification were required, along with clinical data that included the clinical features, treatments, and follow-up information.
Pathology Review Process
The pathology review was conducted in 2 stages. First, an expert hematopathologist at 1 of 5 regional centers reviewed and classified all cases according to the WHO classification.1 The phenotype was determined using available tissue blocks to perform a standard phenotype panel and, if indicated, cytogenetic and molecular studies were done. The local and regional phenotype data, along with any cytogenetic or molecular results, were tabulated for review. Then, the regional expert pathologist rendered the diagnosis and quantitated various pathologic parameters.
In the second phase, 4 expert hematopathologists reviewed each case individually in 2 steps. First, they made a diagnosis based on the diagnostic slides and the immunostains, along with any available flow cytometry, cytogenetic, or molecular data. This diagnosis used minimal clinical data including only the age, sex, biopsy site, and site of the largest mass. The hematopathologists then made a second diagnosis after reviewing all of the pretreatment and follow-up clinical data. This second step determined if the more detailed clinical data would influence the diagnosis.
Afterward, a consensus diagnosis for each case was obtained when at least 3 of the 4 experts agreed on the second diagnosis. Any disagreements were settled in daily consensus conferences. The North American study site reviewed 25% of the cases, the European sites reviewed 34%, and the Far East site reviewed 41%.
Diagnoses
The most common subtype was PTCL-NOS, which was diagnosed in 25.9% of all the cases. The diagnosis was AITL in 18.5% of the cases, NK/TCL in 10.4%, and ATLL in 9.6%. Among the anaplastic large cell lymphomas, 6.6% were ALK-positive and 5.5% were ALK-negative. These were the most common lymphomas in the study. The less common lymphomas included the enteropathy type, which made up 4.7% of cases. The rest of the lymphomas made up 2% or less of the cases (Figure 1).2
A total of 12.2% of cases in this study were diagnosed as not being PTCL or NK/TCL. The diagnosis was wrong in 10.4% of the cases, and included diseases such as Hodgkin lymphoma (3%), B-cell lymphoma (1.4%), or a diagnosis other than lymphoma (2.3%).
Expert Agreement on Consensus Diagnoses
The experts’ second diagnosis (made after reviewing all of the pretreatment and follow-up clinical data) agreed with the consensus diagnosis in more than 90% of the cases of ALK-positive anaplastic large cell lymphoma, ATLL, and NK/TCL. This high agreement is likely due to the specific diagnostic markers that facilitate a very accurate diagnosis for these conditions. For example, in ALK-positive anaplastic large cell lymphoma, the t(2;5) and staining for the ALK protein are highly sensitive and specific.5 For ATLL, serology and molecular techniques allow the detection of HTLV-1 infection.6 For NK/TCL, the clinical presentation is very distinctive and EBV is present in the tumor cells.7
The agreement rates were 80% or less for the other subtypes, which were AITL, enteropathy type, PTCL-NOS, panniculitis-like, hepatosplenic, ALK-negative anaplastic large cell lymphoma, and cutaneous anaplastic large cell lymphoma. This low rate of agreement indicates the need for more specific markers and better diagnostic criteria for these entities.
After the regional experts re-reviewed a subset of the cases with the minimal clinical data, their diagnoses remained unchanged 81% of the time. This value varied among the 5 reviewers from 67–95%. This finding also reflects the lack of specific markers and precise criteria for the entities, which results in diagnoses that are less accurate than desired.
A total of 6.4% of the first diagnoses were changed to the consensus diagnosis after the second tier of review when all clinical data were included. The most common diagnostic change was from PTCL-NOS to ATLL, which made up almost 40% of the changed diagnoses; the addition of serology data for HTLV-1 allowed a more accurate diagnosis.
Subtype Frequencies
The frequencies of the subtypes vary by geography. The most common subtype in North America was PTCL-NOS, and AITL was most common in Europe. Anaplastic large cell lymphoma that is ALK-positive was more common in North America than in Europe or the Far East, whereas ALK-negative anaplastic large cell lymphoma was more common in Europe and very uncommon in the Far East. NK/TCL and ATLL made up more than 20% of the cases in the Far East, a much higher proportion than in North America or Europe.
Among the less common subtypes, the enteropathy type was most common in Europe, particularly in northern Europe where the frequency of celiac disease is also high. Among the other entities, hepatosplenic T-cell lymphoma was very uncommon in the Far East. Cutaneous anaplastic large cell lymphoma was more common in North America than in Europe, likely because in Europe these patients are seen by dermatopathologists and were not included in the study. Cutaneous anaplastic large cell lymphoma appeared to be uncommon in the Far East.
Survival Curves
The survival curves show marked differences in survival among the 6 most common entities (Figure 2A).2 Patients with anaplastic large cell lymphoma that is ALK-positive have an excellent overall survival, and the ALK-negative form has the next best survival. The worst survival is seen in patients with ATLL.
Among the less common entities (Figure 2B), primary cutaneous anaplastic large cell lymphoma has an excellent prognosis, and subcutaneous panniculitis-like T-cell lymphoma also has a good prognosis. These are likely to mostly be alpha-beta type cases. The prognosis is very poor for the enteropathy type and for the hepatosplenic type.
Among just the NK/TCLs (Figure 2C), the survival is markedly different. The prognosis is relatively good for cases that present in the nasal or upper aerodigestive tract, with a plateau in the survival curve suggesting that about 40% of the patients are cured. However, the extranasal cases and the aggressive or unclassifiable cases had a dismal overall survival.
More detailed clinicopathologic analyses for the common subtypes in the study have recently been published,8-13 and have delineated important prognostic factors. For example, the International Prognostic Index and the number of transformed tumor cells (>70%) were found to be independent predictors of survival in PTCL-NOS, and could be used to stratify these patients for novel and risk-adapted therapies.11
Conclusion
Marked differences exist in the clinical features and the survival of patients with PTCL and NK/TCL, and problems exist with classification of these entities. Hence, new strategies are needed to better understand these neoplasms. For example, new classifications or changes in the current classification should be based on real diseases and not on syndromes. Improved classification should be based on specific cell types and molecular or genetic mechanisms, rather than on clinical features or clinicopathologic syndromes. Any new studies should utilize fresh and frozen tissue to allow detailed immunophenotypic, cytogenetic, and molecular genetic studies, and should include examination of gene expression profiles and the use of comparative genomic hybridization arrays. This approach will allow us to better understand these entities and better define them. Finally, because these diseases are rare, any future studies will require an international consortium of researchers that includes clinicians and pathologists in order to obtain the necessary number of cases.
Acknowledgment
Dr. Weisenburger has received fees for non-CME services from Seattle Genetics. He has performed contracted research for Spectrum Pharmaceuticals.
References
1. Jaffe E, Harris N, Stein H, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth ed. Lyon, France: IARC Press; 2008.
2. International T-Cell Lymphoma Project. International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130.
3. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276.
4. Abouyabis AN, Shenoy PJ, Lechowicz MJ, Flowers CR. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma. 2008;49:2099-2107.
5. Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 2007;110:2259-2267.
6. Mahieux R, Gessain A. Adult T-cell leukemia/lymphoma and HTLV-1. Curr Hematol Malig Rep. 2007;2:257-264.
7. Ishida F, Kwong YL. Diagnosis and management of natural killer-cell malignancies. Expert Rev Hematol. 2010;3:593-602.
8. Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111:5496-504.
9. Suzumiya J, Ohshima K, Tamura K, et al. The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: analysis of 126 patients from the International Peripheral T-Cell Lymphoma Project. Ann Oncol. 2009;20:715-721.
10. Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113:3931-3937.
11. Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011;117:3402-3408.
12. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;118:148-155.
13. Federico M, Rudiger T, Bellei M, et al. Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma (AITL): analysis of 243 cases from the International Peripheral T-Cell Lymphoma Project. Submitted.
Standard Therapy for Peripheral T-Cell Lymphomas
Bruce D. Cheson, MD
The current recommendation for initial treatment of PTCL is to enroll the patient in a clinical trial because standard frontline therapies are suboptimal.1 Regimens that have been tried include CHOP and cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD), along with a number of others.2 Most PTCL patients—with the exception of ALK-positive cases—do poorly.
The CHOP regimen is used in PTCL because it has been the standard therapy for aggressive B-cell lymphomas. It has also been used for follicular lymphoma and mantle cell lymphoma. However, clinical data, including a recent meta-analysis,3 make it hard to justify anthracycline as a part of initial treatment. Regimens with and without an anthracycline have a very similar outcome. Nevertheless, instead of trying to move beyond CHOP, CHOP has been used as the basis for a variety of therapies.
Gallamini and coworkers reported a high response rate when they added alemtuzumab to CHOP, although they also reported an increased risk of severe, life-threatening, and fatal opportunistic infections.4 Other groups are looking at this combination using different dosages and schedules, and hopefully they will not encounter the same negative experience.
The German High-Grade Lymphoma Study Group evaluated CHOP with the addition of etoposide (CHOEP) in a large number of patients.5 Most of the patients had anaplastic large cell lymphoma, PTCL-NOS, or AITL. They received 6–8 cycles of either CHOP or CHOEP at various doses and schedules. Because older patients had difficulty tolerating the CHOEP regimen, these investigators recommended that CHOP-21 remain the standard for that group. For younger patients ages 18–60 years, the etoposide-containing regimens appeared to have a better outcome. It should be noted that this trial was not randomized.
Autologous stem cell transplant has been used as frontline therapy.6 However, a drawback to this approach is that most patients have advanced stage disease, plus many have bone marrow involvement. About 40–50% of patients are not suitable for transplant due to progressive disease, and an additional 20–30% progress after the transplant. Autologous stem cell transplant is not something to be entered into with a great deal of optimism.
Fortunately, a variety of new drugs are available or are in clinical trials to treat patients with relapsed and refractory PTCLs.7 These include a number of agents that will be discussed in the next section, such as the antifol pralatrexate; the histone deacetylase inhibitors, such as romidepsin and vorinostat; the alkylating agents, such as bendamustine; the aurora kinase inhibitors; and, most recently, the drug-antibody conjugate brentuximab vedotin (SGN-35), which has a high level of efficacy and is limited to CD30-positive diseases, notably anaplastic large cell lymphoma.8 Also, a number of monoclonal antibodies, including alemtuzumab, have efficacy.9 Other studies involve the monoclonals KW-0761, which targets CCR4,10 and zanolimumab, which targets CD4.
Recommendations for Integrating Current and Emerging Therapies Into Clinical Practice
Clearly, I am not an advocate of CHOP therapy for patients with PTCL. I am excited about the increasing number of effective and tolerable therapies, such as pralatrexate, romidepsin, bendamustine, the monoclonal antibody drug conjugates, and others. However, we need to combine these drugs in a rational fashion. One drug is not going to make a huge impact on the overall survival of these patients. However, preclinical data suggest that it is quite possible that these drugs might be additive or even synergistic.11 Trials of doublet therapy, such as pralatrexate and romidepsin, are in development. Once a doublet has been shown to be highly effective and tolerable, I propose that it be compared directly to CHOP. The goals would be to eliminate CHOP from our armamentarium in T-cell lymphoma, and to replace CHOP with targeted therapies that would be more effective as we develop better approaches for patients in the relapsed setting.
Conclusion
The PTCLs are a heterogeneous group of diseases that are challenging to diagnose. The incidence appears to be growing. Except for the cases that are ALK-positive, the prognosis is relatively poor. Improved treatments are clearly needed. To make progress in these diseases, patients should be accrued to clinical trials to test novel therapeutic approaches.
Acknowledgment
Dr. Cheson is a consultant for Cephalon.
References
1. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphomas. Version 4.2011. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed September 15, 2011.
2. Armitage JO, Hsi ED, Foss FM. T-cell lymphoma: therapeutic overview and disease state awareness. Clin Adv Hematol Oncol. 2010;8(suppl 22):1-15.
3. Azim HA, Santoro L, Bociek RG, Gandini S, Malek RA. High dose intensity doxorubicin in aggressive non-Hodgkin’s lymphoma: a literature-based meta-analysis. Ann Oncol. 2010;21:1064-1071.
4. Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 2007;110:2316-2323.
5. Schmitz N, Trumper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116:3418-3425.
6. Hosing C, Champlin RE. Stem-cell transplantation in T-cell non-Hodgkin’s lymphomas. Ann Oncol. 2011;22:1471-1477.
7. Howman RA, Prince HM. New drug therapies in peripheral T-cell lymphoma. Expert Rev Anticancer Ther. 2011;11:457-472.
8. Mayes S, Brown N, Illidge TM. New antibody drug treatments for lymphoma. Expert Opin Biol Ther. 2011;11:623-640.
9. Boyle EM, Morschhauser F. Ongoing development of monoclonal antibodies and antibody drug-conjugates in lymphoma. Curr Oncol Rep. 2011;13:386-397.
10. Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol. 2010;28:1591-1598.
11. Zain JM, O’Connor O. Targeted treatment and new agents in peripheral T-cell lymphoma. Int J Hematol. 2010;92:33-44.
Newer Treatment Options for Peripheral T-Cell Lymphomas
Steven M. Horwitz, MD
Many advances have recently occurred in treatment options for PTCLs. Most trials are examining either new drugs in the relapsed setting or combinations of new drugs. Meanwhile, some of the newer drugs are more rapidly advancing to the upfront setting. In 2009, pralatrexate became the first drug approved for PTCL.1 This past summer, 2 more drugs were approved: romidepsin in June and brentuximab vedotin in August.2,3 Brentuximab vedotin was approved specifically for anaplastic large cell lymphoma and Hodgkin lymphoma.
Recent Study Data
The PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) trial set a benchmark, with its study of pralatrexate in 109 evaluable patients who had relapsed or refractory PTCL.4 The overall response rate was 29%, and the median duration of response was 10.1 months. The romidepsin trial included 131 patients with PTCL.5,6 The objective response rate was 25%, the complete response rate was 15%, and the median duration of response was 17 months; 94% of complete responders have not progressed as of the study data cutoff date. Both pralatrexate and romidepsin are reasonable options in the study populations, where they were primarily third-line and fourth-line treatments. We would hope that the response would be even better if those drugs were used earlier in the course of treatment (although still in the relapse setting).
Brentuximab vedotin had very high responses in patients who were CD30-positive and in treated subjects limited to relapsed Hodgkin lymphoma or systemic anaplastic large cell lymphoma only.3,7 This antibody-drug conjugate uses an antibody to target CD30 and conjugates the antibody to the antitubulin agent monomethyl auristatin E (MMAE). The CD30 antibody binds to the tumor cell and undergoes endocytosis, which allows the chemotherapy to penetrate the nucleus. In that specific population of systemic anaplastic large cell lymphoma patients, the large T-cell lymphomas always express CD30. The objective response rate among 58 patients in this phase II study was 86%, with 53% of patients achieving complete responses. This activity is really remarkable in that population. Since systemic anaplastic large cell lymphoma is only about 15–20% of all the T-cell lymphoma cases, this is a select patient population, but the response rates were nonetheless very high.
Preliminary data were presented this summer from a trial of bendamustine in patients with relapsed or refractory PTCL.8 A total of 38 evaluable patients had an overall response rate of 47%, although the median duration of response was short, at 157 days. This finding suggests that bendamustine may have activity in these patients, and it represents another option to consider in the relapsed or refractory setting in patients who have exhausted the approved options or to include in future combination studies.
Combining Therapies
Newer combinations should allow us in the clinical trial setting to transition beyond the identification of additional single agents with activity in relapsed patients and try to identify regimens that will improve the prognosis for the majority. Currently, all the newly approved drugs are being studied in the upfront setting. A phase I study in systemic anaplastic large cell lymphoma is examining brentuximab vedotin given either sequentially before CHOP or in combination with modified CHOP.9 This study is hopefully setting the stage for a new upfront regimen for that subset of patients, which, if well tolerated, may lead to a further randomized study in untreated systemic anaplastic large cell lymphoma. Similarly, romidepsin is being combined with CHOP in a phase I study being done in France by the Groupe d’Etude des Lymphomes de l’Adulte (GELA).10 Again, if the results look promising, they could lead to a randomized study in the untreated setting.
Pralatrexate
The approach with pralatrexate has been slightly different. Despite the inadequacies of CHOP in terms of durable remissions, a significant number of PTCL patients reach partial or complete remission with CHOP, and a current international study is evaluating whether that remission can be maintained with pralatrexate.11 Patients are randomized in a 2:1 ratio either to receive pralatrexate maintenance or to be observed. This study is currently open and accruing. A phase I/II study of pralatrexate in cutaneous T-cell lymphoma found an objective response rate of 45% in 18 patients receiving pralatrexate at 15 mg/m2 for 3 of 4 weeks, which is a dose that is a little less than half the standard dose for aggressive T-cell lymphomas.12 A current phase I study in patients with cutaneous T-cell lymphoma is combining pralatrexate with bexarotene, which is a retinoid commonly used for mycosis fungoides.13
Optimal Use of Emerging Treatments
Patients with relapsed disease benefit from emerging treatments because the number of options available is significantly increasing. Although none of these drugs work for everybody, more options mean a better chance that something will work for an individual patient. Most of the newer agents can be given in a continuous or extended fashion, so that if patients do respond, the duration of response can be maximized by keeping them on therapy. In the uniformly CD30-expressing systemic anaplastic large cell lymphoma, a very high percentage of those patients will respond to brentuximab vedotin. New studies are examining brentuximab vedotin in patients with other subtypes of lymphoma and with present, but varying, levels of CD30 expression.14 The goal is to evaluate the level of CD30 expression needed for activity and identify if a threshold level exists. These studies will allow us to determine who will benefit from this drug.
For other drugs, such as pralatrexate, romidepsin, and newer therapies, we still lack markers or other ways to predict which patients are likely to respond. The pralatrexate data suggest that patients with AITL may not respond as well, as there was a non–statistically insignificant lower response rate in those with AITL in the PROPEL study.4 Although that lower rate may be an accurate reflection of response, caution in interpreting these results is warranted. The early NCI study of romidepsin reported a lower response rate for AITL than for other subtypes,15 but trials in larger registrational settings found that the response rate was similar across subtypes.16 Current studies have too few patients of the individual subtypes to specifically determine which subtypes have a better or worse response.
Studies in Progress
Other interesting drugs include KW-0761, an antibody targeting CCR4. Many T-cells and many T-cell lymphomas express CCR4. A phase II study of KW-0761 in patients with HTLV-1–associated lymphoma from Japan found a 50% objective response rate in the 26 patients evaluable for efficacy.17 The enrolled patients had relapsed CCR4-positive, aggressive subtypes of ATLL. Efforts are under way to develop a larger study with the goals of confirming the response rate in HTLV-1 lymphomas and of expanding the activity or seeking activity in more common types of T-cell lymphoma.
For patients with nasal NK/TCL, L-asparaginase may be practice-changing. Nasal NK/TCL occurs primarily in Asia and is an EBV-positive lymphoma that usually, although not always, presents in the nasopharynx. A few studies have looked at the activity of L-asparaginase in those patients.18
A novel chemotherapy regimen—steroids, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE)—has been developed in Japan.19 It is a very intense combination regimen with response rates that are quite high in nasal NK/TCL. We have recently treated patients with this regimen and also found high responses. Therefore, SMILE appears to be a very active chemotherapy regimen for that disease. Identification of especially active chemotherapy agents has the potential to improve the prognosis in nasal NK/TCL. Another study in the United States for untreated patients with aggressive T-cell lymphomas incorporates pralatrexate in a different way into the upfront regimen: it takes a variation of CHOP and alternates it with pralatrexate.11 This regimen is akin to such alternating regimens as HyperCVAD.
Adverse Events
Because 2 of the new drugs for T-cell lymphoma, pralatrexate and romidepsin, are used only for this condition, many doctors may not be familiar with the side effects. The primary side effect of pralatrexate has been mucositis, specifically oral stomatitis.4 Patients receiving various doses of pralatrexate have developed mouth sores that are usually mild but occasionally severe. In early studies done at Memorial Sloan-Kettering Cancer Center, it appeared that premedication with folic acid and vitamin B12—to optimize homocysteine and methylmalonic acid levels—correlated with a decrease in mucositis, particularly high-grade mucositis.20 At the current dose of 30 mg/m2, some patients will experience grade 3/4 mucositis. The best intervention is probably to hold the dose for a week; in most patients, mucositis will resolve during this time. The use of other specific interventions, such as leucovorin, ice chips, or mouth rinses, has been reported anecdotally, but no data suggest that this approach eliminates or significantly reduces the risk of mucositis.21 In a patient with relatively mild disease, pralatrexate is sometimes started at a lower dose, such as 20 mg/m2 given 3 of 4 weeks, and titrated up if no side effects are seen. This approach is partly based on a study of cutaneous T-cell lymphoma patients, in which the pralatrexate dose was reduced from 30 mg/m2 to 10 mg/m2.22 Good rates of response were seen in doses as low as 15 mg/m2 every 3 of 4 weeks. Below 15 mg/m2 every 3 of 4 weeks, significant responses were not seen. In this study, the rates of mucositis were less than those in the larger PROPEL study, and there was very little grade 3/4 mucositis. The most common hematologic side effect of pralatrexate is thrombocytopenia, which usually resolves when the drug is held for a week.
Romidepsin has been reasonably well tolerated. There had been some older concerns that romidepsin can cause QT prolongation. In more recent studies of patients with cutaneous T-cell lymphoma and PTCL, there has been almost no grade 3 QT prolongation and an absence of grade 4 QT prolongation.6 Original studies used higher doses of the drug, which probably led to an overestimation of the rate of QT prolongation. In addition, there is a current awareness that many other drugs used in these patients, including antiemetics and antibiotics, could be additive in QT prolongation when given with a histone deacetylase inhibitor. In the more recent studies of romidepsin, which show almost no clinically significant QT prolongation, patients were counseled to avoid other QT–prolonging drugs, particularly antibiotics; their electrolytes were frequently checked; and normalization of potassium and magnesium was performed routinely throughout cycles of treatment. It appears that under those parameters—in which exposure to other QT-prolonging agents is minimized and electrolytes are repleted to their normal value—there is much less risk for QT prolongation. The main hematologic side effect of romidepsin is, again, thrombocytopenia. As with pralatrexate, if the drug is held for a week, the platelet counts will usually return to an adequate level.
In the phase II study by Pro and colleagues, brentuximab vedotin was associated with grade 3/4 neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (10%).7 These adverse events were considered manageable.
Integrating Emerging Therapies Into Clinical Practice
This is a very exciting time, but in practice the excitement must be tempered and built upon with caution. Since T-cell lymphoma patients have often not done well with standard therapies like CHOP, doctors have a strong and understandable desire to try to incorporate these new medicines. The best way to do that is on clinical studies. In the laboratory, the combination of pralatrexate with gemcitabine looked very promising, but the phase I study found significantly increased toxicity and lack of added efficacy.23 We must try to do better when we mix drugs together in the upfront setting, where patients are not cured at a high rate. As much as possible, drugs should be combined in the context of a well-designed clinical trial. Efforts should be made to enroll sufficient numbers of patients in trials so that we avoid combining drugs in an ad hoc manner without appropriate safety data.
Acknowledgment
Dr. Horwitz is a consultant for Allos Therapeutics, Celgene, Seattle Genetics, Merck, Quest Diagnostics, and Spectrum Pharmaceuticals.
References
1. Malik SM, Liu K, Qiang X, et al. Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2010;16:4921-4927.
2. Vandermolen KM, McCulloch W, Pearce CJ, Oberlies NH. Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. J Antibiot (Tokyo). 2011;64:525-531.
3. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821.
4. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29:1182-1189.
5. Coiffier B, Pro B, Prince HM, et al. Final results from a pivotal, multicenter, international, open-label, phase 2 study of romidepsin in progressive or relapsed peripheral T-cell lymphoma (PTCL) following prior systemic therapy. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 114.
6. Horwitz S, Coiffier B, Foss FM, et al. Complete responses (CR/CRu) on a phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2011;29(suppl). Abstract 8033.
7. Pro B, Advani R, Brice P, et al. Durable remissions with brentuximab vedotin (SGN-35): updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2011;29(suppl). Abstract 8032.
8. Damaj G, Gressin R, Bouabdallah K, et al. Preliminary results from an open-label, multicenter, phase II study of bendamustine in relapsed or refractory T-cell lymphoma from the French Goelams Group: the Bently Trial. Ann Oncol (International Conference on Malignant Lymphoma Abstracts). 2011;22(suppl 4):iv125. Abstract 126.
9. ClinicalTrials.gov. Phase 1 study of brentuximab vedotin given sequentially and combined with multi-agent chemotherapy for anaplastic large cell lymphoma. http://clinicaltrials.gov/show/NCT01309789. Accessed September 16, 2011.
10. ClinicalTrials.gov. A study of escalating doses of romidepsin in association with CHOP in the treatment of peripheral T-cell lymphomas (Ro-CHOP). http://clinicaltrials.gov/ct2/show/NCT01280526. Accessed September 20, 2011.
11. ClinicalTrials.gov. Study of pralatrexate versus observation following CHOP-based chemotherapy in previously undiagnosed peripheral T-cell lymphoma patients. http://clinicaltrials.gov/ct2/show/NCT01420679. Accessed September 19, 2011.
12. Horwitz S, Duvic M, Kim Y, et al. Pralatrexate is active in cutaneous T-cell lymphoma (CTCL): results of a multicenter, dose-finding trial. Blood (ASH Annual Meeting Abstracts). 2009;114(22). Abstract 919.
13. ClinicalTrials.gov. Pralatrexate and bexarotene in patients with relapsed or refractory cutaneous T-cell lymphoma. http://clinicaltrials.gov/ct2/show/NCT01134341?term=bexarotene+pralatrexate&rank=1. Accessed September 19, 2011.
14. ClinicalTrials.gov. Pilot study of brentuximab vedotin (SGN-35) in patients with MF with variable CD30 expression level. http://clinicaltrials.gov/ct2/show/NCT01396070?term=brentuximab+vedotin&rank=6. Accessed September 19, 2011.
15. Sandor V, Bakke S, Robey RW, et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res. 2002;8:718-728.
16. Piekarz RL, Frye R, Prince HM, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117:5827-5834.
17. Utsunomiya A, Tobinai K, Yamamoto K, et al. Promising results of an anti-CCR4 antibody, KW-0761, for relapsed adult T-cell leukemia-lymphoma (ATL). Retrovirology. 2011;8(suppl 1):A40.
18. Jaccard A, Hermine O. Extranodal natural killer/T-cell lymphoma: advances in the management. Curr Opin Oncol. 2011;23:429-435.
19. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: The NK-Cell Tumor Study Group Study. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
20. Mould DR, Sweeney K, Duffull SB, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin’s or Hodgkin’s lymphoma. Clin Pharmacol Ther. 2009;86:190-196.
21. Azzoli CG, Patel JD, Krug LM, et al. Pralatrexate with vitamin supplementation in patients with previously treated, advanced non-small cell lung cancer: safety and efficacy in a phase 1 trial. J Thorac Oncol. 2011;6:1915-1922.
22. Horwitz SM, Kim YH, Foss FM, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL): final results of a multicenter dose-finding study. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 2800.
23. Horwitz S, Vose J, Advani R, et al. A phase 1/2A open-label study of pralatrexate and gemcitabine in patients with relapsed or refractory lymphoproliferative malignancies. Blood (ASH Annual Meeting Abstracts). 2008;112. Abstract 1570.
Target Audience
This activity has been designed to meet the edu-cational needs of oncologists, hematologists, and other healthcare professionals involved in the management of patients with T-cell lymphoma.
Statement of Need/Program Overview
In the United States, there are approximately 66,000 new cases of non-Hodgkin lymphoma each year; peripheral T-cell lymphoma (PTCL) represents approximately 10–15% of these cases. Approximately 70% of PTCL patients present with stage III or IV disease, often with impaired performance status. Marked differences exist in the clinical features that relate to the survival of these patients, and problems exist with classification. Improved classifications should be based on specific cell types and molecular or genetic mechanisms, rather than on clinical features and clinical pathologic syndromes. The current recommendation for initial treatment of PTCL is to enroll the patient in a clinical trial because standard frontline therapies are suboptimal. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen is used in PTCL because it has been the standard therapy for aggressive B-cell lymphomas. Clinical data, however, make it hard to justify anthracycline as a part of initial treatment. Currently, an increasing number of effective and tolerable therapies are becoming available, including pralatrexate, brentuximab vedotin, romidepsin, and bendamustine.
Educational Objectives
After completing this activity, the participant should be better able to:
• Identify areas of diagnostic confusion in peripheral T-cell lymphomas
• Describe clinical data in the treatment of peripheral T-cell lymphomas
• Use evidence-based decision-making to select optimal treatment for patients with peripheral T-cell lymphomas
• Assess clinical data on emerging treatment strategies in patients with peripheral T-cell lymphomas
• Outline strategies for the integration of new agents into current clinical practice
Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Millennium Medical Publishing. PIM is accredited by the ACCME to provide continuing medical education for physicians.
Credit Designation
The Postgraduate Institute for Medicine designates this journal-based CME activity for a maximum of 1.25/AMA PRA Category 1 Credit(s)TM/. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure of Conflicts of Interest
Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, plan-ners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care rec-ommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest or a commercial interest.
The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Disclosures
Bruce D. Cheson, MD—Consultant: Cephalon.
Steven M. Horwitz, MD—Consultant: Allos Therapeutics, Celgene, Seattle Genetics, Merck, Quest Diagnostics, and Spectrum Pharmaceuticals.
Dennis D. Weisenburger, MD—Fees for non-CME services: Seattle Genetics. Contracted research: Spectrum Pharmaceuticals.
The following PIM planners and managers, Jan Hixon, RN, BSN, MA, Trace Hutchison, PharmD, Julia Kimball, RN, BSN, Samantha Mattiucci, PharmD, Jan Schultz, RN, MSN, CCMEP, and Patricia Staples, MSN, NP-C, CCRN, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Jacquelyn Matos: No real or apparent conflicts of interest to report.
Method of Participation
There are no fees for participating and receiving CME credit for this activity. During the period November 2011 through November 30, 2012, participants must 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. You may also complete the post-test online at www.cmeuniversity.com. On the navigation menu, click on “Find Post-tests by Course” and search by project ID 8400. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.
A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better. Your statement of credit will be mailed to you within three weeks.
Media
Monograph
Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM, Millennium Medical Publishing, Allos Therapeutics, and Seattle Genetics do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Millennium Medical Publishing, Allos Therapeutics, and Seattle Genetics. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.